Khan 2020

Seminars in Cancer Biology xxx (xxxx) xxx–xxx
Contents lists available at ScienceDirect
Seminars in Cancer Biology

journal homepage: www.elsevier.com/locate/semcancer
Role of non-coding RNAs in the progression and resistance of cutaneous

malignancies and autoimmune diseases
Abdul Q. Khana,*, Fareed Ahmada,b,c,d, Syed Shadab Razae, Lubna Zariff, Kodappully S. Siveena,
Gulab Shera, Maha Victor Aghaa, Khalid Rashidg, Michal Kulinskia, Joerg Buddenkottea,b,c,
Shahab Uddina,b,c, Martin Steinhoffa,b,c,h,i,j
a
Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
b
Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar
c
Department of Dermatology and Venereology, Rumailah Hospital, Hamad Medical Corporation, Doha 3050, Qatar
d
Department of Dermatology, University Hospital Heidelberg, 69120 Heidelberg, Germany
e
Department of Stem Cell Biology and Regenerative Medicine, Era University, Lucknow, India
f
Department of Biological and Environmental Sciences, Qatar University, Doha 2713, Qatar
g
Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
h
Department of Medicine, Weill Cornell Medicine Qatar, Qatar Foundation-Education City, Doha 24144, Qatar
i
Department of Medicine, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA
j
College of Medicine, Qatar University, Doha 2713, Qatar
ARTICLE INFO ABSTRACT
Keywords: Skin, the largest organ of human body, is vital for the existence and survival of human beings. Further, devel
Cutaneous malignancies opmental and physiological mechanisms associated with cutaneous biology are vital for homeostasis as their
nc-RNAs deregulations converge towards pathogenesis of a number of skin diseases, including cancer. It has now been
Cancer resistance and metastasis well accepted that most of the transcribed human genome lacks protein translational potential and has been
Epigenetic changes
termed as non-coding RNAs (nc-RNAs), which includes circular RNA (circRNA), small nuclear RNA (snRNA),
Autoimmune diseases
small nucleolar RNA (snoRNA), micro RNA (miRNA), long noncoding RNA (lncRNA), and piwi-interacting RNA
(piRNAs). These nc-RNAs have gained great attention in both preclinical and clinical research as they are critical
in most of the regulatory mechanisms of biological homeostasis and disease development by controlling the gene
expression at transcriptional, post-transcriptional and epigenetic level. In this review we have illustrated how nc-
RNAs are critical in the development and maintenance of cutaneous homeostasis and functioning and also, most
importantly, how the dysregulated expression and functioning of nc-RNAs play critical role in the pathogenesis
Abbreviations: nc-RNAs, non-coding RNAs; cirRNA, Circular RNA; snRNA, small nuclear RNA; snoRNA, small nucleolar RNA; miRNA, micro RNA; lncRNA, long
noncoding RNA; piRNA, piwi-interacting RNA; SSC, squamous cell carcinoma; BCC, basal cell carcinoma; tRNA, transfer RNA; rRNA, ribosomal RNA; mRNA,
messenger RNA; primiRNA, primary miRNA; AGO, Argonaute; UTR, 3′untranslated region; ORF, open reading frames; ecircRNAs, exon circular RNAs; ciRNAs,
circular intronic RNAs; EIciRNAs, exon-intron circRNAs; f-circRNAs, fusion circular RNAs; RBPs, RNA-binding proteins; SHIP2, SH2-containing inositol phosphatase-
2 (SHIP2), and also aberreviated as INPPL1 (inositol polyphosphate 5′-phosphatase-like protein-1); MITF, microphthalmia transcription factor; Tyr, Tyrosinase; Hyal,
Hyalurodinase; ANCR, Antidifferentiation noncoding RNA; TINCR, Terminal differentiation-induced noncoding RNA; ANRIL, Antisense non-coding RNA in the INK4
locus; DNMT, DNA methyltransferase; HDFs, human dermal ibroblasts; HFSCs, human hair follicle stem cells; PICSAR, p38 inhibited cSCC associated lincRNA; SBHA,
Suberic bishydroxamate; MALAT1, metastasis-associated lung adenocarcinoma transcript 1; UCA1, urothelial carcinoma-associated 1; ASncmtRNAs, antisense
noncoding mitochondrial RNAs; CASC15, cancer susceptibility candidate 15; PRINS, psoriasis susceptibility–related RNA gene induced by stress; MSX2P1, Msh
homeobox 2 pseudogene 1; PASI, Psoriasis Area and Severity Index; CASC15 lincRNA, Cancer susceptibility candidate 15 long intergenic noncoding RNA; CRNDE,
Colorectal Neoplasia Differentially Expressed; DRAIC, Downregulated RNA In Cancer; GAS5, Growth arrest-specific 5; HOTAIR, HOX transcript antisense RNA;
HOTTIP, HOXA transcript at the distal tip; HOXD-AS1, HOXD antisense 1; MEG3, maternally expressed 3; PVT1, Plasmacytoma Variant Translocation 1; SLNCR, SRA-
like non-coding RNA; SNHG5, small nucleolar RNA host gene 5; UCA1, Urothelial Cancer Associated 1; TUG1, Taurine Up-Regulated 1; XIST, X-inactive specific
transcript; lncRNA-NEAT1, lncRNA-Nuclear paraspeckle assembly transcript 1; lncRNA ZFAS1, ZNFX1 antisense RNA 1; LncRNA WAKMAR1, wound and kerati
nocyte migration-associated lncRNA 1; NK cells, natural killer cells
⁎
Corresponding author at: Translational Research Institute, Academic Health System, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar.
E-mail address: [email protected] (A.Q. Khan).
https://doi.org/10.1016/j.semcancer.2020.07.003
Received 1 June 2020; Received in revised form 28 June 2020; Accepted 6 July 2020
1044-579X/ © 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: , Seminars in Cancer Biology, https://doi.org/10.1016/j.semcancer.2020.07.003

A.Q. Khan, et al. Seminars in Cancer Biology xxx (xxxx) xxx–xxx
of cutaneous diseases including cancer and the autoimmune skin diseases. Considering the vital role of nc-RNAs
in cancer resistance, metastasis and autoimmune diseases, we have also highlighted their role as promising
prognostic and therapeutic targets for the cutaneous diseases.
1. Introduction of challenges associated with the disease pathogenesis and therapeutic

failures. This calls for a focus on novel molecular targets for diagnosis,
The term “cancer” itself has now become very frightening as the therapy and prognosis of the disease.
devastations including morbidity, mortality and economic burden as Available findings suggest that cancer progression and resistance
sociated with this disease are growing exponentially. According to ex against therapy are the prime causes for the poor clinical outcomes
perts’ estimates, the disease was expected to be diagnosed in 18.1 associated with cancer patients. Progression of cancer is a complex and
million new individuals globally, and result in 9.6 million deaths heterogenic process and the main cause of the cancer patients’ deaths,
worldwide by the year 2018, the latest year for which such statistics are and thus deciphering the cellular and molecular changes of cancer
available [1]. Furthermore, the economic burden due to cancer is also progression would pave the way for effective cancer therapy.
increasing at an alarming rate [2,3]. The basic concept of human cancer Furthermore, resistance of cancer cells towards therapeutics is another
development has been explained centuries ago. Since then, a number of very important concern for cancer management. Increasing evidence
reports which entail the various mechanisms including cell signaling, suggest that non-coding RNAs (nc-RNAs) play vital role in cancer pro
genetic, epigenetic, cellular, and histological changes associated with gression and drug resistance and a number of factors (external as well
the pathophysiology of cancer are appearing on regular basis conver as internal) within and outside the tumor microenvironment affect the
ging on how to manage the malignant disease at clinical level [4–7]. expression and functioning of these noncoding signatures which act
Carcinogenesis is a complex, heterogenous phenomenon due to the primarily on gene expression at the posttranscriptional stage.
accretion of various genetic, molecular, and histological aberrations Furthermore, genetic profiling of various human malignancies and
with dysregulated energy metabolism, cell proliferation, angiogenesis, molecular findings reveal that the deregulated expression and func
and immune surveillance [5,8]. In a nutshell, cancer development can tioning of nc-RNAs is critical in cancer pathogenesis, including the drug
be divided into three stages viz; initiation, promotion and progression. resistance, cancer progression and metastasis, via interacting with
Cancers of the skin or cutaneous malignancies include melanoma various cellular moieties such as DNA, RNA and proteins [11–14]. nc-
(cancer of the melanocytes), non-melanoma (SSC: squamous cell car RNAs are also well known for their potential in maintaining the growth
cinoma and BCC; basal cell carcinoma) and less prevalent types such as and stemness features of cancer stem cells, the small population of cells
Merkel cell carcinoma, Kaposi’s sarcoma and T-cell lymphoma, re inside tumors that are capable of developing resistance, disease relapse,
presenting one of the most common form of human cancer which is progression and metastasis etc., [15–18].
further increasing in incidence and mortality over the globe every year
[9]. A number of etiological factors, including the most common ones
such as fair skin, ultraviolet B radiation, tanning and aging have been 2. Non-coding RNAs (nc-RNAs)
reported [10]. Despite the great work and progress made to understand
and manage the burden of cancer globally, we are still facing a number It has now become evident that more than 98 % of human RNA
transcripts account for non-coding genome while the remaining less
Fig. 1. Types of non-coding RNA. Advent of the sophisticated high throughput technologies have greatly helped in the understating and identification of the genetic
and non-genetic components associated with human genome and revealed that most of the transcribed human genome contains non-protein coding sequence called
nc-RNA. On the basis of structure, size and functional properties these nc-RNAs are further categorized into various types such as miRNA, IncRNA, circRNA and
piRNA.
2
than 2% RNA transcripts constitute protein coding regions which are miRNA genes first transcribed into primary miRNA (primiRNA) and
integral for maintaining of biological homeostasis and development finally processed in to mature miRNA [23]. These miRNAs are integral
[19] as shown in Fig. 1. Complex analysis of the human genome tran in the regulatory mechanisms of biological phenomenons including
scripts reveals that transfer RNA (tRNA), ribosomal RNA (rRNA), homeostasis, development, proliferation, differentiation and apoptosis
messenger RNA (mRNA) and nc-RNA (cirRNA, snRNA, snoRNA, via posttranslational silencing of gene expression and through various
miRNA, lncRNA, and piRNAs) represent 89 %, 8.9 %, 0.9 % and around feedback mechanisms of more than 60 % protein encoding genes
1% respectively [20]. Decades of investigations have refined the con [24,25]. MiRNA-mediated gene silencing or suppression involves de
cept of noncoding ‘junk’ RNA transcripts of human genome to func gradation of mRNA by Argonaute (AGO) proteins that target 3′ un
tional regulatory moieties having a number of molecular and cellular translated region (UTR) of mRNAs [26]. Various mechanisms such as
potential integral for various biological phenomenon including post- protein translational regulation, methylation, histone modification and
transcriptional modifications, chromatin remodeling and signaling controlled degradation are well known for miRNA expression and
pathways as represented in Fig. 1 [21]. Furthermore, a number of functioning. Furthermore, a single miRNA can regulate/silence the
findings elucidated that these nc-RNAs interact with, and affect the expression of hundreds of genes while multiple miRNAs can regulate
functioning of various molecular targets to initiate specific cellular re the expression of a single gene [24,27].
sponses and fates, confirming that these non-coding transcripts are the
important regulators of cellular and biological homeostasis and dysre 2.2. Long-noncoding RNAs (lncRNAs)
gulation in the expression and functioning of these non-coding tran
scripts associated with the pathogenesis of a number human diseases LncRNAs are another important class of nc-RNA transcripts
including cancer [22]. The following types of nc-RNAs have been ex with > 200 nucleotides in length that have been well studied in the
plained well: human physiology and diseases including cancer [28]. Thousands of
lncRNA have been identified and many of which are uniquely expressed
2.1. MicroRNAs (miRNAs) by differentiated cells similar to mRNAs and contain both exons and
introns splicing regions. They are mostly transcribedby RNA poly
MiRNAs are the most widely studied, around 22 nucleotides long merase II, lack open reading frames (ORF) with little or no coding
family members of nc-RNAs, with evolutionary conserved sequence potential, exhibit histone modifications similar to protein coding genes,
across species and tissues, that were first discovered in nematode C. comparatively less stable as compared to miRNAs, and are detectable in
elegans in the year 1993 [23]. They are transcriptional products of both cytoplasm and nucleus [29]. Furthermore, lncRNAs acquire
Fig. 2. Role of non-coding RNA in skin biogenesis and function. Nc-RNA transcriptome research and functional studies has shown important roles of nc-RNAs,
particularly miRNAs and lncRNAs in skin development and function. Nc-RNAs play important role at transcriptional, post transcriptional and epigenetic levels to
control cell proliferation, cell differentiation, apoptosis, senescence, and angiogenesis associated with skin structure maintenance, hair growth, pigmentation,
keratinization and wound healing.
3
thermodynamically stable complex structures which are integral for 3.1. miRNA
their regulatory functions and help to control the gene transcriptional
expression both directly and indirectly [29,30]. MiRNAs have the ability to modulate different physiological func
tions in the skin such as proliferation of keratinocytes, pigmentation,
aging, wound healing, skin immune system and skin microbiota.
2.3. Circular noncoding RNAs (circRNAs) Therefore, skin disorders can result due to deregulation of miRNAs. It
has been shown that genetic ablation of Dicer (miRNA-processing en
CircRNAs, formed due to aberrant or back-splicing of RNA, are the zyme) in skin keratinocytes resulted in a number of abnormal skin
nc-RNA transcripts that play vital role in the development and patho phenotypes showing deregulated migration of dermal papillae into the
genesis of a number of human diseases, including cancer [13,31]. Cir epidermis and altered hair growth with germ-like cysts suggesting that
cRNAs are 100 bp to 4 kb in size, first discovered in plant viruses in the Dicer plays critical role in skin biogenesis and functioning [40,41]. In
year 1977. Decades of research work using advance genetic and mo 2009, another study which conditionally deleted Dgcr8 (required
lecular tools has demonstrated that structurally they are covalently component for miRNA processing) reported a similar skin phenotype
attached closed loops lacking 5′ or 3′ ends which provides stability and [42].
resistance towards the action of RNases and other degrading enzymes The first miRNA which was investigated in the skin was miR-203
[32]. There are four different types of circRNA detected in cytoplasm [43]. Its potential role in the control of cell proliferation and differ
and nucleus, namely; exon circRNAs (ecircRNAs), circular intronic entiation was highlighted by its expression; throughout epidermal de
RNAs (ciRNAs), exon-intron circRNAs (EIciRNAs) and intergenic cir velopment, as Keratinocytes moved forward from the basal layer and
cRNAs or fusion circRNAs (f-circRNAs) [32,33]. Interestingly, high le became differentiating cells, miR-203 expression intensified. miR-203
vels of circRNAs in human body fluids can be used as biomarkers of acts like a switch between cell proliferation and differentiation by
various diseases including cancer [34]. In addition, increasing evidence controlling stem cell functioning in stratified tissues via targeting p63
suggests that circRNAs are highly abundant, stable and widely ex [43]. It inhibited cell proliferation in squamous-cell carcinoma cell line,
pressed in eukaryotic cells having evolutionary conserved sequence therefore it can be considered as tumor suppressor [44].
across species, and have the potential to target gene via the response A number of findings revealed that miR-200 and miR-205 miRNAs
element through interactions with miRNAs as well as RNA-binding regulate mRNAs of E-cadherin transcriptional repressors ZEB1 and
proteins (RBPs) [35,36]. ZEB2 by targeting their mRNAs. E-cadherin (an adhesion molecule)
play critical role in barrier functions of the skin [48,49]. Further, an
other investigation showed that miR-205 is critical in keratinocytes
2.4. Piwi-interacting RNAs (piRNAs) growth and migration via targeting lipid phosphatase, the SH2-domain-
containing inositol 5-phosphatase (SHIP2) [52]. It has been also found
piRNAs, another important category of 26- to 32-neucleotide long that miR-205 plays a very important role the development of skin and
nc-RNAs previously considered as "dark matter" of nc-RNAs, play cri proliferation of neonatal stem cell via modulating PI3K signaling
tical role in development, epigenetic regulation and transposon silen pathway [53].
cing. Recently discovered in mouse germ cells and subsequently in The skin is protected from the effects of UV by pigmentation. In this
humans, piRNAs play very important role in the maintenance of the process, epidermal melanocytes produce melanin and disperse to
cellular and biological homeostasis while aberrant expression has been neighbouring keratinocytes. MiRNAs play role in melanogenesis by
observed in various human diseases including cancer [37–39]. In controlling microphthalmia transcription factor (MITF), a key regulator
creasing research based data suggest that piRNAs, the master regulators of colour genes coding for Tyrosinase (Tyr) and Hyalurodinase (Hyal).
of gene expression mostly present in germ cells, show a strong tendency miR-25 represses MITF, miR-21−5p controls MITF via Sox-5 and miR-
for uridine (U) at the 5′ end. They do not possess a loop structure and 434−5p targets Tyr and Hal genes to control melanin production
are well known to interact with PIWI proteins [37]. Due to their high [54–56].
abundance and expression in humans, piRNAs can be of great clinical Global miRNA profiling in mouse showed that expression of ncRNAs
importance with respect to disease detection and therapy. varies during various stages of hair cycle and it has been observed that
Here in this review we have illustrated how nc-RNAs are critical for miR-31 plays critical role in the expression and functioning of tran
the development and maintenance of cutaneous homeostasis func scription factors, growth regulatory and cytoskeletal proteins [57].
tioning and also, most importantly, how the dysregulated expression Another finding further supported the critical role miR-31 plays in
and functioning of these nc-RNAs play important role in the patho maintenance of hair follicles where miR-31 was found transcriptionally
genesis of cutaneous diseases including cancer and the autoimmune downregulated in hair follicle degradation in “hairpoor” (mutant hair
skin diseases. Considering the critical role of nc-RNAs in cancer re loss animal model) [58]. MiR-214 has been reported to show high ex
sistance, metastasis and autoimmune diseases, we have also highlighted pression in the hair matrix and outer root sheath of anagen hair follicles
their role as promising prognostic and therapeutic target for the cuta where it inhibits hair growth. When it was overexpressed in mouse
neous disease. keratinocytes, the hair follicle was shorter due to direct targeting of β-
catenin and the altered Wnt and Shh signaling pathways [59,60]. In an
interesting investigation, it was found that miR-24 is expressed in dif
3. Non-coding RNAs in skin morphogenesis and function ferentiated keratinocytes of the inner root sheath while its over
expression in the outer root sheath leads to premature differentiation in
Nc-RNA transcriptome research has shown important roles for nc- the hair follicles [61]. Aberrant expression of miR-125b, a stem cell-
RNAs, particularly miRNAs and lncRNAs in skin development and specific miRNA, which acts as a repressor of stem cell differentiation by
function. Functional studies which target critical components of the nc- targeting vitamin D receptor and the transcriptional repressor Blimp1,
RNAs’ biogenesis pathways and the role of individual nc-RNA are very in the outer root sheath causes inhibition of hair growth, epidermal
helpful in understanding their control in skin morphogenesis and thickening, and enlarged sebaceous glands [62]. MiR-22 expression is
function. Recent research shows that nc-RNAs play important role at upregulated during catagen phase of hair cycle in which hair follicles
transcriptional, post transcriptional and epigenetic levels to control cell regress. It controls multiple transcriptional factors such as Dlx3, Foxn1,
proliferation, cell differentiation, apoptosis, senescence, and angio and Hoxc13 and the Wnt/Bmp antagonist Sostdc1 which are vitally
genesis. Here, we describe few nc-RNAs in skin development and important for hair follicle differentiation and its dysregulated expres
function as represented in the Fig. 2. sion in mouse skin promoted anagen-catagen transition by inhibition of
4
cell differentiation and induction of apoptosis [63]. the genetic material which includes hyper- or hypomethylation of
A deregulated expression of miRNAs has been observed during DNA, histone modification such as phosphorylation, acetylation, me
wounding . Inflammatory mediators during inflammatory phase of thylation, ubiquitination, and sumoylation, and changes in expression
wound healing can regulate and be regulated by miRNAs [64,65]. MiR- profile of nc-RNAs that lead to gene activation or repression. Recent
31 has been shown to promote keratinocyte proliferation and migration advancements in high-throughput technologies for genome sequencing
via targeting epithelial membrane protein 1 (EMP-1) [66]. Further, have enabled researchers to identify several nc-RNAs that are aber
miR-21 has been found to promote cell migration and proliferation and rantly expressed in various human cancers. The loss of the delicate
wound healing via targeting Smad7-Smad2/3-Elastin pathway [67]. balance between up- or down-regulation of proto-oncogenes and tumor
Interesingly, a battery of miRNAs has been explored for their critical suppressor genes is associated with development and progression of
role in wound healing steps such as inflammation, proliferation, and cancer and this imbalance in homeostasis is sometimes triggered by nc-
remodeling via regulating multiple proteins and associated signaling RNAs and RNA modifiers [99]. The fact that 98 % the human genome is
pathways [68,69,80]. not encoding for protein forming RNAs while 80 % of genome is still
transcribed in to RNA [100] is a reminder of the possible diversity of nc-
3.2. lncRNA RNAs.
In general, the short nc-RNAs (miRNA, siRNA and piRNA) are
lncRNAs perform vital functions within the skin by regulating the mainly involved in the degradation and/or translational repression of
expression of genes that are primarily linked to modification of chro target gene products, while lncRNAs may regulate every step of gene
matin architecture, splicing, protein translation and post translational expression via histone modification, transcriptional, post-transcrip
modification as well as localization of subnuclear architecture within tional, and/or translational regulation [101]. Moreover, recent studies
the cells during health and diseased conditions [84–86]. Two IncRNAs, show that lncRNAs can act as tumor suppressors and oncogenes in a
anti-differentiation noncoding RNA (ANCR) and terminal differentia way similar to protein-coding genes. The aberrant expression of nc-
tion-induced noncoding RNA (TINCR) play a central role in controlling RNAs is observed in most human cancers including leukemia [102],
epidermal differentiation. ANCR negatively regulates epidermal dif hepatocellular carcinoma [103], lymphoma [104], melanoma
ferentiation; it suppresses premature differentiation in the basal layer of [105,106], colon [107], lung [108], prostate [109], etc., and depending
the epidermis: its loss in progenitor cells induces differentiation [87]. upon the specific nc-RNA and the disease condition, deregulation is
TINCR is generally overexpressed in the differentiated epidermal layer often associated with either inhibition of cancer proliferation or in
and promotes the stability of mRNAs which are vital for terminal ker crease in cancer development and progression.
atinocyte differentiation by forming a complex with the RNA-binding Metastasis, the process in which a cancer cell moves from the pri
protein STAU1 as its downregulation causes dramatic loss in expression mary tumor site to form secondary malignant growths in distant organs,
of terminal differentiation genes [88]. H19 is another nuclear inter is one of the primary causes of death in cancer patients. A few of these
genic lncRNA which has pro-differentiation effect on keratinocyte dif metastatic cancer cells may even linger in a dormant state for several
ferentiation [89]. years, while some will finally colonize secondary organs and establish
lncRNA SPRIGHTLY (SPRY4 intronic transcript 1, SPRY4-IT1), a as a clinical metastatic disease. An essential factor to successfully me
703 bp cytoplasmic intronic lncRNA can alter melanocyte functions by tastasize is the ability of cancer cells to adapt to the new micro
stimulating their proliferation while lncRNA UCA1 suppressed mela environment and this may create a pattern of favorable distant organs
nogenesis [90,91]. lncRNA PlncRNA-1 (also known as CBR3-AS1), a to form colonies depending on the initial cancer type [110]. Usually
743 bp cytoplasmic lncRNA, promotes growth, proliferation and dif metastasis is associated with a drastic reduction in survival rate. Given
ferentiation of human hair follicle stem cells (HFSCs) by targeting TGF- the key roles of nc-RNAs in transcriptional regulation of several onco
β1-Wnt/β-catenin signaling pathway [92]. lncRNA H19, RP11-766N7.3 genes involved in cell motility, survival and invasion, it is predictable
and HOTAIR play important role in dermal papilla (DP) cells via in that nc-RNAs will play a key role in the process of cancer metastasis,
hibiting Wnt/β-catenin signalling pathway [93]. lncRNAs play im and thus present themselves as novel biomarkers and/or therapeutic
portant function in healing of wound in human skin. LOC105372576 targets that will be specific for this process. Several studies have shown
(also referred as WAKMAR1) is DNMT (DNA methyltransferase) asso that in most human cancers, nc-RNAs directly regulate metastasis
ciated lncRNA which promotes keratinocyte motility and re-epithelia progression by either suppressing or promoting the process. The nc-
lization in wound healing [94]. LncRNAs have also been shown to en RNAs that mostly promote metastasis include HOTAIR, H19, treRNA,
hance the impaired wound healing process in diabetes: H19 promoted CCAT2, MALAT1, Linc-ROR, GClinc1, LncRNA-ATB, SCHLAP1, BCAR4,
fibroblast activation and proliferation to attenuate wound healing in EBIC, SDMGC, UCA1, and the nc-RNAS such as LET, NKILA, DREH and
mice [95]. Further, antisense nc-RNA in the INK4 locus (ANRIL) has FENDRR were found to generally inhibit metastasis [101], while there
been found to augment lymph angiogenesis wound healing process is contradictory report on several non-coding RNAs like MALAT1.
most likely by modulating miR-181a-Prox1 (Prospero homeobox 1)
expression [96]. 5. Non-coding RNA and epigenetic modifiers in skin
carcinogenesis
3.3. circRNA
5.1. Non-coding RNAs in skin cancer
CircCOL3A1-859267, a circRNA, has been reported to be down
regulated in UVA-exposed human dermal fibroblasts (HDFs) and reg As discussed above, nc-RNAs are the RNAs that do not code for any
ulates type I collagen expression by sponging and sequestering miR-29c protein product. They are very abundant and make up the vast majority
in HDFs [97]. circRNA circ-Amotl1′s expression has been shown to of human genome [21]. Non-coding RNAs such as lncRNAs have been
enhance the wound healing in a mouse model by interacting with proposed as skin cancer biomarkers and/or therapeutic targets [111].
STAT3 to increase its nuclear translocation and repair wound by lncRNAs are now known to play an important role in skin cancer pro
modulating Dnmt3a and miR-17 [98]. gression [105,112–114], particularly its metastasis [115–117]
(Table 1).
4. Non-coding RNA in cancer development, progression and In consideration of the protective role of Vitamin D signaling against
metastasis skin cancer, an lncRNA profiling study was performed in a mouse
keratinocyte model where vitamin D receptor was deleted [118]. The
Most human cancers exhibit numerous inheritable modifications in study evaluated ninety lncRNAs and found increased expression of
5
Table 1 provide only the most novel information on the topic.

List of Non-coding RNA and their reported role in skin cancer progression. In addition to lncRNAs, a few reports have also highlighted the
Non-coding RNA Effect Reference possible role of circRNAs in skin cancer pathogenesis. In basal cell
carcinoma, comparison of microarray circRNA profile of basal cancer
AK144841 Induced in cutaneous squamous cell carcinoma [287] carcinoma vs. control, followed by quantitative RT-PCR validation re
ATB Induces melanoma growth [288]
vealed significantly differentially expressed 23 circRNAs that were
CASC15 lincRNA Gained in metastatic melanomas [289]
CRNDE Promotes proliferation and metastasis [290]
upregulated and 48 circRNAs that were downregulated in cancer
DRAIC Biomarker for good prognosis [291] samples [153]. A study focused on cSCC compared six cSCC biopsies
GAS5 Tumor suppressor activity [292,293] with six non-lesional skin control bopsies and reported an even larger
H19 Promotes melanoma growth and progression [294,295] number of differentially expressed circRNAs [154]. In all, 143 circRNAs
HEIH Sponges tumor suppressive miRNAs and [296]
were upregulated while 179 circRNAs were down-regulated in biopsies
promotes melanoma progression
HOTAIR Promotes invasion and metastasis [297,298] from cancer patients, compared to control samples. Based on these re
HOTTIP Tumor promoting role in Vitamin D signaling [295] ports, there seems to be a role of circRNAs in the pathogenesis of skin
HOXD-AS1 Suppresses RUNX3 expression and promotes [299] cancer subtypes. However, more mechanistic studies need to be per
melanoma growth
formed to fully understand the underlying mechanism(s).
ILF3-AS1 Promotes melanoma invasion [300]
Nespas Tumor promoting role in Vitamin D signaling [295]
Kcnq1ot1 Tumor suppressing role in Vitamin D signaling [295] 5.2. Epigenetic modifiers in skin cancer
LINC00162 Promotes growth of cutaneous squamous cell [301]
carcinoma It has long been realized that epigenetic mechanisms play a key role
LINC00319 Indicates poor prognosis of cutaneous squamous [302]
in melanoma gene regulation [155]. In particular, DNA methylation,
cell carcinoma
lincRNA-p21 Tumor suppressing role in Vitamin D signaling [295] histone modifications as well as miRNA-mediated regulation represent
MALAT1 Promotes lymph node metastasis of melanoma [303,304] some of the key epigenetic changes that affect skin cancers [156–158]
MEG3 Suppresses wnt signaling and melanoma [305] as shown in Fig. 3. Various findings show the critical role of miRNA in
progression human cutaneous malignancies mediated through epigenetic regulation
PVT1 Promotes melanoma progression [306]
RMEL3 Required for oncogenic MAPK and PI3K signaling [307]
of tumor suppressor genes and oncogenes [159,160]. Aberrant expres
in melanoma sion of miRNA125b has been shown to regulate vitamin D receptor
SLNCR Recruits androgen receptor for melanoma [308] expression and in drug resistance in melanoma cells via epigenetic
progression mechanisms as use of histone deacetylase inhibitor (HDACI) and the
SNHG5 Biomarker for melanoma progression [309]
DNA methyltransferase inhibitor (DNMTI) suggesting critical involve
UCA1 Positively correlates with melanoma stage [304,310]
TUG1 Promotes melanoma metastasis [311,312] ment of miRNA and epigenetics and melanoma pathogenesis [161].
XIST Induces oxaliplatin resistance in melanoma [313] Interestingly, microRNA-155 has been shown to negatively regulate
expression of SATB1, a Pivotal epigenetic biomarker in cutaneous T-cell
lymphomas [162]. MicroRNA-29(miR-29) negatively regulate DNA
lncRNAs H19, HOTTIP and Nespas, along with reduced expression of methyltransferases which are essential to the methylation of tumor-
Kcnq1ot1, lincRNA-p21. Increased H19 was later correlated with in related genes (TRGs) as hypermethylation of TRGs is critical in mela
creased glucose metabolism and poor prognosis of melanoma patients noma progression. In this line, in stage I–IV cutaneous melanoma spe
[119] and its expression was reported higher in tumors of 47 of 49 cimens, an inverse correlation was detected between miR-29c expres
melanoma patients, relative to adjacent healthy tissue [120]. In a study sion protein expression of DNA methyltransferases [163]. Acetylation is
that evaluated serum samples of multiple malignant melanoma pa another epigenetic event with several reports in the progression of skin
tients, lnc SNHG5 (snoRNA host gene 5) was significantly higher in cancer. This section focuses on the reported roles of epigenetic events,
melanoma patients, compared to healthy controls and also correlated particularly methylation and acetylation in skin cancers.
positively with melanoma grade [121].
In recent years, a number of non-coding RNAs have been reported to 5.2.1. Methylation
be involved in skin cancer progression. For example, lncRNAs RMEL3 Suggestive of the immense potential of DNA methylation analysis,
[122], PVT1 [123], HEIH [124], ILF3-AS1 [125], HOXD-AS1 [126], blood DNA methylation can help assess the risk of melanoma [164] and
TUG1 [109,127], ATB [128], CRNDE [129] and SLNCR [130] promote improved capabilities, particularly as applied to analyses of epigenetic
melanoma progression. On the contrary, some non-coding RNAs have changes, are helping unravel novel subclasses of skin cancers [165].
been reported to be tumor suppressors in melanoma patients or cell line Since methylation and demethylation of genes is critical for their
models. These include GAS5 (growth arrest-specific 5) [131,132] and expression, the epigenetic studies often focus on the methylation status
MEG3 [133]. of individual genes and their eventual expression. For example, de
LncRNAs have also been evaluated in cutaneous squamous cell methylation of EGFR resulting in its increased expression has been
carcinomas (cSCC) [134]. In one such study, LINC00162 / PICSAR (p38 correlated with resistance to BRAF inhibitors in melanoma models
inhibited cSCC associated lincRNA) was reported to be highly expressed [166]. On the other hand, increased promoter methylation of MGMT
in tumor cells where it associated with extracellular signal-regulated has been reported to result in its reduced expression in melanoma pa
kinase 1/2 activity [135]. Further, its knockdown resulted in increased tients cohorts [167]. Since MGMT is a tumor suppressor, such epige
cell adhesion and decreased migration [136]. A later study identified netic silencing of MGMT ensures resistance against temozolomide
AK144841 as a novel lncRNA which is absent in normal skin but ex [167,168]. Such role of methylation in predicting response to immune
pressed in cSCC [137]. More recently, LINC00319 has been linked with checkpoint blockers has also been assessed, and it has been reported
poor prognosis of cSCC [138] while LINC00520 expression seems to that promoter methylation of CTLA4 is a reliable indicator of response
indicate a good prognosis of cSCC patients [139]. Taken together, there to anti-PD-1 as well as anti-CTLA-4 immunotherapy [169]. Further,
is ample evidence to suggest a mechanistic role of nc-RNAs, particularly methylation of not just genes, but even miRNAs can modulate sensi
the lncRNAs in skin cancer. It is worth mentioning that miRNAs re tivity to therapy, as exemplified by the methylation-mediated silencing
present a major class of nc-RNAs that have been extensively studied in of miR-211 which resulted in significantly diminished sensitivity to
skin cancer and skin diseases, as well as reviewed extensively cisplatin [170].
[140–152]. Therefore, we have not included miRNAs in our discussion A number of genes either over-expressed or silenced due to their
on nc-RNAs in skin cancer, so as to keep the discussion focused and differential promoter methylation in melanoma patients’ tumors or the
6
Fig. 3. Non-coding RNA and epigenetic regulation in skin. It is well known that epigenetic mechanisms play a key role in skin homeostasis and in the development of
cutaneous diseases including cancer. In this figure we have shown the role of nc-RNA as epigenetic modifiers in normal skin and in skin diseases by modulating the
expression of epigenetic regulatory moieties associated with chromatin, chromosome inactivation and histone modifications. Dysregulated expression and func
tioning of nc-RNA lead to the aberrant expression of various regulatory proteins associated with cell growth and proliferation including the tumor suppressor and
oncogenes that ultimately contribute to disease development.
cell lines representing melanoma. DSS1 [171] represents the upregu 5.2.2. Acetylation
lated gene while the downregulated ones include TFAP2A [172], MITF Acetylation is another important epigenetic event that profoundly
[173], SPINT2 [174], SYNPO2 [175], E-cadherin [176], ASC [177], affects gene expression. Most of the studies on acetylation in skin cancer
GOS2 [178] and MC1R [179]. It is quite apparent that promoter me have been in the context of HDACs (histone deacetylases). HDAC in
thylation of tumor suppressors is a frequent event in melanomas [180]. hibitors are under investigation as potential anticancer therapeutics for
There is evidence to suggest that epigenetic changes such as differential many years. In one of the early reports in melanoma, an HDAC inhibitor
methylation might not just potentiate skin cancer in individual patients, SBHA (Suberic bishydroxamate) sensitized melanoma cells to TRAIL-
but may also play a role in making families particularly prone to mel induced apoptosis [192], thus making a case for relevance of acetyla
anoma [181]. In addition to possible use of epigenetic signatures for tion to research on skin cancers. Since tumor suppressor p21 is silenced
skin cancer diagnosis [182,183], methylation can also help determine by deacetylation [193,194], overexpression of HDAC1 results in re
the risk of metastasis as evident by hypermethylation of LINE-1 in sistance to DNA damaging agents [195] and metastasis suppressor
metastatic melanoma patients [184]. Further, promoter methylation NME1 acetylates and induces ITGβ3 (integrin-beta3) resulting in re
has also been suggested as prognostic biomarker in melanomas duced cell motility [196], inhibition of deacetylation can be beneficial
[185,186]. in management of malignant melanomas [197–199].
Methylation of nc-RNA is another important mechanism underlying HDAC inhibitors can sensitize human melanoma cells to radio
the pathogenesis of human malignancies including skin cancer. therapy [200], chemotherapy [201] as well as immunotherapy [202]. A
Recently it was reported that deregulated expression of miR-148a due recent report has described the role of HDAC8 in mediating chemo-
to methylation is critical for the progression and metastasis in mela resistance in melanoma cells [203]. Introduction of HDAC8 was suffi
noma patients [187]. Resistance or therapeutic failure is also related to cient to induce resistance against BRAF-targeting therapy, both in vitro
the epigenetic regulation of nc-RNA expression and functioning as it and in vivo. A number of HDACs have now been characterized and
was observed that deregulated expression of miR-211 due to DNA inhibition of many of them has been tested for potential use an antic
methylation causes anticancer drug resistance in melanoma cells [188]. ancer therapy. For example, inhibition of HDAC3 has been linked to up-
Interestingly, in cutaneous SCC, aberrant or low miR-204 expression regulation of tumor suppressor p53 [204]. Selective HDAC6 inhibitor
due to DNA methylation of its promoter is critical in the progression of ACY1215 [205] as well as synthetic inhibitors specific for HDAC6 [206]
actinic keratosis (AK) to cutaneous SCC via targeting STAT3 signaling have shown initial promise as antitumor compounds against melanoma
[189]. Further, it was also demonstrated that epigenetic silencing of cells. HDAC6 is a member of class II HDACs, and inhibitors specific for
miR-34b due to DNA methylation of its promoter associated with this class can suppress binding of c-Jun to IL-8 promoter, leading to
melanoma pathogenesis [190]. It has been also reported that the epi suppression of IL-8 expression and cell growth [207]. The specificity of
genetic regulation of miR-200a expression in melanoma cells is asso natural HDAC inhibitors, on the contrary, seems to be much broader as
ciated with disease progression and a higher number of lymph node they can inhibit multiple HDACs belonging to different HDAC classes
metastases via targeting CDK4/6 [191]. (classes I, II and IV) [208]. Such activity is also exhibited by natural
7
compounds such as isothiocyanates [209]. Interestingly, synthetic acetylation [216]. In an interesting in vivo study, it has been shown
HDAC inhibitors have been shown to be effective only against mela that chemo-preventive effect of various compounds against 7, 12-di
noma cells, and not the normal melanocytes [210], thus generating a lot methylbenz [a] anthracene (DMBA) induced mouse skin tumorigenesis
of interest for further characterization. is due to the epigenetic regulation of miR-203 status [217].
Sirtuin1 (SIRT1) is a class-III histone deacetylase (HDAC), critically
associated with the epigenetic regulation of gene expression critical for
cell survival and homeostasis particularly glucose and lipid metabolism, 5.3. Non coding-RNAs in skin cancer progression and resistance
and its aberrant expression has been detected in number of human
diseases including skin cancer [211]. Worth mentioning, miR-34a- In an early study that sought lncRNA signature of melanoma me
mediated regulation of SIRT1, has been shown to play critical in the tastasis [218], six metastasis-associated lncRNAs were tested for their
skin cancer pathogenesis and it was further reported that p53 mutation possible role in lymph node-metastasis of melanoma and lncRNA HO
causes drug resistance by interfering with miR-34a-mediated regulation TAIR was found to be highly expressed in lymph node metastases, re
of SIRT1 [212]. In addition, low expression of miR-340 in angiosarcoma lative to matched primary melanomas. Its suppression resulted in re
is critical for the growth and migration of angiosarcoma cells via tar duced invasion and suppression of gelatin matrix degradation [218].
geting SIRT7 and thus indicates that miR-340/SIRT7 axis is critical for Such role of HOTAIR in melanoma progression is supported by other
therapeutic intervention angiosarcoma [213]. Further, miR-211 often analysis as well [219]. Another study [220] that also evaluated six
dysregulated in cutaneous melanoma has been shown to modulate the lncRNAs for a similar metastasis signature of melanoma, reported an
expression of histone deacetylase 9 (HDAC9) [214]. Aberrant expres association of MALAT1 (metastasis-associated lung adenocarcinoma
sion of tumor suppressor miR-150 due to acetylation play critical role in transcript 1) with lymph node metastasis and that of UCA1 (urothelial
the pathogenesis and progression of the advanced cutaneous T-cell carcinoma-associated 1) with advanced melanoma stages [220]. The
lymphoma (CTCL) and restoration of miR-150 expression due to HDAC role of UCA-1 in melanoma cell proliferation and invasion was further
inhibits metastasis and thus supporting important role of HDAC in confirmed in a later study where it was shown to function through
cancer pathogenies and treatment [215]. Another report shows that regulation of FOXM1 [221]. Similarly, MALAT1 was shown in a later
deregulated JAK/STAT signaling promotes CTCL pathogenesis via in study to sponge miR-22, thus promoting melanoma progression and
hibiting miR-22 and use of HDAC inhibitor attenuates CTCL patho metastasis [222].
genesis though miR-22 upregulation further supporting the role of In support of a role of non-coding RNAs in melanoma therapy,
knock-down of antisense noncoding mitochondrial RNAs
Fig. 4. Non-coding RNA in cancer progression and drug resistance.

Nc-RNA play critical role in skin cancer metastasis and drug resistance as shown in the figure. Here we have depicted how deregulated expression of nc-RNA affects
the expression and functioning of regulatory moieties related to cell cycle arrest, DNA repair, Stemness, immune check points. Deregulated expression or modulation
of nc-RNA expedite the proliferation of tumor cells with DNA damage through unchecked cell cycle, inhibition of DNA repair enzymes, epigenetic regulation,
activation of the survival signaling pathways which ultimately lead to the expression of a number of dysregulated proteins in order to maintain the microenvironment
and heterogeneity and resistance and progression of cancer. Modulation of the stemness markers, inactivation of the immune checkpoint inhibitors, and deregulated
expression of a number of critical signaling proteins by the aberrantly functioning nc-RNA is another very important critical phenomenon associated with skin cancer
progression and metastasis.
8
(ASncmtRNAs) in melanoma models has been shown to result in in 6. Nc-RNA in cutaneous autoimmune diseases
duction of apoptosis [223]. Additionally, lncRNAs do not just modulate
melanoma proliferation, invasion and metastasis, they are also known Dysregulation of lncRNAs has been reported in a number of multi
to play a role in therapy resistance [224]. Further, there have been faceted human diseases, including autoimmune diseases, coronary ar
efforts with regards to possible applications of lncRNAs towards per tery diseases, neurological disorders and cancers, signifying the po
sonalized management of melanoma patients. As possible steps in this tential roles of IncRNAs in these diseases [170,232–237]. lncRNAs also
direction, first a four-lncRNA signature was proposed to help stratify function as regulators of several immune functions. Recent reports
melanoma patients and predict patients’ duration of survival [225] and suggest that lncRNAs dysregulation possibly affects autoimmune dis
more recently a six-lncRNA signature has been proposed to risk-stratify eases, including rheumatoid arthritis, systemic lupus erythematosus
melanoma patients [226]. Expression of lncRNA DRAIC associates with psoriasis and Sjögren´s syndrome [238]. However, it is unclear if the
better prognosis in melanoma [227] and based on the emerging data, dysregulation of lncRNAs can exert an impact on autoimmune disease
non-coding RNAs are increasingly being valued for their possible role in pathogenesis and skin cancer. In this section, we will review our present
clinics as therapeutic targets [228]. In addition to the lncRNAs dis knowledge of lncRNAs in autoimmune diseases.
cussed above, the long intergenic noncoding RNAs (lincRNAs), parti
cularly the chromosome 6p22.3 CASC15 (cancer susceptibility candi 6.1. LncRNAs in autoimmune diseases
date 15) lincRNA locus has been identified as the candidate genomic
segment frequently gained in metastatic melanomas [229]. Recently it Autoimmune is a disease condition when immune system starts
was documented that lncRNA, AFAP1-AS1 triggers the progression of producing antibodies that attack its own normal body cells or tissues
melanoma features such as proliferation, migration, invasion and EMT (autoantibodies) [239]. The production of autoantibodies is triggered
via modulating the miR-653-5p/RAI14 Axis [230]. Furthermore, by combination of multiple interactions, including genetic, im
miRNAs have been shown to regulate the expression of an array of munological, and environmental factors. Previously, autoimmune dis
genes associated with growth, proliferation and progression of mela eases were thought to be rare, however, current global predominance of
noma and various clinical studies have shown therapeutic importance autoimmune diseases is found 3%–5% in a common population
of miRNAs both as prognostic therapeutic relevance [231]. In Fig. 4 we [240,241]. Accumulating evidence indicates that lncRNAs play an in
have shown how ncRNA play critical role in skin cancer progression tegral role in immune regulation and development of autoimmunity
and drug resistance. [242–244]. lncRNAs are expressed in various innate and adaptive im
mune cells including T lymphocytes, B lymphocytes, NK cells, dendritic
Fig. 5. Role of non-coding RNA in cutaneous autoimmune diseases.

Emerging evidence suggests that Nc-RNA play critical role not only in skin cancer but also in pathogenesis of the skin autoimmune diseases like psoriasis and systemic
sclerosis. In this figure we have represented how skin prone to develop psoriasis and systemic sclerosis if not identified and treated early. Exposure of a number of
hazardous biochemical to the skin causes various changes including the deregulation of nc-RNA expression and functioning which induces the modulation of a
number of genes associated with psoriasis and systemic sclerosis. At molecular level, nc-RNA modulate genes related to endothelial damage, inflammation, immunity,
cytotoxicity and a number of cytokines and growth factors which eventually coordinate and function that results into autoimmune disorders such as psoriasis and
systemic sclerosis.
9
cells, macrophages and neutrophils and are also engaged in the acti irradiation can also upregulate PRINS RNA level. Overexpression of
vation, differentiation and effector-function of these cells [243,244]. PRINS in the keratinocytes from non-lesional psoriatic skin drives the
Cardiovascular diseases, along with cancer and neurological diseases, modification of stress response genes in the non-lesional epidermis that
have been the top attention of lncRNA studies [245]. However, accu subsequently contributes to psoriasis pathogenesis [265,266]. System
mulating evidence suggests that lncRNAs contribute to immune cell atically, PRINS IncRNAs play critical role in psoriasis by suppressing
responses and differentiation, reflecting their critical role in the pro keratinocyte apoptosis by G1P3 regulation [265].
gression of autoimmune diseases [243,244,246–248]. The evidence Tsoi et al. has characterized IncRNAs by RNA-seg in the psoriatic
that lncRNAs are coupled to immunological responses reveals that the skin lesion, where they compared expressed lncRNAs in lesional psor
dysregulation of lncRNAs contributes to the progression of various iatic skin with non-lesional psoriatic skin as well as with healthy skin
autoimmune diseases including the cutaneous autoimmune diseases as biopsies [267]. They detected skin specific 1080 novel differentially
shown in the Fig. 5. Here, we review current findings of lncRNAs in expressed lncRNAs that were also found differentially co-expressed
systemic sclerosis and psoriasis. with the genes associated with immune functioning and regulations,
implicating important role of lncRNAs in psoriasis pathogenesis [267].
6.2. Non-coding RNAs in systemic sclerosis (SSc) Another study by Liao group [268] defines a number of networks of
non-coding and coding genes that are linked with psoriasis develop
Systemic sclerosis is a highly heterogeneous autoimmune disease ment. They characterized the lncRNAs in psoriatic and healthy skin as
characterized by fibrosis and vascular abnormalities in the skin and well as analyzed the lncRNA transcriptome in psoriatic skin lesion be
other organs accompanied by immune abnormalities. A number of re fore and after treatment with the TNF-α inhibitor (adalimumab). They
search groups have conducted gene expression studies in the skin of SSc identified 971 differentially expressed lncRNAs between lesional psor
patients to better understand cellular and molecular alterations asso iasis and healthy skin, 157 differentially expressed lncRNAs in the skin
ciated with the processes involved in SSc pathophysiology [249–252]. lesion of psoriatic patients before and after treatment, and 377 differ
Messemker et al. studied differentially expressed non-coding genes to entially expressed lncRNAs between lesional skin after treatment and
understand systemic sclerosis pathogenesis and reported that out of 676 healthy skin. The reduce number of differentially expressed IncRNAs
lncRNA genes; 122 were decreased, while the expression of 554 genes after adalimumab treatment in the lesional psoriatic skin underlining
was increased in SSc patients, compared to healthy controls [253]. The the significance of lncRNAs in the pathogenesis of psoriasis [268].
non-coding circRNA has not been explored yet in systemic sclerosis. Furthermore, a weighted gene co-expression network analysis
MiRNAs have been recognized in skin fibroblasts and sera of pa (WGCNA) of RNA-Seq data of psoriasis patients and healthy controls
tients with SSc [253]. The aberrant expression of miRNAs is an im reveals the involvement of several networks of coding and noncoding
portant factor for pro- or antifibrosis, and it is interrelated to the in genes where most of the non-coding genes were connected with psor
itiation and progression of SSc [254]. Zhu et al. identified miRNA-21, iasis, suggesting the critical role of noncoding RNA in psoriasis [269].
miRNA-145 and miRNA-29b in the skin samples and fibroblasts from A recent finding shows that cytoplasmic lncRNA Msh homeobox 2
SSc patients. MiRNA-21 and miRNA-145 promote skin fibrosis and pseudogene 1 (MSX2P1) is overexpressed in psoriatic skin lesions and
upregulate SMAD3 while miRNA-29b upregulates COL1A1 expression enhances the proliferation and growth of IL-22 treated keratinocytes by
and suppresses fibrosis [255]. Further, miRNA-92a and miRNA-196 assisting as an endogenous sponge to miR-6731-5p and activating cal
have been reported in skin fibroblasts and serum of SSc patients, where cium binding protein S100A7, thus suggesting a possible role of
they promote skin fibrosis [254,256,257]. In contrast, miRNA-7, MSX2P1 IncRNA-miR-6731-5p-S100A7 network in psoriasis pathogen
miRNA-29a, miRNA-129-p and miRNA-150 downregulate collagen ex esis [270].
pression and suppress skin fibrosis [258–261]. Inhibiting the function of The differentially expressed miRNAs and circRNAs in psoriatic skin
miRNAs that promote fibrosis while endorsing the functions of anti lesions influence many processes in pathogenesis such as keratinocytes
fibrotic miRNAs, through gene or antisense technology, will provide differentiation, angiogenesis and cytokines production. Among dif
novel therapeutic option for future therapy. ferent miRNAs reported in psoriasis, miR-203, misR-125b and miR-31
are differentially expressed in psoriatic skin lesions and drive enhanced
6.3. Non-coding RNA in psoriasis keratinocytes differentiation and proliferation, modulate proin
flammatory cytokine production and promote inflammation [271,272],
Psoriasis is a common chronic skin disease, characterized by the while miR-146a and miR-369−3p are present in lesioned skin and in
occurrence of well-demarcated, large erythematous, scaly plaques and peripheral blood of psoriasis patients regulate IL-17 expression and
silvery scales usually found on the scalp, trunk, and extensor surfaces of show a positive correlation with PASI (Psoriasis Area and Severity
affected patients. Roughly, 2%-3% of the global population is suffering Index) score [273,274]. Furthermore, miR-21 and miR-210 are reported
from psoriasis [262]. Histologically, psoriatic skin lesions are illustrated in T cells of psoriatic patients to regulate TIMP-3 and FoxP3 expression,
by hyperproliferative keratinocytes and a mixed immune cellular (both resulting in skin inflammation and dysregulated immune response
innate and adaptive) infiltration in the dermal and epidermal layers of [275,276].
the skin. The initiation of psoriasis lesions starts with immune activa A circRNA, chr2:206992521I206994966 is reported in skin me
tion in vulnerable individuals following environmental stimuli (trauma senchymal stem cell of psoriasis patients that suppresses T cell pro
or infection) or loss of immune tolerance against psoriasis autoantigens liferation and secretion of cytokines including IL-6, IL-11 and hepato
[262,263]. It has been observed that the deregulated proliferation and cyte growth factor (HGF) [277]. Likewise, has_circ_0061012,
differentiation of basal keratinocytes in psoriasis lesions is mainly due has_circ_0003689, chr4:121675708I121732604 and has_circ_0003718
the deregulated expression and functioning of genes [264]. In addition have been reported in psoriatic skin lesions that probably flare psoriasis
to changing the gene expression pattern and affecting the encoded disease progression by interacting with miRNAs associated with psor
proteins with characterized biological functions, evolving data suggests iasis [278,279]. In summary, the differential expression profiles of nc-
that lncRNAs also have an important role in psoriasis pathogenesis. RNA (LncRNA, miRNA and circRNA) in RNA-seq analysis of psoriasis
Initial evidence of IncRNAs in psoriasis came after an overexpression of skin and functional studies suggest that nc-RNAs are significant con
psoriasis susceptibility–related RNA gene induced by stress (PRINS) was tributors to key alterations and mechanisms involved in psoriasis pa
found in the non-lesional epidermis of psoriatic patients, compared to thogenesis.
both psoriatic lesional and healthy epidermis, signifying the function of
PRINS in psoriasis vulnerability [265]. In addition, during stress con
dition, such as viral infection, translational inhibition and UVB
10
Table 2
Role nc-RNAs in cutaneous diseases and therapy.
Nc-RNA type Cutaneous disease type and Underlying mechanisms Effect Clinical and therapeutic importance References
expression
A.Q. Khan, et al.
lncRNA MIR155 host gene (MIR155HG) Cutaneous melanoma, high Strong correlation in the upregulated expression of Promotes tumor progression, invasion, Critical in prognosis and in the [314]
expression the immune check point inhibitors (PD-1, PD-L1, and metastasis evaluation of patients' immune
CTLA4, LAG3, and TIM3) status and immune therapy
lncRNA HCP5 Downregulated in skin Modulates RARRES3 expression Aberrant expression associated with Can be used in clinics for its [315]
cutaneous melanoma tissue invasion and metastasis prognostic and therapeutic values
LncRNA-ILF3-AS1 Upregulated in melanoma tissues Exerts oncogenic action via modulating miR-200b/ Induces melanoma cell proliferation, May be used as a potential [316]
and cell lines a/429 expression migration prognostic biomarker and
therapeutic target for melanoma
LncRNA-LINC00162 / PICSAR- p38 inhibited Over expressed in cSCC Activates ERK1/2 mediated signaling pathway by Promotes progression and metastasis of Putative biomarker and therapeutic [317]
cutaneous squamous cell carcinoma associated downregulating DUSP6 expression cSCC target in cSCC.
lincRNA
LncRNA-TUG1 High expression in melanoma Critical in melanoma metastasis via modulating Promotes cell growth and metastasis Suppression of lnc TUG1 may be a [318]
specimens and cell lines AEG1 expression mediated by targeting promising therapeutic strategy in
miR-129−5p. the treatment of malignant
melanoma.
lncRNA GAS5 Under expressed in skin cancer A tumor suppressor that is often downregulated Induces cell growth, proliferation and Targeting lncRNA GAS5 may [319]
tissues metastasis provide a better therapeutic
outcome
LncRNA MEG3 Under expressed in psoriatic Affects cell proliferation and apoptosis by regulating Affects psoriatic cell proliferation and Could inhibit the proliferation of [320]
keratinocytes miR-21 apoptosis psoriatic keratinocytes and promote
cell apoptosis.
lnc-NEAT1 Over expressed in melanoma Enhances melanoma cell proliferation and Induces melanoma cells’ proliferation, NEAT1/miR-23a-5p/KLF3 axis [321]
tissue specimens metastasis via sponging miR-23a-5p mediated migration, and invasion might be a promising therapeutic
targeting of KLF3 target for melanoma
11
LINC01638 lncRNA Highly over expressed in Enhances proliferation of melanoma cells Enhances melanoma cell proliferation Putative therapeutic target [322]
melanoma patients and associated with melanoma
recurrence
LncRNA WAKMAR1 Enhanced during physiological Enhances E2F1 expression by interfering with E2F1 Affects Keratinocyte migration May be an important target for the [323]
wound healing promoter methylation through the sequestration of treatment of chronic wounds
DNA methyltransferases
lncRNA ZFAS1 Overexpressed in melanoma Downregulates miR-150−5p/RAB9A axis Enhances cell proliferation, migration, Putative therapeutic target [324]
patient tissues and cells invasion, and epithelial-mesenchymal
transition potential of melanoma cells.
LncRNA SNHG5 Overexpressed in melanoma Inhibits miR-26a-5p and facilitates TRPC3 Induces cell proliferation, apoptosis and Plausible therapeutic target [325]
patient tissues and cells expression invasion
lncRNA-ATB Upregulated in melanoma tissues Induces growth promotion and metastasis via acting Affects cell proliferation, cell migration, Can be targeted to reduce metastasis [326]
and cells as a competing endogenous RNA (ceRNA) to and cell invasion of MM cells in vitro,
enhance Yes associated protein 1 expression by and tumor growth in vivo
sponging miR-590-5p
lncRNA-NEAT1 Expressed in paraspeckle nuclear Onco-suppressive effect involves ATR signaling Affects cell growth and development Can be targeted for sensitizing [327]
bodies mediated attenuation of oncogene-dependent cancer cells to both chemotherapy
activation of p53 and p53 reactivation therapy
MiR-223 Over expressed in peripheral Increased proliferation and inhibits apoptosis of IL- Affects cell growth and proliferation Can be of both clinical and [328]
blood mononuclear cells in 22-stimulated keratinocytes by modulating PTEN/ therapeutic use in psoriasis
psoriasis patients Akt signaling
miR-579−3p. Down regulated in melanoma Functions as an tumor suppressor by targeting BRAF Down regulation enhances progression, Could be used as both prognostic [329]
cancer specimens and an E3 ubiquitin protein ligase, MDM2, leading metastasis and resistance and therapeutic target for melanoma
to metastasis and therapy resistance
miR-203 Suppressed in cSCC Exerts its tumorigenic action via targeting c-MYC cell proliferation, cell motility, and the Have potential to be used both [330]
angiogenesis- prognostic and therapeutic target for
cSCC.
(continued on next page)
Table 2 (continued)
Nc-RNA type Cutaneous disease type and Underlying mechanisms Effect Clinical and therapeutic importance References
expression
A.Q. Khan, et al.
miR-203 Down regulated in melanoma – Enhances, proliferation and tumor Could be used as potential [331]
growth prognostic and therapeutic target for
the treatment of melanoma.
nco-miR-365 Over expressed in cSCC Modulates genes expression associated with cell Causes increased cell proliferation and Potential therapeutic target for cSCC [332]
growth, proliferation tumor development
miR-146a Expressed in human melanoma Plays central role in STAT1/IFN-γ signaling and Induces migration, proliferation and Can be utilized in immune [333]
tissues specimen increase PD-L1 levels metabolism of melanoma cells checkpoint-therapy to enhance
antitumor response
miR-146a, miR-155, miR-125b, miR-100, let-7e, Increased in circulating CD14+ Associated with myeloid-derived suppressor cells Causes myeloid cell differentiation, Can be used as potential biomarker [334]
miR-125a, miR-146b, miR-99b monocytes, plasma, and tumor MDSCs and therapeutic resistance polarization and cancer-related in immunotherapy
samples of melanoma patients immunosuppression
miR-338−3p Downregulated in malignant Targets MACC1 Suppresses migration cell proliferation, Can be used as a potential target for [335]
melanoma patients invasion treatment of MM patients.
miR-143−3p Downregulated in melanoma Acts on cyclooxygenase-2 (COX-2) Affects proliferation, migration, invasion Can be used a diagnostic and [336]
cells and tissue specimen of therapeutic target in melanoma
melanoma patients
miR-203 Suppressed in melanoma Targets SLUG Suppresses cell growth, proliferation and Putative target for therapy [337]
patients with metastatic disease angiogenesis
miR-153−3p Low levels detected in melanoma Exerts effect by upregulating the expression of snail Affects cell proliferation, invasion Potential biomarker for diagnosis [338]
tissue specimen and cells family transcriptional repressor 1 (SNAI1) and therapy of melanoma
miR-579−3p Low in specimens and cell lines Acts as an onco suppressor by targeting the 3′UTR of Influences drug resistance Can be used in therapies against [330]
resistant to BRAF/MEK BRAF and an E3 ubiquitin protein ligase, MDM2 resistance
inhibitors
miRNA-221 Over expressed in cSCC Directly inhibits the transcriptional expression of Increases cell growth and proliferation Can be utilized as potential [339]
PTEN diagnostic and therapeutic target for
12
cSCC
miR-34a Suppressed in CSCC specimens Controls cell growth and proliferation by HMGB1 Decreases growth and proliferation, Can be used as a promising [340]
and cell lines mediated migration and invasion therapeutic target
Circ008913 Suppressed in immortalized Acts as sponge for miR-889 regulation of DAB2IP/ Affects cell proliferation, invasion and May be important therapeutic target [341]
human keratinocytes ZEB1 stemness in arsenite induced carcinogenesis
miR-375 Over expressed in Merkel cell Targets lactate dehydrogenase B (LDHB) Induces cell proliferation and migration May be an important therapeutic [342]
carcinoma (MCC) target for MCC
miR-21, miR-99a, miR26-a-2, let-7f, let-7 g, let-7i, Strongly overexpressed in sBCCs Dicer mutations play important role in the aberrant Associated with deregulated cell May have role in progression of BCC [343]
miR-100, and miR-205 human samples miRNA expression in BCC signaling related in BCCs
circRNA chr2:206992521|206,994,966 Elevated in the skin Targeting genes associated with K-STAT signaling T-cell proliferation and psoriasis Can be a potential target to better [344]
mesenchymal stem cells (S- pathogenesis managepsoriasis pathogenesis
MSCs) from psoriatic lesions
7. Diagnostic and prognostic potential of nc-RNAs in cutaneous great clinical and therapeutic importance in developing better diag
diseases nostic and therapeutic strategies and protocols. Though, the scientific
community has made a great progress in elucidating the roles of ncRNA
It has been now well accepted that cancer and its associated con in biology of cellular and biological homeostasis and diseases, there are
sequences can be well managed if diagnosed early and through proper numerous lacunas and opportunities in the signaling and disease pa
management of cancer progression and resistance. Role of nc-RNAs has thogenies which need to be addressed for better therapeutic and clinical
been critical not only in underlying mechanisms related to regulation of outcome and disease management. In addition, more studies need to be
cellular and biological homeostatic machinery, disease pathogenesis designed to explore the role of various recently discovered nc-RNAs
but also in various clinical aspects and hence nc-RNAs are the viable (circRNAs, piRNAs and snRNAs) in skin diseases and pathology, in
tools for understanding as well as for the diagnosis of human diseases. A cluding mechanistic studies to understand the association of nc-RNAs
number of studies show that nc-RNAs constitute a significant portion of with progression and metastasis so that further progress can be made in
the noncoding human genome and the aberrant/de-regulated expres disease diagnosis and therapy.
sion and function of ncRNAs play critical role in the pathogenesis of
human malignancies and hence can be used as biomarker as well as Declaration of competing interest
therapeutic target [13,16,17,31,142,145] . Furthermore, nc-RNAs work
in highly controlled interconnected regulatory machineries and any The authors declare that there are no conflicts of interest.
change or disturbance in the functioning of this network results in
cancer pathogenesis and related complications [280]. Acknowledgements
A number of nonclinical and clinical investigations converging to
wards the diagnostic and therapeutic importance of nc-RNAs are com This study was supported by National Priorities Research Project
pelling evidence suggesting the clinical importance of nc-RNAs in the (NPRP)11S-0117-180326 grant funded by Qatar National Research
management of human diseases [33,281–283]. Cutaneous diseases in Fund, Doha, Qatar; IRGC-04-SI-17-151, IRGC-04-NI-17-155 and MRC-
cluding malignancies and associated complications have been in 01-18-186, funded by Medical Research Center (MRC), Hamad Medical
creasing at an alarming rate and needs better diagnostic and ther Corporation, Doha, State of Qatar.
apeutic measures. Advent of the modern high throughput genetic and
molecular biology techniques has played very important role in un References
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Seminars in Cancer Biology xxx (xxxx) xxx–xxx

Contents lists available at ScienceDirect

Seminars in Cancer Biology

Role of non-coding RNAs in the progression and resistance of cutaneous

ARTICLE INFO ABSTRACT

Please cite this article as: , Seminars in Cancer Biology, https://doi.org/10.1016/j.semcancer.2020.07.003

1. Introduction of challenges associated with the disease pathogenesis and therapeutic

Table 1 provide only the most novel information on the topic.

Fig. 4. Non-coding RNA in cancer progression and drug resistance.

Fig. 5. Role of non-coding RNA in cutaneous autoimmune diseases.

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