Journal of Cancer 2019, Vol.

10 4054

Ivyspring
International Publisher
Journal of Cancer
2019; 10(17): 4054-4062. doi: 10.7150/jca.29765
Review

Multifaceted Mechanisms of Areca Nuts in Oral

Carcinogenesis: the Molecular Pathology from
Precancerous Condition to Malignant Transformation
Yi-Chen Li1*, Ann-Joy Cheng2,3*, Li-Yu Lee4, Yu-Chen Huang5, Joseph Tung-Chieh Chang3,6,
1. Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine,
Kaohsiung 833, Taiwan.
2. Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
3. Department of Radiation Oncology, Chang Gung Memorial Hospital-Linkou, Taoyuan 333, Taiwan
4. Department of Pathology, Chang Gung Memorial Hospital-Linkou, Taoyuan 333, Taiwan
5. Department of Oral Maxillofacial Surgery, Chang Gung Memorial Hospital-Linkou, Taoyuan 333, Taiwan
6. Department of Radiation Oncology, Xiamen Chang Gung Memorial Hospital, Xiamen, Fujian, China

*First and second authors contributed equally

 Corresponding author: Joseph T Chang, Professor, Department of Radiation Oncology, Chang Gung Memorial Hospital-Linkou, Taoyuan 333, Taiwan. Fax:
886-3-2118247; E-mail: [email protected]

© The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/).
See http://ivyspring.com/terms for full terms and conditions.

Received: 2018.09.06; Accepted: 2019.03.29; Published: 2019.07.08

Abstract
Oral cancer is one of the most frequent malignant diseases worldwide, and areca nut is a primary
carcinogen causing this cancer in Southeast Asia. It has been widely reported that areca nut induced
several cytotoxic effects in oral cells, including ROS generation, inflammation, tissue hypoxia, DNA
damage, and cell invasion. Recently, through chronic exposure model, more extensive pathological
effects due to areca nut have been found. These include the induction of autophagy, promotion of
epithelial- mesenchymal transition, and facilitation of cancer stemness conversion. Clinical findings
support these adverse effects. Oral submucosal fibrosis, a premalignant condition, is prevalent in the
area with habitual chewing of areca nuts. Consistently, oral cancer patients with habitual chewing
areca nut exhibit more aggressive phenotypes, including resistance to chemo-radiotherapy. In this
review, we comprehensively discuss and concisely summarize the up-to-date molecular and cellular
mechanisms by which areca nuts contribute to malignant transformation. This review may provide
critical information regarding clinical applications in risk assessment, disease prevention, diagnosis,
and personalized therapeutics for areca nut-induced oral malignancy.
Key words: areca nut, oral cancer, oral submucosal fibrosis, reactive oxygen species, tissue hypoxia, cell invasion,
epithelial-mesenchymal transition, cancer stemness

1. Introduction
Oral cancer, including the common squamous differ in different geographical regions. Cancers of the
cell carcinomas of the oral cavity and oropharynx, is tongue and buccal mucosa constitute the majority of
the sixth most frequent cancer worldwide [1, 2]. The oral cancers in India and Southeast Asia [1-4]. In
disease is more prevalent among males than females contrast, the western regions show that cancers of the
[1, 2]. Epidemiologic studies have shown wide mouth floor are the most frequent, with cancer of the
variations in its incidence in different geographical gums or tongue being rare [1-4]. Apparently, oral
areas. Oral cancer is highly prevalent in Southeast cancer also shows various clinicopathological features
Asia, comprising 35-40% of all malignancies in India, in different global regions.
compared to approximately 9% in Taiwan and 2-4% in The association of carcinogen exposure with oral
western countries [1-4]. The tumor sites of this disease cancer has been reported [3-5]. Carcinogens include

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habitual alcohol consumption, areca nut chewing, and benz(a)anthracene (DMBA)- induced tumor
cigarette smoking. Cigarette smoking and alcohol formation in the cheek pouch of hamster [15].
consumption are common habits in oral cancer Similarly, combinational exposure of arecoline and
patients in western countries. Cigarette smoking may 4-nitroquinoline-1-oxide (4-NQO) induces oral
render a significant carcinogenic effect on the upper cancerous lesions in C57BL/6JNarl mice [11, 16]. Since
aerodigestive tract, including oral areas [3-5]. Areca the carcinogenic effect of areca nuts has become more
nut chewing is a common habit among oral cancer visible, in 1992, the International Agency for Research
patients in Southeast Asia, indicating a close link of on Cancer (IARC) announced that areca nut chewing
this habit with the specific disease. In Taiwan, for combined with cigarette smoking is a human
example, approximately 85% of all oral cancer carcinogen. In 2004, IARC announced that the areca
patients are associated with this habit [3, 4]. It has nut itself is a human carcinogen [17].
been shown that areca nut chewers have a much
greater risk of developing oral cancer than 2.2 Oral submucosal fibrosis is a common
nonchewers [3-6]. Furthermore, the 5-year survival premalignant disorder induced by areca nut
rate of oral cancer patients who chew areca nuts is chewing
much lower than that of those who do not chew these The carcinogenesis of oral cancer is a
nuts [7, 8]. Therefore, the distinct clinicopathological multiple-step progressive process [6]. It is started
characteristics of oral cancer in global regions may from normal epithelial cells, gradually evolving to
result from different environmental carcinogenic premalignant lesions. After malignant transformation,
exposures in addition to genetic factors. In this paper, these cells eventually become aggressive types of
we comprehensively review and concisely summarize cancers. Clinically, the premalignant oral disorders
recent reports of the molecular and cellular effects of can be classified by distinct pathological features.
areca nuts that lead to the development of oral cancer. These include hyperkeratosis, dysplasia, leukoplakia,
erythroplakia, and fibrosis. Among these, leukoplakia
2. Molecular pathology of areca nut is the most common disorder, while erythroplakia
although rare, is more serious [18]. Both leukoplakia
2.1 Areca nuts are a primary carcinogen in and erythroplakia are considered as premalignant
Southeast Asia, with several active lesions [18]. Oral submucosal fibrosis is a chronic
components progressive process, presenting an inflammatory
Areca nuts have been one of the most commonly fibrosis in oral mucosa stroma, being considered as
used psychoactive substances for a century, especially premalignant condition [19-21]. This disorder is
in Southeast Asia. For better chewing flavor in using, prevalent in India and Southeast Asia, a common
areca nuts are usually covered with piper betel leaves premalignant condition caused by prolonged areca
or inflorescence to form betel quids [3, 4]. Areca nut nut chewing [18-22]. Approximately 18% of the
extract is composed of saccharides (26-47%), premalignant oral lesions will develop into squamous
polyphenols (11-26%), fats (1.3-17%), various cell carcinoma [3]. Transformation of oral submucosal
alkaloids (0.15-0.67%), and some crude fiber and rare fibrosis may be variable, begin estimated between 2%
tannins [4-6]. Although alkaloids constitute only a few to 8% and up to 13% [20-22].
percent of all components, they are the most active The pathological effect of areca nut contributing
ingredients associated with pathological to oral submucosal fibrosis is supported by several
development. Arecoline is the most abundant lines of studies. In a mouse model, the subcutaneous
alkaloid, and it can be converted to arecaidine by injection of areca nut extract-induced skin lesions and
salivary enzymes [4,6]. These alkaloids are converted fibrosis [11]. This is accompanied with the expression
to nitroso-derivatives, the primary inducers of oral of fibrotic marker proteins including alpha-smooth
mucosal lesions [4,6]. muscle actin (α-SMA) and connective tissue growth
In the past few decades, accumulated studies factor. In a cellular study, treatment of oral
have demonstrated that areca nuts can induce keratinocytes with arecoline upregulated the
premalignant and malignant transformation of oral expression of αvβ6 integrin and α-SMA to promote
tissues. In animal model studies, areca nut extract (or the formation of submucosal fibrosis [23, 24].
the ingredient cocktail) can be an effective tumor Treatment of fibroblast cells with areca nut extract
initiator or promoter and can induce premalignant also induced cell contraction mediated by several
oral lesions, including submucosal fibrosis [9, 10] and signaling pathways, including the JNK/ATF2/Jun
squamous hyperplasia [11-13], or result in malignant axis, Ca2+/calmodulin axis, and Rho protein
transformation [13-16]. For example, arecaidine activation, leading to actin filament polymerization
displays a synergistic effect in the 7,12-dimethyl- [23, 25].

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The accumulation of collagen is a notable inflammatory responses and upregulates several

pathological alteration in the patients with oral cytokines, including NF-kB, Cox-2, PGE2, TGM2, and
submucosal fibrosis [26]. In fibroblast cells, arecoline IL-1 [40]. Similarly, in fibroblasts and keratinocytes,
increased collagen expression by 1.5-fold [27], and areca nut extract or arecoline triggers ROS generation
this might result from elevating TIMP-1 and and induces tumor promoting mediators or oncogenic
inhibiting gelatinase A activity [28]. Other areca nut signaling pathways, including IL-6, TGF-b, EGFR,
components, such as flavonoids, catechins and ERK and Ras [36, 41-43]. The different cytokines or
tannins, facilitate the crosslinking of collagen fibers, signaling pathways in response to areca nut treatment
resulting a decreased susceptibility to collagenase may be cell type-specific. Clinically, the inflammation
[29]. Increases in transforming growth factor β1 associated cells are increased in the surrounding
(TGF-β1) during areca nut-induced oral submucosal tissues of oral submucosal fibrosis and oral cancers in
fibrosis has also been observed in many studies [10, the patients from areca nut chewing prevalent area
23, 30]. In the condition of submucous fibrosis, TGF-β [44]. In summary, areca nut extract may increase ROS
plays a critical role in regulating the degradation of levels, which facilitate cellular inflammation and
the extracellular matrix, including collagen [31]. tumor progression via multiple molecular regulators.
Consistently, it has been shown that arecoline
augments collagen levels through the TGF-β pathway 2.4 Areca nuts may elicit genotoxicity, growth
in keratinocytes [32]. In summary, the areca nut arrest, and apoptosis
promotes oral fibrosis by increasing collagen Many studies have demonstrated that areca nut
production, which may occur by various mechanisms, extract exerts multiple cellular effects. Genotoxicity
including reduction of degradation by proteinase and can be caused by areca nut exposure. The alkaloids of
activation of the TGF-β regulatory pathway. the areca nut are the major contributing factors to
The malignant transformation from oral genotoxicity [6]. In oral keratinocytes or epithelial
submucosal fibrosis to squamous carcinoma involves cells, areca nut extract or arecoline can induce genetic
multifactorial mechanisms. These include damage, including hyperdiploid chromosomal
inflammation, genotoxicity, cytotoxicity, autophagy, changes [45-47]. These DNA damage effects are
tissue hypoxia, and epithelial-mesenchymal transition associated with the inhibition of DNA repair
(EMT), as discussed respectively in the following mechanism, such as impairing p53 function [46, 47]. In
sections. a mouse model study, arecadine increased the
frequency of sister chromatid exchanges during
2.3 Chewing areca nuts increases ROS levels mitosis [48]. In a transgenic mouse study, arecoline
and induces inflammation increased the frequency of mutations at DNA G:C
Reactive oxygen species (ROS) are chemically sites in oral tissue cells [49]. These genotoxic results
reactive chemical species containing oxygen that can are consistent with clinical findings in betel quid
be generated during mitochondrial oxidative chewers. In the oral mucosal cells, the levels of
metabolism. chromosome damage, such as cytokinesis-block
Under environmental stress, cellular ROS levels micronucleus, chromatid breaks or DNA strand
can become dramatically elevated and directly cause exchanges, are positively correlated with habitual
significant damage to cell structures at DNA, protein, areca nut chewing in oral cancer patients [50-52]. Note
or lipid levels [33]. Many studies have demonstrated that these cytogenetic alterations are less frequently
that areca nuts can stimulate cellular ROS levels [34]. observed in oral cancer patients who chew tobacco
The mechanisms include the enhancement of ROS [51, 52].
generation by mitochondrial metabolizing enzymes, Areca nuts may cause cytotoxicity in various
such as cytochrome P450s (CYPs) [35], by the NADPH types of human tissues and result in growth arrest,
oxidase enzymes NOX-1 and NOX-4 [36], and the cellular senescence or apoptosis. In oral endothelial
inhibition of antioxidant systems by the suppression cells, arecoline induces G2/M cell cycle arrest and
of superoxide dismutase activities [37, 38]. increases the sub-G0/G1 population, suggesting
The induction of ROS by areca nut extract has causal links among endothelial damage, vascularity
been further shown to act as a molecular signal to reduction, and the pathogenesis of oral submucosal
elicit redox-related inflammation or signaling fibrosis [53, 54]. Similarly, in oral keratinocytes,
pathways in many types of cells. For example, in epithelial cells, or neutrophils, areca nut ingredients
endothelial cells, arecoline stimulates ROS production or arecoline may contribute to G1/S cell cycle arrest,
to suppress the expression of the cytoprotective cellular senescence or apoptosis [37, 42, 55-59]. These
enzyme hemeoxygenase-1 [39]. In lymphocytic cells, effects may be caused by the activation of various
areca nut extract elicits oxidative stress and signaling pathways, including Chk1/Chk2,

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MEK/ERK or AKT associated pathways [42, 59]. The mechanisms, such as ROS generation, autophagy
different cytotoxic effects and molecular pathways in formation, and tumor suppressor inhibition.
response to areca nut stimulation may be dependent
on specific cell types or the differential 2.6 Area nuts may induce tissue hypoxia to
microenvironmental factors. In all, growth inhibition promote malignant transformation
or cell suicide may be the optimal cellular defense Hypoxia is a low oxygen stress condition in
mechanism to avoid further catastrophe of malignant tissue microenvironment, giving rise to altered
transformation. cellular metabolism and triggers various
pathophysiological responses [69]. This condition
2.5 Areca nuts may induce autophagy and may be associated with the cellular oxidative stress
inhibit tumor suppressors [65, 69], and induce anaerobic respiratory pathway via
Although areca nut ingredients may lead to up-regulations of hypoxia inducing factor (HIF),
growth arrest and cell apoptosis, prolonged treatment glucose transporter (GLUT), or lactate dehydrogenase
with areca nut extract or arecoline may further [70-72]. Currently, hypoxia has been shown as an
facilitate malignant transformation. This is important underlying factor to promote
presumably via the induction of cellular autophagy or tumorigenesis and cancer progression. It may incite
the inhibition of tumor suppressors. Autophagy is a several cellular mechanisms including autophagy,
process by which cells degrade unnecessary angiogenesis, epithelial to mesenchymal transition,
organelles and recycle intracellular proteins to ensure cancer stemness, and lead to therapeutic resistance
survival in adverse environments. Although [73-74]. For examples, in oral submucous fibrosis, the
autophagy may play dual roles in carcinogenesis, in tissue hypoxia resulted from vascular construction
most contexts, it promotes tumorigenesis [60]. The may further facilitate malignant transformation
premalignant submucous fibrotic tissue or cancer cells [20-22, 71]. Tissue hypoxia may further trigger EMT
may upregulate autophagy to survive process via up-regulation of several transcriptional
microenvironmental stress and become more factors, such as Snail and Twist1, to promote tumor
aggressive [4, 61]. Recent reports have shown that progression [75-76]. In cancer cells, the induction of
areca nut extract may induce autophagy via several HIF-1α molecule in the adaptation of hypoxic
pathways. For example, areca nut ingredients may be condition may elite angiogenic pathway via
engulfed by oral cancer cells via clathrin-mediated up-regulation of vascular endothelial growth factor
endocytosis to initiate an autophagy program [62]. (VEGF) [77]. Hypoxic condition in tumor
The other autophagy associated mechanisms, such as microenvironment may also lead to therapeutic
the LC3-II transition, Beclin-1 or Atg5 accumulation, resistance by activation of stemness associated
and autophagosome formation, have also been pathways, including Oct3/4, Sox2, and AKT/Notch1
demonstrated in oral cancer cells treated with areca molecular signals [78, 79].
nut extract [62-64]. The contribution of areca nut The hypoxia inducing factor-1 (HIF-1) is a
extract to autophagy may be explained by ROS predominant regulatory molecule induced by
generation or hypoxic condition in cancer cells, hypoxia tissue and emerges to malignant function [72,
following the stimulation by various signaling 73, 77]. Recent reports have shown that areca nut
pathways of PI3/AKT, MEK/ERK, AMPK/mTOR, or causative to oral malignancy may associate with the
HIF-1α [63, 65-66]. Clinically, higher LC3 expression hypoxic condition through the induction of HIF-1. In
and poorer prognoses are found in advanced oral either oral fibroblast or oral cancer cells, arecoline
cancer patients who habitually chew areca nuts [66]. may increase HIF-1α gene expression with a
In addition to autophagy induction, areca nuts dose-dependent manner [80, 81]. In oral cancer cells,
may inhibit tumor suppressor molecules to promote treatment of areca nut extract may induce ROS
malignant transformation. It has been demonstrated generation and up-regulate HIF-1α, which may
that areca nut extract or arecoline may inhibit the further lead to autophagy to benefit cell survival [65].
expression of cell cycle checkpoint suppressors, The prolong treatment of areca nut extract in oral
including p53, p21, p27, and Ches1, which may enable cancer cells results to a stronger tolerance in hypoxic
cell cycle progression with error-prone DNA condition via acquisition of autophagy and leads to
replication [46, 67, 68]. Clinical findings also support chemoresistance [82]. Consistently, under a stress
this concept. The reduced expression of the Ches1 condition, areca nut extract induced VEGF expression
suppressor has been found in oral cancer patients in oral cancer cells, suggesting the mechanism of areca
with the areca nut chewing habit [67]. In summary, nut contributes to angiogenesis and cancer metastasis
the areca nut may contribute to cellular [83]. Clinically, higher levels of HIF-1α and PAI-1
transformation by activating cellular stress response have been found in the tissues of oral submucosa

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fibrosis or oral cancer cells compared to the normal associated transcription factors ZEB1, Twist, and Slug
mucosa [81, 84]. In summary, areca nut may incite [98-100]. This fibrotic activity was found
tissue hypoxia to promote malignant transformation accompanying with collagen gel contraction, increase
via multiple mechanisms. of marker protein expression (α-SMA), and elevation
of migration capability [99, 100]. Similarly, in gingival
2.7 Areca nuts may promote cell motility and fibroblasts or epithelial cells, areca nut stimulates
epithelial–mesenchymal transition fibrotic activation, preassembly through induction of
Cell motility is an important characteristic of the EMT process via TGF-β signaling pathways [23, 101,
malignancy response for cancer invasion and 102]. Consistently, in either oral keratinocytes or
metastasis. In cells, the matrix metalloproteinases cancer cells, areca nut facilitates EMT process, as
(MMPs) constitute a family of proteinases that shown by the increases of mesenchymal markers
degrade the extracellular matrix to accelerate cellular (N-cadherin, vimentin) and decreases of epithelial
motility and invasion, whereas the tissue inhibitors of markers (E-cadherin, involucrin), via activating the
the metalloproteinases (TIMP) counteract this PI3/AKT pathway [103, 104]. In oral epithelial or
enzymatic activity. The areca nut contributes to oral cancer cells, chronic or long-term treatment of areca
malignancy by promoting cell motility as well. It has nut extract facilitates mesenchymal
been widely reported that treatment with areca nut trans-differentiation, along with the induction of
extract or arecoline can increase cellular migration, multiple EMT associated transcription factors,
invasion or anchorage-independent growth in oral including ZEB1, Snail, Slug, Twist, FOXC2, and Grp78
cancer cells, normal epithelial cells and fibroblast cells [86, 105, 106]. Furthermore, a keratin family member,
[85-91]. This response may result from the elicitation Krt-17, was found to be upregulated by areca nut
of MMP activities, including MMP-1 [80, 91], MMP-2 extract to facilitate cell motility and malignant
[81, 90], MMP-8 [85], and MMP-9 [59, 88, 89], and the transformation via EMT conversion in a mouse model
suppression of TIMP functions [59, 92]. Multiple study [11]. Clinically, the expression of EMT
molecular signaling pathways, such as PI3K, p38 associated factor Slug has been found up-regulated in
MAPK, Erk1/2, and NF-kB may be involved in the oral fibroblastic tissues and associated with various
modulation of MMP and TIMP expression [87, 88, 93] myofibroblast markers, such as α-SMA [99, 100]. The
and may through the muscarinic M4 receptor [93]. loss of E-cadherin expression and augmentation of
Clinical findings support this cell motility mechanism. Krt-17 or EMT-associated transcription factors have
High levels of MMP-1 or MMP-9 are found in the also been shown to be significantly associated with
cancer tissues or saliva specimen of oral cancer oral cancer in patients who habitually chewed betel
patients who chewed betel nuts [85, 86, 93]. quid [11, 86, 107].
Apparently, the areca nut promotes cell motility
through MMP activation, although different MMP 2.8 Areca nuts may facilitate
proteins may respond differentially in different chemo-radioresistance and cancer stemness
individuals. conversion
The epithelial–mesenchymal transition (EMT) Chemotherapy and radiotherapy are integral
plays an important role in cell motility conversion parts of the treatment for oral cancer. However, local
leading to cancer aggressiveness [94-97]. The EMT recurrence after radio-chemotherapy is a major cause
confers tumor plasticity by transforming epithelial of therapeutic failure. Although areca nuts may elicit
cells into spindle-like fibroblastic mesenchymal cells genotoxicity leading to cell death, recent studies
via functional loss of cell adhesion and the acquisition showed that chronic areca nut exposure may
of migratory properties [94, 95]. This process involves eventually result in chemo- and radio-resistance. In
disassembling cell-cell and cell-matrix junctions by oral cancer cells or normal keratinocytes, long-term
downregulating epithelial markers (such as exposure to arecoline or areca nut extract resulted in
E-cadherin) and upregulating mesenchymal markers higher tolerance to cisplatin or fluorouracil [82, 86,
(such as N-cadherin) [94, 95]. It may be induced by 105]. This areca nut-induced drug resistance may be
several EMT/stemness associated transcription attributed to overexpression of the ABCG2 protein, a
factors, allowing cells to gain stemness-related well-known drug efflux pump in cancer cells [86].
properties and create a pro-tumorigenic setting [96, Consistent with these reports, oral cancer cells
97]. Recent studies show that areca nut extract may chronically exposed to areca nut extract exhibited
induce oral fibrogenesis and carcinogenesis through greater resistance to irradiation [86]. This survival
EMT process. In buccal mucosa fibroblasts, areca nut advantage is accompanied by the reduction of ROS
extract or arecoline induces fibroblast production by the elevation of the scavenger enzymes
trans-differentiation, which may be mediated by EMT GCLC and GCLM [86]. Similarly, in keratinocytes,

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treatment with sublethal doses of arecoline although comprise a small fraction within a tumor,
upregulated the expression of multiple antioxidant possess a strong malignant potential, with
enzymes, including G6PD, GCLC and glutathione self-renewal ability, stress tolerance, and high
reductase [108]. Clinically, the habitual use of areca mobility, which results in aggressive cancer
nuts is an independent prognostic factor of poor phenotypes and resistance to chemo-radiotherapy
survival of oral cancer patients receiving induction [110-112]. These types of stem-like cells are often
chemotherapy with docetaxel, cisplatin, or characterized by specific surface proteins, such as
fluorouracil [8, 109]. The ERCC1 molecule, a critical CD44, CD133 and ALDH1, in oral cancer tissues [86,
DNA repair gene associated with chemoresistance, is 113, 114]. Recent reports provide new insights that
up-regulated in oral cancer patients in the areca nut areca nuts may play a role in cancer stemness
prevalent area [109]. Similarly, oral cancer patients conversion. In oral cancer cells or normal
who chew areca nuts habitually exhibit higher keratinocytes, chronic areca nut exposure or
incidences of local recurrence [7]. Thus, chronic long-term arecoline treatment facilitates the cancer
exposure to areca nuts facilitates stemness conversion. These were demonstrated by the
chemo-radioresistance, which may due to the enhanced spheroid cell formation and enriched
activation of cellular defense mechanisms to minimize subpopulations of CD24-/CD44+, CD133+, and
the toxic damage in malignant transformed cells. ALDH1+ cells [86, 105]. Furthermore, these chronic
A cancer stem cell (CSC) model has been recently areca nut exposures exerted a pluripotent effect to
proposed to explain tumor heterogeneity. These cells, upregulate several stemness mediators, including

Figure 1. Multifaceted mechanisms of areca nuts in oral carcinogenesis: the molecular pathology from precancerous lesions to malignant transformation. ROS: Reactive oxygen
species. EMT: Epithelial–mesenchymal transition.

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Grp78, Slug, Snail, Oct4, Nanog, and Sox2 [86, 105]. Competing Interests
This phenomenon is confirmed in clinical
The authors have declared that no competing
investigations. Oral cancer patients who habitually
interest exists.
chewed areca nuts exhibited high levels of stemness
regulators, such as Grp78 and snail, which was References
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