Abstract
Oral squamous cell carcinoma (OSCC), one of the most deadliest malignancies in the world, is caused primarily by areca nut chewing in Southeast Asia. The mechanisms by which areca nut participates in OSCC tumorigenesis are not well understood. In this study, we investigated the effects of low dose long-term arecoline (10 μg/mL, 90-days), a major areca nut alkaloid, on enhancement cancer stemness of human oral epithelial (OE) cells. OE cells with chronic arecoline exposure resulted in increased ALDH1 population, CD44 positivity, stemness-related transcription factors (Oct4, Nanog, and Sox2), epithelial-mesenchymal transdifferentiation (EMT) traits, chemoresistance, migration/invasiveness/anchorage independent growth and in vivo tumor growth as compared to their untreated controls. Mechanistically, ectopic miR-145 over-expression in chronic arecoline-exposed OE (AOE) cells inhibited the cancer stemness and xenografic. In AOE cells, luciferase reporter assays further revealed that miR-145 directly targets the 3′ UTR regions of Oct4 and Sox2 and overexpression of Sox2/Oct4 effectively reversed miR-145-regulated cancer stemness-associated phenomenas. Additionally, clinical results further revealed that Sox2 and Oct4 expression was inversely correlated with miR-145 in the tissues of areca quid chewing-associated OSCC patients. This study hence attempts to provide novel insight into areca nut-induced oral carcinogenesis and new intervention for the treatment of OSCC patients, especially in areca nut users.
Highlights
In spite of the recent advancements in the multidisciplinary treatment for oral squamous cell carcinoma (OSCC), Oral squamous cell carcinoma (OSCC) remains one of the leading causes of cancer-related mortality worldwide [1]
Recent studies have revealed that cancer stem cells (CSCs) or termed tumor initiating cells (TICs) with tumors could contribute to tumor maintenance, metastasis, radio-resistance and chemo-resistance in a variety of cancers, including OSCC [6,7,8,9,10,11]
Epidemiological analysis has demonstrated the majority of OSCC arise in Southeast Asia are due to areca nut chewing together with tobacco smoking [18]
Summary
In spite of the recent advancements in the multidisciplinary treatment for oral squamous cell carcinoma (OSCC), OSCC remains one of the leading causes of cancer-related mortality worldwide [1]. Extensive epidemiologic evidence have demonstrated increased risk for the development of OSCC associated with areca nut chewing in Southeast Asia [2, 3]. Mounting short-term assay studies have demonstrated that arecoline, a major areca nut alkaloid, contributes pathogenesis of OSCC [4, 5]. Recent studies have revealed that cancer stem cells (CSCs) or termed tumor initiating cells (TICs) with tumors could contribute to tumor maintenance, metastasis, radio-resistance and chemo-resistance in a variety of cancers, including OSCC [6,7,8,9,10,11]. The first connection of between CSCs and epithelialmesenchymal transdifferentiation (EMT), a dynamic process in which cells lose epithelial features and gain mesenchymal properties, is demonstrated in breast cancer stem cells model [12]. Understanding the relationships between areca nut and CSCs/EMT is important to improve further OSCC therapeutics
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