Abstract 4073: The potential role of oral mucosa stem cell altruistic behavior as the initiating event of malignant transformation

Oral cancer presents a major health burden across the globe, specially in developing countries. Kamrup, a district of India, where the KaviKrishna laboratory is located has the highest incidence of oral cancer in the entire world. The mechanism of oral cancer carcinogenesis process is not clearly known. Previous studies indicate the potential role of HPV-16 virus as well as tobacco consumption as major contributing factors of oral cancer. In mouse, the carcinogen agent 4-NQO was found to induce oral cancer having similar phenotype as human oral mucosa cancer. 4-NQO may exert tobacco like oxidative stress toxicity to oral mucosa. Hence, developing both in vitro and in vivo models of HPV-16 and 4-NQO mediated oral carcinogenesis might help to understand the initiating event of oral carcinogenesis. In this study, we propose that oral mucosa stem cells (OMSCs) could be the target of HPV-16, and 4-NQO induced carcinogensis. Thus, in vitro treatment of oral mucosa cells of healthy human volunteers with HPV-16 protein E6, and 4-NQO led to expansion of CD271+ cells, which are enriched in OMSCs. Importantly, the expanded CD271+ cells exhibited high HIF-2alpha, low p53, and high glutathione secretion, a phenotype of stem cell altruism that we recently described in human embryonic stem cells (Das B et al. Stem Cells, 2012). In human ES cells, the altruistic reprogramming served as an initiating event of malignant transformation by altering p53/MDM2 oscillation, in an abnormal state of low p53 and high MDM2. Therefore, we performed a complete evaluation of E6 protein and 4-NQO treated CD271+ oral mucosa cells for altruistic behavior, including low p53 and high MDM2 state. For this purpose, the carcinogen treated oral mucosa cells were subjected to immunomagnetic sorting for CD271+ cells. We found that post-carcinogen treated CD271+ cells exhibited in vitro self-renewal activity, high GSH secretion, and importantly activation of a HIF-2alpha/MYC co-operation. ChiP assay revealed the MYC binding to HIF-2alpha, and Sox-2, an stemness associated transcription factor. Importantly, HIF-2alpha was important for the reversible but prolonged suppression of p53 for more than two weeks. We also found that the high HIF-2alpha and low p53 expressing CD271+ cells could be enriched in a ABCG2+ population. Thus, we were able to enrich a CD271+/ABCG2+ cell population in oral mucosa cells of both human and mouse. Based on these findings we propose to use HPV-16 and 4NQO derived carcinogenesis models to study the potential role of altruistic reprogramming in the malignant transformation of oral mucosa stem cells to oral cancer stem cell like cells. Our study may unravel a novel mechanism of malignant transformation, the failure of altruistic stem cells to sacrifice its fitness (altruism) as a potential initiating event of malignant transformation of stem cells to cancer stem cells. Citation Format: Sukanya Gayan, Hong Li, Rashmi Bhuyan, Sora Sandhya, Joyeeta Talukdar, Bidisha Pal, Jaishree Garhyan, Wael Tasabehji, Manaf Muhammad Alkurdi, Heidar Zohrehei, Seema Bhuyan, Anupam Sarma, Gayatri Gogoi, A.C. Kataki, Rakesh Bhatnagar, Debabrata Baishya, Bikul Das. The potential role of oral mucosa stem cell altruistic behavior as the initiating event of malignant transformation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4073.