Abstract 3357: Role of miRNA dynamics in governing cancer stem cell properties via CD44v6/Nanog/ PTEN axis in head and neck cancer: Modulating the master regulators
Authors: Patel Shanaya , Rawal. Dr. Rakesh 
Published: July 2016

Background:

Head and Neck Squamous cell carcinoma (HNSCC) is a major cause of morbidity and mortality worldwide. Late diagnosis, metastasis and therapeutic resistance are major confounders for the poor 5 year survival rate and are attributed to the existence of Cancer Stem Cells (CSCs). Several evidences have demonstrated the key role of nicotine in Tobacco related Cancers; however, the plausibility of nicotine modulating CSC markers still needs to be elucidated. Propelling evidences strongly suggest that HNSCC is a genetic disease, regulated by epigenetic mechanisms. Thus, understanding the role of miRNAs in regulation of CSCs and its contributions to improvise the prognostic and therapeutic implications is of great importance.

Methodology:

Orosphere was generated from primary habituated and non-habituated HNSCC tumors using CD44+ immunomagnetic cell separation and ex-vivo expansion. Characterization of these in-vitro models to evaluate spheroid formation ability and expression profile of CSC markers (CD44v3, CD44v6, BMI1 and Nanog) was carried out using quantitative Real Time PCR. Further, miRNA profiling of the upstream regulators (miR5423p, miR34a and miR21) was conducted in order to understand the miRNA mediated pathway that regulate these CSC features in tumor development, metastasis and response to chemotherapy. Correlation analysis of these miRNA profile along with the expression levels of its CSC target gene, were analyzed in specimens from patients with HNSCC.

Result:

Orosphere assay facilitated the propagation of CD44+ cells that retained CSC phenotype and self-renewal property. In-vitro model of habituated tumor showed an increased spheroid forming efficiency as compared to non-habituated models. In addition, these models showed higher expressions of CSC markers (CD44v3, CD44v6, Nanog & BMI1) and a significantly reduced expression of PTEN and ATM as compared to the healthy individual; however the habituated and non-habituated were found to have a trivial difference in their behavioral patterns. Furthermore, a significantly increased expression of upstream miRNA was observed which eventually leads to the modulation CD44 interaction with Nanog/PTEN, thus forming an unexplored axis which can have prognostic and therapeutic implications. Clinically, altered miRNA expression not only positively correlated with CSC expression patterns but also associated with increased progression of the disease.

Conclusion:

Collectively, this study indicates that miR5423p and miR34a targets the HA-induced CD44v6 -Nanog-PTEN axis playing a vital role in regulating the CSC properties comprising of self renewal, clonal proliferation and resistance to chemotherapy in Head and Neck Cancers. Furthermore, our results depict an undisputable role of these miRNA mediated pathways in the development of tobacco related carcinogenesis

Citation Format: Shanaya Patel, Dr. Rakesh Rawal. Role of miRNA dynamics in governing cancer stem cell properties via CD44v6/Nanog/ PTEN axis in head and neck cancer: Modulating the master regulators. [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 3357.