Human Head and Neck Squamous Cell Carcinoma (HNSCC) is a highly malignant cancer associated with major morbidity and mortality. In this study we determined that human HNSCC-derived HSC-3 cells contain a subpopulation of cancer stem cells (CSCs) characterized by a high levels of CD44v3 and aldehyde dehydrogenase-1 (ALDH1) expression. These tumor cells also express several stem cell markers (the transcription factors-Oct4, Sox2 and Nanog) and display the hallmark CSC properties of self-renewal/clonal formation and the ability to generate heterogeneous cell populations.

Importantly, hyaluronan (HA) stimulates the CD44v3 (an HA receptor) interaction with Oct4/Sox2/Nanog leading to both a complex formation and the nuclear translocation of three CSC transcription factors. Further analysis reveals that microRNA-302 (miR-302) is controlled by an upstream promoter containing Oct4/Sox2/Nanog binding sites, while chromatin immunoprecipitation (ChIP) assays demonstrate that stimulation of miR-302 expression by HA/CD44 is Oct4/Sox2/Nanog-dependent in HNSCC-specific CSCs. This process results in suppression of several epigenetic regulators (AOF1/AOF2 and DNMT1) and the upregulation of several survival proteins (cIAP-1, cIAP-2 and XIAP) leading to self-renewal, clonal formation and cisplatin resistance. These CSCs were transfected with a specific anti-miR-302 inhibitor in order to silence miR-302 expression and block its target functions. Our results demonstrate that the anti-miR-302 inhibitor not only enhances the expression of AOF1/AOF2 and DNMT1, but also abrogates the production of cIAP-1, cIAP-2 and XIAP and HA/CD44v3-mediated cancer stem cell functions. Taken together, these findings strongly support the contention that the HA-induced CD44v3 interaction with Oct4/Sox2/Nanog signaling plays a pivotal role in miR-302 production leading to AOF1/AOF2/DNMT1 downregulation and survival protein activation. All of these events are critically important for the acquisition of cancer stem cell properties including self-renewal, clonal formation and chemotherapy resistance in HA/CD44v3-activated head and neck cancer.

Note: This abstract was not presented at the meeting.

Citation Format: Lilly Y W Bourguignon, Gabriel Wong, Christine Earle. Hyaluronan-CD44v3 interaction with oct4/sox2/nanog promotes miR-302 expression leading to self-renewal, clonal formation and cisplatin resistance in cancer stem cells from head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3861. doi:10.1158/1538-7445.AM2014-3861