MicroRNA dysregulation has been shown to be nearly universal in cancer biology, driving oncogenic signaling networks. However, microRNA mediated global regulatory mechanisms underlying malignant phenotypes of head and neck squamous cell carcinoma (HNSCC) remain unclear. In this study, we have performed genome-wide small RNA sequencing on a panel of nine HNSCC cell lines and three normal primary oral keratinocyte cell lines, as well as matched primary tumor and normal tissues using the SOLiD parallel sequencing platform. A panel of microRNAs with altered expression was identified, including several novel oncogenic microRNAs which are upregulated in parallel with altered activation of NF-KB c-REL, TP53 family members ΔNp63α and TAp73, and potentially involved in the down-modulation of p53 and Notch1, two genes most often mutated or inactivated in HNSCC. To examine the hypothesis that these microRNAs could potentially be regulated by NF-KB and p53 pathways, NF-KB inducer TNF-α was used to treat an HNSCC cell line with high expression of mtTP53, ΔNp63α and TAp73. Genome-wide small RNA sequencing revealed significant changes in microRNA expression modulated by TNF-α that overlaps with the panel of constitutively dysregulated microRNAs in HNSCC. Furthermore, genome-wide ChIP-sequencing revealed that TNF-α modulated DNA binding activities of c-REL, ΔNp63α and TAp73 aligned within the regulatory regions of several differentially expressed microRNAs. Modulation of these microRNAs with anti-miR repression altered cell cycle and reduced proliferation in HNSCC cell lines, which confirmed the oncogenic activity of the microRNAs and their potential for therapeutic targeting.
Citation Format: Anthony D. Saleh, Han Si, Xingping Yang, Jamie Coupar, Zhong Chen, Carter Van Waes. Transcriptome sequencing identifies oncogenic microRNA signatures related to NF-kB, TP53 and Notch family members in head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3050. doi:10.1158/1538-7445.AM2013-3050
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.