| Summary: | 博士 === 國防醫學院 === 醫學科學研究所 === 105 === Epigenetic changes of head and neck cancer may illuminate its pathogenic roots. Through gene set enrichment analysis, we found that the oncogenic transcription factor, RUNX2, belongs to the osteoblast differentiation pathway and is widely upregulated in head and neck squamous cell carcinoma (HNSCC) with lymph node metastasis and cell proliferation. The presence of oncogenic RUNX2 also predicts poor prognosis in HNSCC patients. Enforced expression of ectopic RUNX2 promoted the cancer progression of HNSCC, whereas silencing RUNX2 impedes progression. Investigating its mechanism, showed that manipulating levels of activin A (INHBA) and autocrine ligands, Parathyroid Hormone-Like Hormone (PTHLH) could rescue or compromise the RUNX2-mediated metastatic or proliferation abilities of HNSCC cells. In addition, an up-stream regulator of RUNX2, WNT-7B, acts as an activator of the WNT-β-catenin pathway, thereby enhancing the WNT-β-catenin signaling pathway in HNSCC and promoting cancer progression. Taken together, the osteoblast differentiation pathway may be crucial in the HNSCC tumorigenesis and progression. Further, miR-376c-3p, encoded in the 3'-untranslated region (3’-UTR) of RUNX2, and miR-329 and miR-410 in the WNT-7B 3’-UTR all played a pivotal role in regulating the osteoblast differentiation pathway in highly malignant HNSCC cells. miR-376c, miR-329 and miR-410 are mapped to chromosome 14q32.2 miRNA cluster region, which resides within a parentally imprinted region designated as Dlk-Dio3 and known to be important in development and growth. Epigenetic silencing of 14q32.2 miRNA cluster due to the betel nut alkaloid, arecoline, increases DNA methylation on the DLK1-MEG3 intergenic differentially methylated region and silences the miRNAs expression. Restoring miRNA expression in this setting suppressed expression of RUNX2/INHBA axis or WNT-β- catenin pathway along with the cancer progression ability. Clinically, inverse relationships exist between miR376c-3p expression and the RUNX2/INHBA axis, and miR-329 and miR-410 expression and WNT-7B level in HNSCC specimens and tumor samples. In summary, this thesis propose a novel role of osteoblast differentiation pathway including the dysregulation of the RUNX2/INHBA-PTHLH axis and WNT-β-catenin pathway due to miRNAs downregulation foster cancer progression in HNSCC.
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