Abstract 455: Identification of hsa-miR-6794-3p as a key regulatory factor in human pancreatic cancer metastasis

Abstract Metastasis is a major factor in treatment failure in patients with pancreatic cancer, but the underlying mechanisms remain unclear, and new, effective treatment strategies are needed. Here, we sought to identify novel microRNAs (miRNAs) with a key role in pancreatic cancer metastasis. Using a microarray analysis to evaluate miRNA expression in metastatic and non-metastatic pancreatic cancer, we found that expression of the miRNA, hsa-miR-6794-3p, was significantly lower in metastatic pancreatic cancer tissues than in non-metastatic pancreatic cancer tissues. Methylation-specific polymerase chain reaction analyses revealed that hsa-miR-6794-3p expression was downregulated in metastatic pancreatic cancer cells by hypermethylation of CpG islands within the hsa-miR-6794-3p promoter. Gain- and loss-of-function approaches using the human pancreatic cancer cell lines, MIA-PaCa-2 and HPAF-II, expressing low and high levels of hsa-miR-6794-3p, respectively, suggested a role for hsa-miR-6794-3p in decreasing cell invasion, migration, and epithelial-mesenchymal transition (EMT) signaling. Notably, we found that hsa-miR-6794-3p exerts its effects by inhibiting expression of the chromatin remodeling factor, RBBP4, through direct binding to the 3’-untranslated region of its mRNA. The resulting suppression of RBBP4 expression increases levels of the transcription factor GRHL2, which is involved in regulating invasion, migration, and EMT signaling in metastatic pancreatic cancer cells. Thus, lower levels of hsa-miR-6794-3p disrupt GRHL2-mediated regulation of these pathways by disinhibiting expression of the GRHL2 negative regulator, RBBP4. Consistent with these findings, an investigation of the relationship between hsa-miR-6794-3p and clinicopathological features in pancreatic cancer patients using publicly available datasets and immunohistochemistry showed that low levels of hsa-miR-6794-3p are correlated with a poorer prognosis in pancreatic cancer patients. Additional preclinical experiments in nude mice clearly demonstrated that hsa-miR-6794-3p is capable of suppressing pancreatic cancer cell metastasis. Taken together, these results suggest that hsa-miR-6794-3p suppresses tumor metastasis and thus represents a promising prognostic biomarker and therapeutic target in pancreatic cancer. Citation Format: Ha Gyeong Kim, Eun-Taex Oh, Yunmi Cho, Heon Joo Park. Identification of hsa-miR-6794-3p as a key regulatory factor in human pancreatic cancer metastasis abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 455.