Identification of miR-6794-3p as a suppressor in pancreatic cancer metastasis

Metastasis is a major cause of treatment failure in patients with pancreatic cancer, highlighting the urgent need for effective therapeutic strategies. Here, we focused on identifying novel miRNAs with key roles in metastasis of pancreatic cancer. Microarray analysis of miRNA expression in metastatic and non-metastatic pancreatic cancer samples revealed significantly lower expression of miR-6794-3p in the metastatic tumor group. Gain- and loss-of-function approaches using the pancreatic cancer cell lines MIA-PaCa-2 and HPAF-II expressing low and high levels of miR-6794-3p, respectively, indicated a role of miR-6794-3p in suppression of cell invasion, migration, and EMT signaling. Importantly, our results showed that miR-6794-3p exerts its effects by inhibiting expression of the chromatin remodeling factor, RBBP4. The resulting suppression of RBBP4 induced an increase in the levels of GRHL2 involved in regulating invasion, migration, and EMT signaling in metastatic pancreatic cancer cells. Consistent with these findings, low miR-6794-3p expression levels correlate with poor pancreatic cancer patient survival. Additional preclinical experiments on nude mice clearly demonstrated inhibitory effects of miR-6794-3p on pancreatic cancer cell metastasis. The collective results highlight the functional significance of miR-6794-3p as a suppressor of metastasis and support its predictive utility as a prognostic biomarker and therapeutic target in pancreatic cancer.