Transcriptional downregulation of microRNA 199a-1 in the tumor microenvironment confers chemoresistance and stemness in ovarian cancer cells

The tumor microenvironment is actively involved in cancer progression and is becoming an attractive therapeutic target. It is increasingly clear that both biotic and abiotic factors in the microenvironment play a crucial role in disease progression. Using a three-dimensional microfluidic platform that mimics the peritoneum, we previously demonstrated that physiologically relevant shear-stress can induce chemoresistance and stemness in ovarian cancer cells. Importantly, this mechanical stimulus resulted in downregulation of microRNA (miR)199a-3p, suggesting a previously unknown mechanosensitive property of this miRNA. In testing other microenvironmental factors known to be involved in ovarian cancer progression in the regulation of miR-199a-3p, we found that hepatocyte growth factor (HGF), which is abundant in malignant ascites, could decrease miR-199a-3p expression in a similar manner to shear stress. Both shear stress and HGF induced this downregulation through a transcriptional regulation of primary mir-199a-1, but not primary mir-199a-2, via a PI3/Akt signaling pathway. Using metanalysis, there was also a decrease of miR-199a-3p in patients' tumor samples, and an increase of Akt in high-risk group. Moreover, ectopic overexpression of primary mir-199a-1 could sensitize ovarian cancer cells to cisplatin and reduce their ability to form multicellular spheroids, confirming a role for this miRNA in chemoresistance and stemness. Taken together, our findings suggest a causal involvement of downregulation of primary mir-199a-1, and ultimately its mature counterpart miR-199a-3p, in the tumor microenvironment mediated induction of stemness and chemoresistance, and represents a potential therapeutic target for the treatment of ovarian cancer (This work is supported by HMRF 05163536). ©2020 American Association for Cancer Research.