Human Cancer Biology A Tumorigenic Factor Interactome Connected through Tumor Suppressor MicroRNA-198 in Human Pancreatic Cancer

Purpose: The majority of pancreatic cancers overexpress mesothelin (MSLN), which contributes to enhanced proliferation, invasion, and migration. However, the MSLN regulatory network is still unclear. Here, we investigated the regulation of a panel of tumorigenic factors and explored the potential of MSLNregulated miR-198 treatment in vivo. Experimental Design: The expression and functional regulation of the tumorigenic factors MSLN, NFkB, and the homeobox transcription factors (TF) POU2F2 (OCT-2), Pre-B-cell leukemia homeobox factor 1 (PBX-1), valosin-containing protein (VCP), andmiR-198were studied inpancreatic cancer cell lines, patient tumor samples, and xenograft pancreatic cancer mouse models. Results: We found that miR-198 is downregulated in pancreatic cancer and is involved in an intricate reciprocal regulatory loop with MSLN, which represses miR-198 through NF-kB–mediated OCT-2 induction. Furthermore, miR-198 repression leads to overexpression of PBX-1 and VCP. The dysregulated PBX-1/ VCP axis leads to increased tumorigenicity. Reconstitution of miR-198 in pancreatic cancer cells results in reduced tumor growth, metastasis, and increased survival through direct targeting MSLN, PBX-1, and VCP. Most interestingly, reduced levels of miR-198 in human tissue samples are associated with upregulation of these tumorigenic factors (MSLN, OCT-2, PBX-1, VCP) and predict poor survival. Reduced miR-198 expression links this tumor network signature and prognosticates poor patient outcome. High miR-198 disrupts the network and predicts better prognosis and increased survival. Conclusions: miR-198 acts as a central tumor suppressor and modulates the molecular makeup of a critical interactome in pancreatic cancer, indicating a potential prognostic marker signature and the therapeutic potential of attacking this tumorigenic network through a central vantage point. Clin Cancer Res; 19(21); 5901–13. 2013 AACR.