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Clin Cancer Res. 2013 Nov 1;19(21):5901-13. doi: 10.1158/1078-0432.CCR-12-3776. Epub 2013 Aug 29.

A tumorigenic factor interactome connected through tumor suppressor microRNA-198 in human pancreatic cancer.

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1
Authors' Affiliations: Molecular Surgeon Research Center, Michael E. DeBakey Department of Surgery, Department of Molecular Virology and Microbiology, Duncan Cancer Center, Baylor College of Medicine; and Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan; Center for Translational Research on Inflammatory Diseases, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas.

Abstract

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 MSLN-regulated miR-198 treatment in vivo.

EXPERIMENTAL DESIGN:

The expression and functional regulation of the tumorigenic factors MSLN, NF-κB, and the homeobox transcription factors (TF) POU2F2 (OCT-2), Pre-B-cell leukemia homeobox factor 1 (PBX-1), valosin-containing protein (VCP), and miR-198 were studied in pancreatic 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-κB-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.

PMID:
23989979
PMCID:
PMC3920728
DOI:
10.1158/1078-0432.CCR-12-3776
[Indexed for MEDLINE]
Free PMC Article

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