MEIS1 and MEIS2 expression and prostate cancer progression: A role for HOXB13 binding partners in metastatic disease

Raj R. Bhanvadia, Calvin Van Opstall, Hannah Brechka, Nimrod S. Barashi, Marc Gillard, Erin M. McAuley, Juan Manuel Vasquez, Gladell Paner, Wen Ching Chan, Jorge Andrade, Angelo Michael Demarzo, Misop Han, Russell Z. Szmulewitz, Donald J. Vander Griend

Research output: Contribution to journalArticle

Abstract

Purpose: Germline mutations within the MEIS-interaction domain of HOXB13 have implicated a critical function for MEIS-HOX interactions in prostate cancer etiology and progression. The functional and predictive role of changes in MEIS expression within prostate tumor progression, however, remain largely unexplored. Experimental Design: Here we utilize RNA expression datasets, annotated tissue microarrays, and cell-based functional assays to investigate the role of MEIS1 and MEIS2 in prostate cancer and metastatic progression. Results: These analyses demonstrate a stepwise decrease in the expression of both MEIS1 and MEIS2 from benign epithelia, to primary tumor, to metastatic tissues. Positive expression of MEIS proteins in primary tumors, however, is associated with a lower hazard of clinical metastasis (HR= 0.28) after multivariable analysis. Pathway and gene set enrichment analyses identified MEIS-associated networks involved in cMYC signaling, cellular proliferation, motility, and local tumor environment. Depletion of MEIS1 and MEIS2 resulted in increased tumor growth over time in vivo, and decreased MEIS expression in both patient-derived tumors and MEISdepleted cell lines was associated with increased expression of the protumorigenic genes cMYC and CD142, and decreased expression of AXIN2, FN1, ROCK1, SERPINE2, SNAI2, and TGFβ2. Conclusions: These data implicate a functional role for MEIS proteins in regulating cancer progression, and support a hypothesis whereby tumor expression of MEIS1 and MEIS2 expression confers a more indolent prostate cancer phenotype, with a decreased propensity for metastatic progression.

Original languageEnglish (US)
Pages (from-to)3668-3680
Number of pages13
JournalClinical Cancer Research
Volume24
Issue number15
DOIs
StatePublished - Aug 1 2018

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Bhanvadia, R. R., Van Opstall, C., Brechka, H., Barashi, N. S., Gillard, M., McAuley, E. M., Vasquez, J. M., Paner, G., Chan, W. C., Andrade, J., Demarzo, A. M., Han, M., Szmulewitz, R. Z., & Vander Griend, D. J. (2018). MEIS1 and MEIS2 expression and prostate cancer progression: A role for HOXB13 binding partners in metastatic disease. Clinical Cancer Research, 24(15), 3668-3680. https://doi.org/10.1158/1078-0432.CCR-17-3673