Mediating Prostate Cancer Metastasis Through the MicroRNA Cluster MiR-23b/-27b

Abstract

Deregulation of microRNAs contributes to progression and metastasis of prostate and other cancers. MiR-23b and miR-27b, encoded in the same miR cluster (miR-23b/-27b), are down-regulated in human metastatic prostate cancer compared to primary tumors and benign tissue. Expression of miR-23b/-27b decreases cell migration, invasion and results in anoikis resistance. Conversely, antagomiR-mediated miR-23b and -27b silencing produces the opposite result in a more indolent prostate cancer cell line. However, neither miR-23b/-27b expression nor inhibition impacts prostate cancer cell proliferation or viability suggesting that miR-23b/-27b selectively suppresses metastasis. To examine the effects of miR-23b/-27b on prostate cancer metastasis in vivo, orthotopic prostate xenografts were established using aggressive prostate cancer cells transduced with miR-23b/-27b or non-targeting control miRNA. While primary tumor formation was similar between miR-23b/-27b-transduced cells and controls, miR-23b/-27b expression in prostate cancer cells decreased seminal vesicle invasion and distant metastases. Gene expression profiling identified the endocytic adaptor, Huntingtin interacting protein 1 related (HIP1R) as being down-regulated by miR-23b/-27b. Ectopic HIP1R expression in prostate cancer cells inversely phenocopied the effects of miR-23b/-27b overexpression on migration, invasion, and anchorage-independent growth. HIP1R rescued miR-23b/-27b mediated repression of migration in aggressive prostate cancer cells. HIP1R mRNA levels were decreased in seminal vesicle tissue from mice bearing miR-23b/-27b-transduced prostate cancer cell xenografts compared with scrambled controls, suggesting HIP1R is a key functional target of miR-23b/-27b. In addition, depletion of HIP1R led to a more rounded, less mesenchymal-like cell morphology, consistent with decreased metastatic properties. Together, these data demonstrate that the miR-23b/-27b cluster targets hip1r and functions as a metastasis-suppressor in pre-clinical models of prostate cancer