The microRNA-23b/-27b cluster suppresses prostate cancer metastasis via Huntingtin-interacting protein 1-related

Deregulation of microRNAs (miRs) contributes to progression and metastasis of prostate and other cancers. miR-23b and -27b, encoded in the same miR cluster (miR-23b/-27b), are downregulated in human metastatic prostate cancer compared with primary tumors and benign tissue. Expression of miR-23b/-27b...

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Bibliographic Details
Published in:Oncogene 2016-09, Vol.35 (36), p.4752-4761
Main Authors: Rice, M A, Ishteiwy, R A, Magani, F, Udayakumar, T, Reiner, T, Yates, T J, Miller, P, Perez-Stable, C, Rai, P, Verdun, R, Dykxhoorn, D M, Burnstein, K L
Format: Article
Language:English
Subjects:
Animals
Anoikis
Cancer metastasis
Cancer prevention
Cell adhesion & migration
Cell growth
Cell Line, Tumor
Cell migration
Cell Movement - genetics
Cell proliferation
Comparative analysis
Cytology
Gene expression
Gene Expression Regulation, Neoplastic
Humans
Huntingtin
Huntingtin-interacting protein 1
Male
Mesenchyme
Metastases
Metastasis
Mice
MicroRNA
MicroRNAs
MicroRNAs - genetics
miRNA
mRNA
Neoplasm Invasiveness - genetics
Neoplasm Metastasis
Oncology
Prostate - pathology
Prostate cancer
Prostatic Neoplasms - genetics
Prostatic Neoplasms - pathology
Proteins
Seminal vesicle
Tumors
Vesicular Transport Proteins - genetics
Xenograft Model Antitumor Assays
Xenografts
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Summary:Deregulation of microRNAs (miRs) contributes to progression and metastasis of prostate and other cancers. miR-23b and -27b, encoded in the same miR cluster (miR-23b/-27b), are downregulated in human metastatic prostate cancer compared with primary tumors and benign tissue. Expression of miR-23b/-27b decreases prostate cancer 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 or inhibition impacts prostate cancer cell proliferation 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. Although 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 downregulated by miR-23b/-27b. Increased 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 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 functions as a metastasis-suppressor by decreasing HIP1R levels in pre-clinical models of prostate cancer.
ISSN:0950-9232
1476-5594
DOI:10.1038/onc.2016.6