MBP-1 upregulates miR-29b that represses Mcl-1, collagens, and matrix-metalloproteinase-2 in prostate cancer cells.

c-myc promoter binding protein (MBP-1) is a multi-functional protein known to regulate expression of targets involved in the malignant phenotype. We have previously demonstrated that exogenous expression of MBP-1 inhibits prostate tumor growth, although the mechanism of growth inhibition is not well understood. We hypothesized that MBP-1 may modulate microRNA (miRNA) expression for regulation of prostate cancer cell growth. In this study, we demonstrated that exogenous MBP-1 upregulates miR-29b by 5-9 fold in prostate cancer cells as measured by real-time quantitative reverse transcription-PCR. Subsequent studies indicated that exogenous expression of miR-29b inhibited Mcl-1, COL1A1, and COL4A1. Further, a novel target with potential implications for invasion and metastasis, matrix metallopeptidase-2 (MMP-2), was identified and confirmed to be a miR-29b target in prostate cancer cells. Together our results demonstrated that exogenous expression of miR-29b regulates prostate cancer cell growth by modulating anti-apoptotic and pro-metastatic matrix molecules, implicating therapeutic potential of miR-29b for prostate cancer inhibition.

[1]  D. Bartel MicroRNAs: Target Recognition and Regulatory Functions , 2009, Cell.

[2]  E. Thompson,et al.  Collagen induced MMP-2 activation in human breast cancer , 2004, Breast Cancer Research and Treatment.

[3]  S. Dooley,et al.  In situ hybridization analysis of genes coding collagen IV α1 chain, laminin β1 chain, and s‐laminin in prostate tissue and prostate cancer: Increased basement membrane gene expression in high‐grade and metastatic lesions , 1998, The Prostate.

[4]  F. Slack,et al.  MicroRNAs as potential cancer therapeutics , 2008, Oncogene.

[5]  Derek Y. Chiang,et al.  The landscape of somatic copy-number alteration across human cancers , 2010, Nature.

[6]  G. Gores,et al.  Serine 64 Phosphorylation Enhances the Antiapoptotic Function of Mcl-1* , 2007, Journal of Biological Chemistry.

[7]  C. Croce,et al.  MicroRNAs in cancer: small molecules with a huge impact. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[8]  Paul Ahlquist,et al.  MicroRNA 29c is down-regulated in nasopharyngeal carcinomas, up-regulating mRNAs encoding extracellular matrix proteins , 2008, Proceedings of the National Academy of Sciences.

[9]  T. Liu,et al.  MBP-1 mediated apoptosis involves cytochrome c release from mitochondria , 2002, Oncogene.

[10]  K. Boudjema,et al.  Increased extracellular matrix remodeling is associated with tumor progression in human hepatocellular carcinomas , 2001, Hepatology.

[11]  W. Filipowicz,et al.  Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? , 2008, Nature Reviews Genetics.

[12]  John Calvin Reed,et al.  Immunohistochemical analysis of bcl-2, bax, bcl-X, and mcl-1 expression in prostate cancers. , 1996, The American journal of pathology.

[13]  Tsung-Cheng Chang,et al.  Widespread microRNA repression by Myc contributes to tumorigenesis , 2008, Nature Genetics.

[14]  Colleen Nelson,et al.  Mechanisms of the development of androgen independence in prostate cancer , 2005, World Journal of Urology.

[15]  P. Albertsen The face of high risk prostate cancer , 2008, World Journal of Urology.

[16]  N. Dubrawsky Cancer statistics , 1989, CA: a cancer journal for clinicians.

[17]  R. Ray,et al.  Cloning and characterization of a human c-myc promoter-binding protein , 1991, Molecular and cellular biology.

[18]  M. Hendrix,et al.  Human breast carcinoma cells transfected with the gene encoding a c-myc promoter-binding protein (MBP-1) inhibits tumors in nude mice. , 1995, Cancer research.

[19]  R. Ray,et al.  Carboxyl-terminal repressor domain of MBP-1 is sufficient for regression of prostate tumor growth in nude mice. , 2005, Cancer research.

[20]  G. Gores,et al.  mir-29 regulates Mcl-1 protein expression and apoptosis , 2007, Oncogene.

[21]  M. Hollingsworth,et al.  Collagen I promotes metastasis in pancreatic cancer by activating c-Jun NH(2)-terminal kinase 1 and up-regulating N-cadherin expression. , 2006, Cancer research.

[22]  G. Morgia,et al.  Matrix metalloproteinases as diagnostic (MMP-13) and prognostic (MMP-2, MMP-9) markers of prostate cancer , 2005, Urological Research.

[23]  R. Gascoyne,et al.  Short Communication Immunohistochemical Analysis of Mci-1 Protein in Human Tissues Differential Regulation of Mcl- 1 and Bcl-2 Protein Production Suggests a Unique Role for Mcl- 1 in Control of Programmed Cell Death In Vivo , 2007 .

[24]  Kou-Juey Wu,et al.  MBP-1 suppresses growth and metastasis of gastric cancer cells through COX-2. , 2009, Molecular biology of the cell.

[25]  H. Klocker,et al.  Type IV collagenase (matrix metalloproteinase-2 and -9) in prostate cancer , 2004, Prostate Cancer and Prostatic Diseases.

[26]  E. Lander,et al.  A molecular signature of metastasis in primary solid tumors , 2003, Nature Genetics.

[27]  J. Sagartz,et al.  MBP-1 inhibits breast cancer growth and metastasis in immunocompetent mice. , 2009, Cancer research.

[28]  C. Tangen,et al.  Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. , 2004, The New England journal of medicine.

[29]  G. Adler,et al.  Collagen type I induces disruption of E-cadherin-mediated cell-cell contacts and promotes proliferation of pancreatic carcinoma cells. , 2006, Cancer research.

[30]  Carlo M. Croce,et al.  Biological Functions of miR-29b Contribute to Positive Regulation of Osteoblast Differentiation* , 2009, The Journal of Biological Chemistry.

[31]  S. Biesterfeld,et al.  Expression of matrix metalloproteinases (MMP-2 and -9) and their inhibitors (TIMP-1 and -2) in prostate cancer tissue , 2003, Prostate Cancer and Prostatic Diseases.

[32]  D. Welch,et al.  Metastamir: the field of metastasis-regulatory microRNA is spreading. , 2009, Cancer research.

[33]  I. Tannock,et al.  Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. , 2004, The New England journal of medicine.

[34]  D. Fuchs,et al.  The antiapoptotic effect of IL-6 autocrine loop in a cellular model of advanced prostate cancer is mediated by Mcl-1 , 2007, Oncogene.