MicroRNAs in the Progression and Metastisis of Prostate Cancer

Summary

Principal Investigator: Rajvir Dahiya
Abstract: DESCRIPTION (provided by applicant): MicroRNAs in the progression of prostate cancer. The main goal of this project is to investigate the role of a set of microRNAs (miRNAs) in the progression of prostate cancer. The rationale of this project is that miRNAs regulate gene expression by repressing translation or directing sequence-specific degradation of complementary mRNA, and our preliminary results have provided a novel concept that miRNAs and non-coding double stranded RNAs can also activate various genes. Based on these novel observations, we hypothesize that down-regulation of a set of microRNAs can inhibit tumor suppressor genes or activate oncogenes and re-expression of these miRNAs can reverse these effects thereby regulating prostate cancer progression. These hypotheses will be tested by pursuing the following three specific aims. Specific Aim # 1. To investigate the expression of a set of miRNAs in human prostate cancer tissues and also analyze whether miRNAs can regulate cell proliferation and progression using prostate cancer cell lines. Based on our preliminary data, we have identified a set of miRNAs that are significantly downregulated in prostate cancer. We will analyze the expression of these miRNAs in human prostate cancer samples. We will over-express a defined set of individual miRNAs in prostate cancer cell lines and the modulation of targeted genes will be evaluated at both the mRNA and protein levels using real-time PCR and Western analysis, respectively. The miRNAs-mediated repression of oncogenes or activation of tumor suppressor genes will be analyzed by luciferase assays using 3'UTR or 5'UTR sequence constructs, respectively. Changes in cell growth will be analyzed by monitoring proliferation, cell cycle distribution, apoptosis and in vitro invasion. Assays to be used include cell proliferation, flow cytometry, migration, clonogenic survival, in vitro invasion and TUNEL-based ELISA apoptosis assays. Specific Aim #2: To investigate the molecular mechanisms of microRNA inactivation in prostate cancer cells. We will test the hypothesis that specific miRNAs are inactivated through epigenetic pathways. Human prostate cancer tissues will be used for analysis of methylation of miRNAs. CpG methylation in putative promoter regions of miRNAs will be examined by sodium bisulfite methylation techniques and confirm by direct DNA sequencing. We will also investigate whether histone acetylation, chromatin remodeling and associated enzymes (histone deacetylases and histone acetyltransferases) play a role in controlling expression of specific miRNAs. Specific Aim #3: Investigate whether microRNAs can inhibit growth and proliferation of human xenograft prostate tumors in a nude mouse model. To validate our in vitro results, we will also use an in vivo model of mouse xenografts with human prostate cancer cells. PUBLIC HEALTH RELEVANCE: Successful completion of these experiments will demonstrate the functional role of specific microRNAs in the suppression of prostate cancer growth and also the mechanism of inactivation of these genes in prostate cancer. In the future, these results may provide better strategies for the management of prostate cancer.
Funding Period: 2010-04-08 - 2015-01-31
more information: NIH RePORT

Top Publications

  1. pmc The functional significance of microRNA-145 in prostate cancer
    M S Zaman
    Department of Urology, San Francisco Veterans Affairs Medical Center and University of California at San Francisco, San Francisco, CA, USA
    Br J Cancer 103:256-64. 2010
  2. pmc Genistein suppresses prostate cancer growth through inhibition of oncogenic microRNA-151
    Takeshi Chiyomaru
    Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California, United States of America
    PLoS ONE 7:e43812. 2012
  3. pmc MicroRNA-1280 inhibits invasion and metastasis by targeting ROCK1 in bladder cancer
    Shahana Majid
    Department of Urology, VA Medical Center and UCSF, San Francisco, California, United States of America
    PLoS ONE 7:e46743. 2012
  4. pmc miR-23b represses proto-oncogene Src kinase and functions as methylation-silenced tumor suppressor with diagnostic and prognostic significance in prostate cancer
    Shahana Majid
    Department of Urology, VA Medical Center and UCSF, San Francisco, California 94121, USA
    Cancer Res 72:6435-46. 2012
  5. pmc miRNA-34b inhibits prostate cancer through demethylation, active chromatin modifications, and AKT pathways
    Shahana Majid
    Department of Urology, VA Medical Center and UCSF, San Francisco, CA 94121, USA
    Clin Cancer Res 19:73-84. 2013
  6. pmc Oncogenic miRNA-182-5p targets Smad4 and RECK in human bladder cancer
    Hiroshi Hirata
    Department of Urology, San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA
    PLoS ONE 7:e51056. 2012
  7. pmc MicroRNA-182-5p promotes cell invasion and proliferation by down regulating FOXF2, RECK and MTSS1 genes in human prostate cancer
    Hiroshi Hirata
    Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California, United States of America
    PLoS ONE 8:e55502. 2013
  8. pmc microRNA-183 is an oncogene targeting Dkk-3 and SMAD4 in prostate cancer
    K Ueno
    Department of Urology, San Francisco Veterans Affairs Medical Center, University of California at San Francisco, 4150 Clement Street, San Francisco, CA 94121, USA
    Br J Cancer 108:1659-67. 2013
  9. pmc Genistein up-regulates tumor suppressor microRNA-574-3p in prostate cancer
    Takeshi Chiyomaru
    Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California, USA
    PLoS ONE 8:e58929. 2013
  10. pmc Genistein downregulates onco-miR-1260b and inhibits Wnt-signalling in renal cancer cells
    H Hirata
    Department of Urology, San Francisco Veterans Affairs Medical Center and University of California at San Francisco, San Francisco, CA 94121, USA
    Br J Cancer 108:2070-8. 2013

Detail Information

Publications29

  1. pmc The functional significance of microRNA-145 in prostate cancer
    M S Zaman
    Department of Urology, San Francisco Veterans Affairs Medical Center and University of California at San Francisco, San Francisco, CA, USA
    Br J Cancer 103:256-64. 2010
    ..Recent studies have shown aberrant expression of miRNAs in prostate cancer tissues and cell lines. On the basis of miRNA microarray data, we found that miR-145 is significantly downregulated in prostate cancer...
  2. pmc Genistein suppresses prostate cancer growth through inhibition of oncogenic microRNA-151
    Takeshi Chiyomaru
    Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California, United States of America
    PLoS ONE 7:e43812. 2012
    ..This study suggests that genistein mediated suppression of oncogenic miRNAs can be an important dietary therapeutic strategy for the treatment of PCa...
  3. pmc MicroRNA-1280 inhibits invasion and metastasis by targeting ROCK1 in bladder cancer
    Shahana Majid
    Department of Urology, VA Medical Center and UCSF, San Francisco, California, United States of America
    PLoS ONE 7:e46743. 2012
    ..Various compounds are currently being used as ROCK1 inhibitors; therefore restoration of tumor suppressor miR-1280 might be therapeutically useful either alone or in combination with these compounds in the treatment of bladder cancer...
  4. pmc miR-23b represses proto-oncogene Src kinase and functions as methylation-silenced tumor suppressor with diagnostic and prognostic significance in prostate cancer
    Shahana Majid
    Department of Urology, VA Medical Center and UCSF, San Francisco, California 94121, USA
    Cancer Res 72:6435-46. 2012
    ..Loss of miR-23b may confer proliferative advantage and promote prostate cancer migration and invasion, and reexpression of miR-23b may contribute to the epigenetic therapy for prostate cancer...
  5. pmc miRNA-34b inhibits prostate cancer through demethylation, active chromatin modifications, and AKT pathways
    Shahana Majid
    Department of Urology, VA Medical Center and UCSF, San Francisco, CA 94121, USA
    Clin Cancer Res 19:73-84. 2013
    ..miRNAs can act as oncomirs or tumor-suppressor miRs in cancer. This study was undertaken to investigate the status and role of miR-34b in prostate cancer...
  6. pmc Oncogenic miRNA-182-5p targets Smad4 and RECK in human bladder cancer
    Hiroshi Hirata
    Department of Urology, San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA
    PLoS ONE 7:e51056. 2012
    ..In conclusion, our data suggests that miR-182-5p plays an important role as an oncogene by knocking down RECK and Smad4, resulting in activation of the Wnt-beta-catenin signaling pathway in bladder cancer...
  7. pmc MicroRNA-182-5p promotes cell invasion and proliferation by down regulating FOXF2, RECK and MTSS1 genes in human prostate cancer
    Hiroshi Hirata
    Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California, United States of America
    PLoS ONE 8:e55502. 2013
    ..Also knock down of miR-182-5p in order to increase expression of tumor suppressor genes FOXF2, RECK and MTSS1 may be of therapeutic benefit in prostate cancer treatment...
  8. pmc microRNA-183 is an oncogene targeting Dkk-3 and SMAD4 in prostate cancer
    K Ueno
    Department of Urology, San Francisco Veterans Affairs Medical Center, University of California at San Francisco, 4150 Clement Street, San Francisco, CA 94121, USA
    Br J Cancer 108:1659-67. 2013
    ..The purpose of this study was to identify prostate cancer (PC) oncogenic microRNAs (miRs) based on miR microarray and to investigate whether these oncogenic miRs may be useful as PC biomarkers...
  9. pmc Genistein up-regulates tumor suppressor microRNA-574-3p in prostate cancer
    Takeshi Chiyomaru
    Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California, USA
    PLoS ONE 8:e58929. 2013
    ..Our results show that genistein up-regulates tumor suppressor miR-574-3p expression targeting several cell signaling pathways. These findings enhance understanding of how genistein regulates with miRNA in PCa...
  10. pmc Genistein downregulates onco-miR-1260b and inhibits Wnt-signalling in renal cancer cells
    H Hirata
    Department of Urology, San Francisco Veterans Affairs Medical Center and University of California at San Francisco, San Francisco, CA 94121, USA
    Br J Cancer 108:2070-8. 2013
    ..Recently, microRNAs (miRNAs) have emerged as new regulators of gene expression. Thus, we focused on miRNAs to examine the regulatory mechanism of genistein on the Wnt-signalling pathway in renal cell carcinoma (RCC)...
  11. pmc MicroRNA-23b functions as a tumor suppressor by regulating Zeb1 in bladder cancer
    Shahana Majid
    Department of Urology, VA Medical Center and UCSF, San Francisco, California, USA
    PLoS ONE 8:e67686. 2013
    ..Furthermore, re-expression of miR-23b may be a beneficial therapeutic strategy for the treatment of human bladder cancer. ..
  12. pmc Genistein inhibits prostate cancer cell growth by targeting miR-34a and oncogenic HOTAIR
    Takeshi Chiyomaru
    Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California, USA
    PLoS ONE 8:e70372. 2013
    ..At present there are no reports about the relationship between gensitein, miRNAs and lncRNAs. In this study, we focused on miRNAs, lncRNA that are regulated by genistein and investigated their functional role in PCa...
  13. pmc MicroRNA-4723 inhibits prostate cancer growth through inactivation of the Abelson family of nonreceptor protein tyrosine kinases
    Sumit Arora
    Department of Urology, Veterans Affairs Medical Center, San Francisco and University of California San Francisco, San Francisco, California, United States of America
    PLoS ONE 8:e78023. 2013
    ..In conclusion, we have identified a novel microRNA that mediates regulation of Abl kinases in prostate cancer. This study suggests that miR-4723 may be an attractive target for therapeutic intervention in prostate cancer. ..
  14. pmc Frizzled homolog proteins, microRNAs and Wnt signaling in cancer
    Koji Ueno
    Department of Urology, San Francisco Veterans Affairs Medical Center and University of California at San Francisco, San Francisco, CA 94121, USA
    Int J Cancer 132:1731-40. 2013
    ..Therefore, the aim of this review is to discuss current knowledge of the functional mechanisms of FZDs in cancer, including regulation by miRNAs and the potential for possible use of miRNAs and FZDs in future clinical applications...
  15. ncbi miRNA-708 control of CD44(+) prostate cancer-initiating cells
    Sharanjot Saini
    Department of Urology, Veterans Affairs Medical Center and University of California, San Francisco, California 94121, USA
    Cancer Res 72:3618-30. 2012
    ..miR-708 therefore may represent a novel therapeutic target or diagnostic and prognostic biomarker in prostate cancer...
  16. pmc MicroRNA-34a modulates c-Myc transcriptional complexes to suppress malignancy in human prostate cancer cells
    Soichiro Yamamura
    Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California, United States of America
    PLoS ONE 7:e29722. 2012
    ....
  17. pmc MicroRNAs 221/222 and genistein-mediated regulation of ARHI tumor suppressor gene in prostate cancer
    Yi Chen
    Department of Urology, Veterans Affairs Medical Center and University of California, San Francisco, San Francisco, California 94121, USA
    Cancer Prev Res (Phila) 4:76-86. 2011
    ..Genistein, a potential nontoxic chemopreventive agent, restores expression of ARHI and may be an important dietary therapeutic agent for treating prostate cancer...
  18. pmc Tumour suppressor microRNA-584 directly targets oncogene Rock-1 and decreases invasion ability in human clear cell renal cell carcinoma
    K Ueno
    Department of Urology, San Francisco Veterans Affairs Medical Center, University of California, San Francisco, 4150 Clement Street, San Francisco, CA 94121, USA
    Br J Cancer 104:308-15. 2011
    ..The purpose of this study was to identify new tumour suppressor microRNAs (miRs) in clear cell renal cell carcinoma (ccRCC), carry out functional analysis of their suppressive role and identify their specific target genes...
  19. ncbi Regulatory Role of mir-203 in Prostate Cancer Progression and Metastasis
    Sharanjot Saini
    Department of Urology, Veterans Affairs Medical Center and University of California, San Francisco, California 94121, USA
    Clin Cancer Res 17:5287-98. 2011
    ..The main objective of the present study was to identify microRNA (miRNA) genes that regulate metastatic PCa...
  20. ncbi IGFBP-4 activates the Wnt/beta-catenin signaling pathway and induces M-CAM expression in human renal cell carcinoma
    Koji Ueno
    Department of Urology, San Francisco Veterans Affairs Medical Center and University of California at San Francisco, San Francisco, CA94121, USA
    Int J Cancer 129:2360-9. 2011
    ..This is a first report documenting that IGFBP-4 expression in RCC activates cell growth, metastasis, Wnt/beta-catenin signaling and may be involved in RCC metastasis...
  21. pmc MicroRNA-205 inhibits Src-mediated oncogenic pathways in renal cancer
    Shahana Majid
    Department of Urology, VA Medical Center and University of California San Francisco, USA
    Cancer Res 71:2611-21. 2011
    ..miR-205 also inhibited tumor cell growth in vivo. This is the first study showing that miR-205 inhibits proto-oncogenic SFKs, indicating a therapeutic potential of miR-205 in the treatment of renal cancer...
  22. pmc MicroRNA-145 is regulated by DNA methylation and p53 gene mutation in prostate cancer
    Seong O Suh
    Department of Urology, Veterans Affairs Medical Center and University of California at San Francisco, 4150 Clement Street, San Francisco, CA 94121, USA
    Carcinogenesis 32:772-8. 2011
    ..The apoptotic cells are increased after WT p53 transfection. In summary, this is the first report documenting that downregulation of miR-145 is through DNA methylation and p53 mutation pathways in prostate cancer...
  23. pmc Curcumin modulates microRNA-203-mediated regulation of the Src-Akt axis in bladder cancer
    Sharanjot Saini
    Department of Urology, Veterans Affairs Medical Center, University of California, San Francisco, USA
    Cancer Prev Res (Phila) 4:1698-709. 2011
    ..Our study suggests that curcumin may offer a therapeutic advantage in the clinical management of refractory bladder cancer over other standard treatment modalities...
  24. pmc MicroRNA-708 induces apoptosis and suppresses tumorigenicity in renal cancer cells
    Sharanjot Saini
    Department of Urology, Veterans Affairs Medical Center, San Francisco, California 94121, USA
    Cancer Res 71:6208-19. 2011
    ..Taken together, our findings define a major tumor suppressive role for miR-708, which may offer an attractive new target for prognostic and therapeutic intervention in RCC...
  25. pmc MicroRNA-1826 targets VEGFC, beta-catenin (CTNNB1) and MEK1 (MAP2K1) in human bladder cancer
    Hiroshi Hirata
    Department of Urology, San Francisco Veterans Affairs Medical Center, San Francisco, CA 94121, USA
    Carcinogenesis 33:41-8. 2012
    ..In conclusion, our data suggest that the miR-1826 plays an important role as tumor suppressor via CTNNB1/MEK1/VEGFC downregulation in BC...
  26. pmc Tumor suppressor microRNA-493 decreases cell motility and migration ability in human bladder cancer cells by downregulating RhoC and FZD4
    Koji Ueno
    Departments of Urology, San Francisco Veterans Affairs Medical Center and University of California at San Francisco, San Francisco, California 94121, USA
    Mol Cancer Ther 11:244-53. 2012
    ..miR-493 also decreased binding of RhoC and Rock-1. miR-493 is a new tumor suppressor miRNA in bladder cancer and inhibits cell motility through downregulation of RhoC and FZD4...
  27. pmc MicroRNA-34a suppresses malignant transformation by targeting c-Myc transcriptional complexes in human renal cell carcinoma
    Soichiro Yamamura
    Department of Urology, San Francisco Veterans Affairs Medical Center and University of California, San Francisco, CA 94121, USA
    Carcinogenesis 33:294-300. 2012
    ..Our results demonstrate that miR-34a suppresses assembly and function of the c-Myc complex that activates or elongates transcription, indicating a novel role of miR-34a in the regulation of transcription by c-Myc...
  28. pmc MicroRNA-1826 directly targets beta-catenin (CTNNB1) and MEK1 (MAP2K1) in VHL-inactivated renal cancer
    Hiroshi Hirata
    Department of Urology, San Francisco Veterans Affairs Medical Center and University of California at San Francisco, San Francisco, CA 94121, USA
    Carcinogenesis 33:501-8. 2012
    ..Our data suggest that the miR-1826 plays an important role as a tumor suppressor by downregulating beta-catenin and MEK1 in VHL-inactivated renal cancers...
  29. pmc Genistein downregulates onco-miR-1260b and upregulates sFRP1 and Smad4 via demethylation and histone modification in prostate cancer cells
    H Hirata
    Department of Urology, San Francisco Veterans Affairs Medical Center and University of California at San Francisco, San Francisco, California, USA
    Br J Cancer 110:1645-54. 2014
    ..Recently several microRNAs (miRNAs) have been found to be regulated by genistein in cancer cells. In this study, we focused on the gene regulatory effect of genistein on microRNA and its target genes in prostate cancer (PC)...

Research Grants30

  1. Genistein, microRNAs and kidney cancer
    Rajvir Dahiya; Fiscal Year: 2013
    ..Since the goal of this proposal is to investigate the dietary mediated inhibition of RCC through activation of tumor suppressor miRNAs, we believe that the work proposed is highly relevant to Veterans health and the VA mission. ..
  2. Re-expression of Aberrantly Silenced Genes Induced by Polyamine Analogues
    Robert A Casero; Fiscal Year: 2013
    ..abstract_text> ..
  3. The Role of NOV (CCN3) in Prostate Cancer Progression
    Jindan Yu; Fiscal Year: 2013
    ..Aim 3 will investigate the functional role of NOV in regulating PCa proliferation, migration, invasion/metastasis, and castration resistance using cell line models and nude mice. ..