MicroRNAs Associated with Metastatic Prostate Cancer

Objective Metastasis is the most common cause of death of prostate cancer patients. Identification of specific metastasis biomarkers and novel therapeutic targets is considered essential for improved prognosis and management of the disease. MicroRNAs (miRNAs) form a class of non-coding small RNA molecules considered to be key regulators of gene expression. Their dysregulation has been shown to play a role in cancer onset, progression and metastasis, and miRNAs represent a promising new class of cancer biomarkers. The objective of this study was to identify down- and up-regulated miRNAs in prostate cancer that could provide potential biomarkers and/or therapeutic targets for prostate cancer metastasis. Methods Next generation sequencing technology was applied to identify differentially expressed miRNAs in a transplantable metastatic versus a non-metastatic prostate cancer xenograft line, both derived from one patient's primary cancer. The xenografts were developed via subrenal capsule grafting of cancer tissue into NOD/SCID mice, a methodology that tends to preserve properties of the original cancers (e.g., tumor heterogeneity, genetic profiles). Results Differentially expressed known miRNAs, isomiRs and 36 novel miRNAs were identified. A number of these miRNAs (21/104) have previously been reported to show similar down- or up-regulation in prostate cancers relative to normal prostate tissue, and some of them (e.g., miR-16, miR-34a, miR-126*, miR-145, miR-205) have been linked to prostate cancer metastasis, supporting the validity of the analytical approach. Conclusions The use of metastatic and non-metastatic prostate cancer subrenal capsule xenografts derived from one patient's cancer makes it likely that the differentially expressed miRNAs identified in this study include potential biomarkers and/or therapeutic targets for human prostate cancer metastasis.

[1]  C. Gilks,et al.  An orthotopic metastatic prostate cancer model in SCID mice via grafting of a transplantable human prostate tumor line , 2005, Laboratory Investigation.

[2]  R. Weinberg,et al.  A Pleiotropically Acting Microrna, Mir-31, Inhibits Breast Cancer Metastasis Accessed Terms of Use Detailed Terms a Pleiotropically Acting Microrna, Mir-31, Inhibits Breast Cancer Metastasis , 2022 .

[3]  Xianqun Fan,et al.  Putative tumor suppressor miR‐145 inhibits colon cancer cell growth by targeting oncogene friend leukemia virus integration 1 gene , 2011, Cancer.

[4]  Xiaowei Wang.  miRDB: a microRNA target prediction and functional annotation database with a wiki interface. , 2008, RNA.

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

[7]  N. Zaffaroni,et al.  Towards the definition of prostate cancer-related microRNAs: where are we now? , 2009, Trends in molecular medicine.

[8]  L. Kiesel,et al.  miR-145-dependent targeting of Junctional Adhesion Molecule A and modulation of fascin expression are associated with reduced breast cancer cell motility and invasiveness , 2010, Oncogene.

[9]  C. Creighton,et al.  Widespread deregulation of microRNA expression in human prostate cancer , 2008, Oncogene.

[10]  Ming Yao,et al.  Gain of miR-151 on chromosome 8q24.3 facilitates tumour cell migration and spreading through downregulating RhoGDIA , 2010, Nature Cell Biology.

[11]  C. Tepper,et al.  miR‐125b promotes growth of prostate cancer xenograft tumor through targeting pro‐apoptotic genes , 2011, The Prostate.

[12]  Li Jin,et al.  miR-24 Regulates Apoptosis by Targeting the Open Reading Frame (ORF) Region of FAF1 in Cancer Cells , 2010, PloS one.

[13]  S. Jayasena,et al.  Functional siRNAs and miRNAs Exhibit Strand Bias , 2003, Cell.

[14]  S. Barik,et al.  Ectopic expression of miR-126*, an intronic product of the vascular endothelial EGF-like 7 gene, regulates prostein translation and invasiveness of prostate cancer LNCaP cells , 2008, Journal of Molecular Medicine.

[15]  T. Tammela,et al.  MicroRNA expression profiling in prostate cancer. , 2007, Cancer research.

[16]  E. Schiffer.  Biomarkers for prostate cancer , 2007, World Journal of Urology.

[17]  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.

[18]  M. Gleave,et al.  ASAP1, a gene at 8q24, is associated with prostate cancer metastasis. , 2008, Cancer research.

[19]  Carola Berking,et al.  Inactivation of miR-34a by aberrant CpG methylation in multiple types of cancer , 2008, Cell cycle.

[20]  Kwang-Soo Kim,et al.  Depletion of Human Micro-RNA miR-125b Reveals That It Is Critical for the Proliferation of Differentiated Cells but Not for the Down-regulation of Putative Targets during Differentiation* , 2005, Journal of Biological Chemistry.

[21]  G. Goodall,et al.  Myc-modulated miR-9 makes more metastases , 2010, Nature Cell Biology.

[22]  Frank Speleman,et al.  miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis , 2010, Nature Cell Biology.

[23]  K. Kelnar,et al.  The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. , 2011, Nature medicine.

[24]  David A. Cheresh,et al.  Nuclear cytokine-activated IKKα controls prostate cancer metastasis by repressing Maspin , 2007, Nature.

[25]  A. Eklund,et al.  MicroRNA profile analysis of human prostate cancers , 2009, Cancer Gene Therapy.

[26]  Christopher P Evans,et al.  An androgen-regulated miRNA suppresses Bak1 expression and induces androgen-independent growth of prostate cancer cells , 2007, Proceedings of the National Academy of Sciences.

[27]  G. Hannon,et al.  Control of translation and mRNA degradation by miRNAs and siRNAs. , 2006, Genes & development.

[28]  R. Aharonov,et al.  hsa-miR-29c* is linked to the prognosis of malignant pleural mesothelioma. , 2010, Cancer research.

[29]  P. Wesseling,et al.  Micronodular transformation as a novel mechanism of VEGF-A-induced metastasis , 2007, Oncogene.

[30]  R. Getzenberg,et al.  Biomarkers for prostate cancer , 2009, Journal of cellular biochemistry.

[31]  W. Gerald,et al.  Endogenous human microRNAs that suppress breast cancer metastasis , 2008, Nature.

[32]  Yidong Chen,et al.  MicroRNA-185 suppresses tumor growth and progression by targeting the Six1 oncogene in human cancers , 2010, Oncogene.

[33]  A. Jemal,et al.  Cancer Statistics, 2010 , 2010, CA: a cancer journal for clinicians.

[34]  Y. Nagano,et al.  Overexpression of the fibroblast growth factor receptor-1 gene correlates with liver metastasis in colorectal cancer. , 2009, Oncology reports.

[35]  G. Kristiansen,et al.  Diagnostic and prognostic implications of microRNA profiling in prostate carcinoma , 2009, International journal of cancer.

[36]  David E. Williams,et al.  Regression of castrate-recurrent prostate cancer by a small-molecule inhibitor of the amino-terminus domain of the androgen receptor. , 2010, Cancer cell.

[37]  Zhiwei Wang,et al.  miR‐200 Regulates PDGF‐D‐Mediated Epithelial–Mesenchymal Transition, Adhesion, and Invasion of Prostate Cancer Cells , 2009, Stem cells.

[38]  R. Stephens,et al.  Genomic profiling of microRNA and messenger RNA reveals deregulated microRNA expression in prostate cancer. , 2008, Cancer research.

[39]  Y. Homma,et al.  miR-148a is an androgen-responsive microRNA that promotes LNCaP prostate cell growth by repressing its target CAND1 expression , 2010, Prostate Cancer and Prostatic Diseases.

[40]  Vassiliki Tzelepi,et al.  Therapeutic targeting of the prostate cancer microenvironment , 2010, Nature Reviews Urology.

[41]  S. Alahari,et al.  miRNA control of tumor cell invasion and metastasis , 2010, International journal of cancer.

[42]  Xiaowei Wang,et al.  Sequence analysis Prediction of both conserved and nonconserved microRNA targets in animals , 2007 .

[43]  G. Hannon,et al.  miRNAs on the move: miRNA biogenesis and the RNAi machinery. , 2004, Current opinion in cell biology.

[44]  C. Scholz,et al.  Expression of microRNA‐221 is progressively reduced in aggressive prostate cancer and metastasis and predicts clinical recurrence , 2009, International Journal of Cancer.

[45]  Kedar S Vaidya,et al.  Breast cancer metastasis suppressor 1 up-regulates miR-146, which suppresses breast cancer metastasis. , 2009, Cancer research.

[46]  David Haussler,et al.  The UCSC Genome Browser database: update 2010 , 2009, Nucleic Acids Res..

[47]  Selene L. Fernandez-Valverde,et al.  Dynamic isomiR regulation in Drosophila development. , 2010, RNA.

[48]  N. Zaffaroni,et al.  Emerging role of microRNAs in prostate cancer: implications for personalized medicine. , 2010, Discovery medicine.

[49]  E. Prakash,et al.  Connective tissue growth factor (CTGF) and cancer progression. , 2008, Journal of biomedical science.

[50]  Yunqing Li,et al.  microRNA-34a is tumor suppressive in brain tumors and glioma stem cells , 2010, Cell cycle.

[51]  Jianhua Zhao,et al.  Advances in whole genome sequencing technology. , 2011, Current pharmaceutical biotechnology.

[52]  Yusuke Yamamoto,et al.  Systemic delivery of synthetic microRNA-16 inhibits the growth of metastatic prostate tumors via downregulation of multiple cell-cycle genes. , 2010, Molecular therapy : the journal of the American Society of Gene Therapy.

[53]  Stefano Volinia,et al.  MicroRNA expression profiling of human metastatic cancers identifies cancer gene targets , 2009, The Journal of pathology.

[54]  Mary Goldman,et al.  The UCSC Genome Browser database: update 2011 , 2010, Nucleic Acids Res..

[55]  Peng Jiang,et al.  MiPred: classification of real and pseudo microRNA precursors using random forest prediction model with combined features , 2007, Nucleic Acids Res..

[56]  M. Degli-Esposti,et al.  Virally mediated inhibition of Bax in leukocytes promotes dissemination of murine cytomegalovirus , 2009, Cell Death and Differentiation.

[57]  Wei Chen,et al.  Molecular signature of epithelial-mesenchymal transition (EMT) in human prostate cancer bone metastasis. , 2010, American journal of translational research.

[58]  Miguel Srougi,et al.  Change in expression of miR-let7c, miR-100, and miR-218 from high grade localized prostate cancer to metastasis. , 2011, Urologic oncology.

[59]  Lan Xu,et al.  miR-21 and miR-31 Converge on TIAM1 to Regulate Migration and Invasion of Colon Carcinoma Cells* , 2010, The Journal of Biological Chemistry.

[60]  Yuzhuo Wang,et al.  Development and characterization of efficient xenograft models for benign and malignant human prostate tissue , 2005, The Prostate.

[61]  A. Barker,et al.  miR-331-3p Regulates ERBB-2 Expression and Androgen Receptor Signaling in Prostate Cancer* , 2009, The Journal of Biological Chemistry.

[62]  Qiongqing Wang,et al.  ADAMTS1 and MMP1 proteolytically engage EGF-like ligands in an osteolytic signaling cascade for bone metastasis. , 2009, Genes & development.

[63]  T. Visakorpi,et al.  Genetic alterations in hormone-refractory recurrent prostate carcinomas. , 1998, The American journal of pathology.

[64]  Stijn van Dongen,et al.  miRBase: tools for microRNA genomics , 2007, Nucleic Acids Res..

[65]  K. Becker,et al.  Analysis of microarray data using Z score transformation. , 2003, The Journal of molecular diagnostics : JMD.

[66]  M. Karin,et al.  Nuclear cytokine-activated IKKα controls prostate cancer metastasis by repressing Maspin , 2009, Nature.

[67]  Robert A. Weinberg,et al.  A Pleiotropically Acting MicroRNA, miR-31, Inhibits Breast Cancer Metastasis , 2009 .

[68]  K. Pienta,et al.  CC chemokine ligand 2 (CCL2) promotes prostate cancer tumorigenesis and metastasis. , 2010, Cytokine & growth factor reviews.

[69]  Margaret S. Ebert,et al.  MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells , 2007, Nature Methods.

[70]  S. Lam,et al.  Establishment in Severe Combined Immunodeficiency Mice of Subrenal Capsule Xenografts and Transplantable Tumor Lines from a Variety of Primary Human Lung Cancers: Potential Models for Studying Tumor Progression–Related Changes , 2006, Clinical Cancer Research.

[71]  Ryan D. Morin,et al.  Application of massively parallel sequencing to microRNA profiling and discovery in human embryonic stem cells. , 2008, Genome research.

[72]  C. Croce,et al.  A microRNA expression signature of human solid tumors defines cancer gene targets , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[73]  Y. Liu,et al.  TGF-beta promotes invasion and metastasis of gastric cancer cells by increasing fascin1 expression via ERK and JNK signal pathways. , 2009, Acta biochimica et biophysica Sinica.

[74]  M. Daidone,et al.  miR-205 Exerts tumor-suppressive functions in human prostate through down-regulation of protein kinase Cepsilon. , 2009, Cancer research.

[75]  Arndt Hartmann,et al.  The MicroRNA Profile of Prostate Carcinoma Obtained by Deep Sequencing , 2010, Molecular Cancer Research.

[76]  Ana M. Aransay,et al.  miRanalyzer: a microRNA detection and analysis tool for next-generation sequencing experiments , 2009, Nucleic Acids Res..

[77]  David Galas,et al.  Complexity of the microRNA repertoire revealed by next-generation sequencing. , 2010, RNA.

[78]  J. Friedman,et al.  Epigenetic therapy upregulates the tumor suppressor microRNA-126 and its host gene EGFL7 in human cancer cells. , 2009, Biochemical and biophysical research communications.

[79]  D. Huntsman,et al.  Establishment of subrenal capsule xenografts of primary human ovarian tumors in SCID mice: potential models. , 2005, Gynecologic oncology.

[80]  T. Kwok,et al.  The miR-18a* microRNA functions as a potential tumor suppressor by targeting on K-Ras. , 2009, Carcinogenesis.

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

[82]  H. Aburatani,et al.  Integration of cap analysis of gene expression and chromatin immunoprecipitation analysis on array reveals genome-wide androgen receptor signaling in prostate cancer cells , 2011, Oncogene.

[83]  R. Place,et al.  miR-449a targets HDAC-1 and induces growth arrest in prostate cancer , 2009, Oncogene.

[84]  I. Fidler,et al.  Critical determinants of metastasis. , 2002, Seminars in cancer biology.

[85]  S. Patnaik,et al.  Lung cancer xenografting alters microRNA profile but not immunophenotype. , 2009, Biochemical and biophysical research communications.