MicroRNA let-7c is downregulated in prostate cancer and suppresses prostate cancer growth

N. Nadiminty, R. Tummala, W. Lou, Y. Zhu, X.-B. Shi, J.X. Zou, H. Chen, J. Zhang, X. Chen, J. Luo, R.W. deVere White, H.-J. Kung, C.P. Evans, A.C. Gao

Research output: Contribution to journalArticle

106 Citations (Scopus)

Abstract

Purpose: Prostate cancer (PCa) is characterized by deregulated expression of several tumor suppressor or oncogenic miRNAs. The objective of this study was the identification and characterization of miR-let-7c as a potential tumor suppressor in PCa. Experimental Design: Levels of expression of miR-let-7c were examined in human PCa cell lines and tissues using qRT-PCR and in situ hybridization. Let-7c was overexpressed or suppressed to assess the effects on the growth of human PCa cell lines. Lentiviral-mediated re-expression of let-7c was utilized to assess the effects on human PCa xenografts. Results: We identified miR-let-7c as a potential tumor suppressor in PCa. Expression of let-7c is downregulated in castration-resistant prostate cancer (CRPC) cells. Overexpression of let-7c decreased while downregulation of let-7c increased cell proliferation, clonogenicity and anchorage-independent growth of PCa cells in vitro. Suppression of let-7c expression enhanced the ability of androgen-sensitive PCa cells to grow in androgen-deprived conditions in vitro. Reconstitution of Let-7c by lentiviral-mediated intratumoral delivery significantly reduced tumor burden in xenografts of human PCa cells. Furthermore, let-7c expression is downregulated in clinical PCa specimens compared to their matched benign tissues, while the expression of Lin28, a master regulator of let-7 miRNA processing, is upregulated in clinical PCa specimens. Conclusions: These results demonstrate that microRNA let-7c is downregulated in PCa and functions as a tumor suppressor, and is a potential therapeutic target for PCa. © 2012 Nadiminty et al.
Original languageEnglish
JournalPLoS One
Volume7
Issue number3
DOIs
Publication statusPublished - Mar 2012
Externally publishedYes

Fingerprint

prostatic neoplasms
MicroRNAs
microRNA
Tumors
Prostatic Neoplasms
Down-Regulation
Growth
Cells
Heterografts
Androgens
Tissue
Cell proliferation
neoplasms
Design of experiments
androgens
Neoplasms
cell lines
Processing
Cell Line
human growth

Keywords

  • androgen
  • lentivirus vector
  • microRNA
  • microRNA let 7c
  • regulator protein
  • tumor suppressor protein
  • unclassified drug
  • green fluorescent protein
  • mirnlet7 microRNA, human
  • animal cell
  • animal experiment
  • animal tissue
  • article
  • cancer cell culture
  • cancer growth
  • cancer inhibition
  • castration resistant prostate cancer
  • cell growth
  • cell proliferation
  • clonogenesis
  • controlled study
  • down regulation
  • drug targeting
  • gene overexpression
  • human
  • human cell
  • in situ hybridization
  • in vitro study
  • male
  • mouse
  • nonhuman
  • protein expression
  • protein function
  • reverse transcription polymerase chain reaction
  • RNA processing
  • tumor volume
  • tumor xenograft
  • upregulation
  • animal
  • experimental neoplasm
  • gene expression regulation
  • genetics
  • Lentivirinae
  • metabolism
  • Northern blotting
  • nude mouse
  • orchiectomy
  • pathology
  • prostate tumor
  • tumor cell line
  • tumor suppressor gene
  • xenograft
  • Androgens
  • Animals
  • Blotting, Northern
  • Cell Line, Tumor
  • Cell Proliferation
  • Down-Regulation
  • Gene Expression Regulation, Neoplastic
  • Genes, Tumor Suppressor
  • Green Fluorescent Proteins
  • Humans
  • In Situ Hybridization
  • Lentivirus
  • Male
  • Mice
  • Mice, Nude
  • MicroRNAs
  • Neoplasms, Experimental
  • Orchiectomy
  • Prostatic Neoplasms
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transplantation, Heterologous
  • Tumor Burden

Cite this

Nadiminty, N., Tummala, R., Lou, W., Zhu, Y., Shi, X-B., Zou, J. X., ... Gao, A. C. (2012). MicroRNA let-7c is downregulated in prostate cancer and suppresses prostate cancer growth. PLoS One, 7(3). https://doi.org/10.1371/journal.pone.0032832

MicroRNA let-7c is downregulated in prostate cancer and suppresses prostate cancer growth. / Nadiminty, N.; Tummala, R.; Lou, W.; Zhu, Y.; Shi, X.-B.; Zou, J.X.; Chen, H.; Zhang, J.; Chen, X.; Luo, J.; deVere White, R.W.; Kung, H.-J.; Evans, C.P.; Gao, A.C.

In: PLoS One, Vol. 7, No. 3, 03.2012.

Research output: Contribution to journalArticle

Nadiminty, N, Tummala, R, Lou, W, Zhu, Y, Shi, X-B, Zou, JX, Chen, H, Zhang, J, Chen, X, Luo, J, deVere White, RW, Kung, H-J, Evans, CP & Gao, AC 2012, 'MicroRNA let-7c is downregulated in prostate cancer and suppresses prostate cancer growth', PLoS One, vol. 7, no. 3. https://doi.org/10.1371/journal.pone.0032832
Nadiminty, N. ; Tummala, R. ; Lou, W. ; Zhu, Y. ; Shi, X.-B. ; Zou, J.X. ; Chen, H. ; Zhang, J. ; Chen, X. ; Luo, J. ; deVere White, R.W. ; Kung, H.-J. ; Evans, C.P. ; Gao, A.C. / MicroRNA let-7c is downregulated in prostate cancer and suppresses prostate cancer growth. In: PLoS One. 2012 ; Vol. 7, No. 3.
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title = "MicroRNA let-7c is downregulated in prostate cancer and suppresses prostate cancer growth",
abstract = "Purpose: Prostate cancer (PCa) is characterized by deregulated expression of several tumor suppressor or oncogenic miRNAs. The objective of this study was the identification and characterization of miR-let-7c as a potential tumor suppressor in PCa. Experimental Design: Levels of expression of miR-let-7c were examined in human PCa cell lines and tissues using qRT-PCR and in situ hybridization. Let-7c was overexpressed or suppressed to assess the effects on the growth of human PCa cell lines. Lentiviral-mediated re-expression of let-7c was utilized to assess the effects on human PCa xenografts. Results: We identified miR-let-7c as a potential tumor suppressor in PCa. Expression of let-7c is downregulated in castration-resistant prostate cancer (CRPC) cells. Overexpression of let-7c decreased while downregulation of let-7c increased cell proliferation, clonogenicity and anchorage-independent growth of PCa cells in vitro. Suppression of let-7c expression enhanced the ability of androgen-sensitive PCa cells to grow in androgen-deprived conditions in vitro. Reconstitution of Let-7c by lentiviral-mediated intratumoral delivery significantly reduced tumor burden in xenografts of human PCa cells. Furthermore, let-7c expression is downregulated in clinical PCa specimens compared to their matched benign tissues, while the expression of Lin28, a master regulator of let-7 miRNA processing, is upregulated in clinical PCa specimens. Conclusions: These results demonstrate that microRNA let-7c is downregulated in PCa and functions as a tumor suppressor, and is a potential therapeutic target for PCa. {\circledC} 2012 Nadiminty et al.",
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author = "N. Nadiminty and R. Tummala and W. Lou and Y. Zhu and X.-B. Shi and J.X. Zou and H. Chen and J. Zhang and X. Chen and J. Luo and {deVere White}, R.W. and H.-J. Kung and C.P. Evans and A.C. Gao",
note = "引用次數:82 Export Date: 5 March 2018 通訊地址: Nadiminty, N.; Department of Urology, University of California Davis, Sacramento, CA, United States; 電子郵件: acgao@ucdavis.edu 化學物質/CAS: Androgens; Green Fluorescent Proteins, 147336-22-9; MicroRNAs; mirnlet7 microRNA, human 參考文獻: Shi, X.-B., Tepper, C.G., deVere White, R.W., Cancerous miRNAs and their regulation Cell Cycle (2008), 7, pp. 1529-1538; Coppola, V., de Maria, R., Bonci, D., (2009) MicroRNAs and prostate cancer, pp. ER0170-ER0172. , Endocr Relat Cancer; Gandellini, P., Folini, M., Zaffaroni, N., Towards the definition of prostate cancer-related microRNAs: where are we now? (2009) Trends in Molecular Medicine, 15, pp. 381-390; Calin, G.A., Sevignani, C., Dumitru, C.D., Hyslop, T., Noch, E., Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers (2004) Proc Natl Acad Sci USA, 101, pp. 2999-3004; Lee, Y.S., Dutta, A., The tumor suppressor microRNA let-7 represses the HMGA2 oncogene (2007) Genes & Development, 21, pp. 1025-1030; Yu, F., Yao, H., Zhu, P., Zhang, Z., Pan, Q., let-7 regulates self-renewal and tumorigenicity of breast cancer cells Cell (2007), 131, pp. 1109-1123; Weidhaas, J.B., Babar, I., Nallur, S.M., Trang, P., Roush, S., MicroRNAs as Potential Agents to Alter Resistance to Cytotoxic Anticancer Therapy (2007) Cancer Res, 67, pp. 11111-11116; Takamizawa, J., Konishi, H., Yanagisawa, K., Tomida, S., Osada, H., Reduced Expression of the let-7 MicroRNAs in Human Lung Cancers in Association with Shortened Postoperative Survival (2004) Cancer Res, 64, pp. 3753-3756; Shell, S., Park, S.-M., Radjabi, A.R., Schickel, R., Kistner, E.O., Let-7 expression defines two differentiation stages of cancer (2007) Proc Natl Acad Sci USA, 104, pp. 11400-11405; Boyerinas, B., Park, S.-M., Hau, A., Murmann, A.E., Peter, M.E., The role of let-7 in cell differentiation and cancer (2010) Endocr Relat Cancer, 17, pp. F19-F36; Ozen, M., Creighton, C., Ozdemir, M., Ittmann, M., Widespread deregulation of microRNA expression in human prostate cancer (2007) Oncogene, 27, pp. 1788-1793; Jiang, J., Lee, E.J., Gusev, Y., Schmittgen, T.D., Real-time expression profiling of microRNA precursors in human cancer cell lines (2005) Nucl Acids Res, 33, pp. 5394-5403; Johnson, S., Grosshans, H., Shingara, J., Byrom, M., Jarvis, R., RAS is regulated by the let-7 microRNA family Cell (2005), 120, pp. 635-647; Kumar, M.S., Lu, J., Mercer, K.L., Golub, T.R., Jacks, T., Impaired microRNA processing enhances cellular transformation and tumorigenesis (2007) Nat Genet, 39, pp. 673-677; Barh, D., Malhotra, R., Ravi, B., Sindhurani, P., MicroRNA let-7: an emerging next-generation cancer therapeutic (2010) Current Oncology, 17 (1), pp. 70-80; Esquela-Kerscher, A., Trang, P., Wiggins, J., Patrawala, L., Cheng, A., The let-7 microRNA reduces tumor growth in mouse models of lung cancer Cell Cycle (2008), 7, pp. 759-764; Viswanathan, S.R., Powers, J.T., Einhorn, W., Hoshida, Y., Ng, T.L., Lin28 promotes transformation and is associated with advanced human malignancies (2009) Nat Genet, 41, pp. 843-848; Iliopoulos, D., Hirsch, H., Struhl, K., An epigenetic switch involving NF-kappaB, Lin28, Let-7 microRNA and IL6 links inflammation to cell transformation Cell (2009), 139, pp. 693-706; Peng, S., Maihle, N., Huang, Y., Pluripotency factors Lin28 and Oct4 identify a sub-population of stem cell-like cells in ovarian cancer (2010) Oncogene, 29, pp. 2153-2159; Viswanathan, S.R., Daley, G.Q., Gregory, R.I., Selective Blockade of MicroRNA Processing by Lin28 (2008) Science, 320, pp. 97-100; Viswanathan, S.R., Daley, G.Q., Lin28: A microRNA regulator with a macro role Cell (2010), 140, pp. 445-449; Chang, T.-C., Zeitels, L.R., Hwang, H.-W., Chivukula, R.R., Wentzel, E.A., Lin-28B transactivation is necessary for Myc-mediated let-7 repression and proliferation (2009) Proc Natl Acad Sci USA, 106, pp. 3384-3389; Dangi-Garimella, S., Yun, J., Eves, E.M., Newman, M., Erkeland, S.J., Raf kinase inhibitory protein suppresses a metastasis signalling cascade involving LIN28 and let-7 (2009) EMBO J, 28, pp. 347-358; Lu, J., Getz, G., Miska, E.A., Alvarez-Saavedra, E., Lamb, J., MicroRNA expression profiles classify human cancers (2005) Nature, 435, pp. 834-838; Nadiminty, N., Lou, W., Lee, S.O., Lin, X., Trump, D.L., Stat3 activation of NF-kappaB p100 processing involves CBP/p300-mediated acetylation (2006) Proc Natl Acad Sci USA, 103, pp. 7264-7269; Nadiminty, N., Dutt, S., Tepper, C., Gao, A.C., Microarray analysis reveals potential target genes of NF-kappaB2/p52 in LNCaP prostate cancer cells (2009) Prostate, 70, pp. 276-287; Nadiminty, N., Lou, W., Sun, M., Chen, J., Yue, J., Aberrant Activation of the Androgen Receptor by NF-kappaB2/p52 in Prostate Cancer Cells (2010) Cancer Research, 70, pp. 3309-3319; Nadiminty, N., Chun, J.Y., Lou, W., Lin, X., Gao, A.C., NF-kappaB2/p52 enhances androgen-independent growth of human LNCaP cells via protection from apoptotic cell death and cell cycle arrest induced by androgen-deprivation (2008) Prostate, 68, pp. 1725-1733; Dunn, T.A., Chen, S., Faith, D.A., Hicks, J.L., Platz, E.A., A novel role of myosin VI in human prostate cancer (2006) Am J Pathol, 169, pp. 1843-1854; Lee, S.O., Lou, W., Hou, M., de Miguel, F., Gerber, L., Interleukin-6 promotes androgen-independent growth in LNCaP human prostate cancer cells (2003) Clin Cancer Res, 9, pp. 370-376; Lee, S.O., Chun, J.Y., Nadiminty, N., Lou, W., Gao, A.C., Interleukin-6 undergoes transition from growth inhibitor associated with neuroendocrine differentiation to stimulator accompanied by androgen receptor activation during LNCaP prostate cancer cell progression (2007) The Prostate, 67, pp. 764-773; Nadiminty, N., Tummala, R., Lou, W., Zhu, Y., Zhang, J., MicroRNA let-7c suppresses androgen receptor expression and activity via regulation of Myc expression in prostate cancer cells (2011), Journal of Biological Chemistry [Epub ahead of print]; Andersen, R.J., Mawji, N.R., Wang, J., Wang, G., Haile, S., Regression of Castrate-Recurrent Prostate Cancer by a Small-Molecule Inhibitor of the Amino-Terminus Domain of the Androgen Receptor (2010) Cancer Cell, 17, pp. 535-546; Tsang, W., Kwok, T., Let-7a microRNA suppresses therapeutics-induced cancer cell death by targeting caspase-3 (2008) Apoptosis, 13, pp. 1215-1222; Guled, M., Lahti, L., Lindholm, P.M., Salmenkivi, K., Bagwan, I., CDKN2A, NF2, and JUN are dysregulated among other genes by miRNAs in malignant mesothelioma-A miRNA microarray analysis (2009) Genes, Chromosomes and Cancer, 48, pp. 615-623; Lawrie, C.H., Chi, J., Taylor, S., Tramonti, D., Ballabio, E., Expression of microRNAs in diffuse large B cell lymphoma is associated with immunophenotype, survival and transformation from follicular lymphoma (2009) J Cell Mol Med, 13, pp. 1248-1260; Dong, Q., Meng, P., Wang, T., Qin, W., Qin, W., MicroRNA Let-7a Inhibits Proliferation of Human Prostate Cancer Cells In Vitro and In Vivo by Targeting E2F2 and CCND2 (2010) PLoS ONE, 5, pp. e10147",
year = "2012",
month = "3",
doi = "10.1371/journal.pone.0032832",
language = "English",
volume = "7",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "3",

}

TY - JOUR

T1 - MicroRNA let-7c is downregulated in prostate cancer and suppresses prostate cancer growth

AU - Nadiminty, N.

AU - Tummala, R.

AU - Lou, W.

AU - Zhu, Y.

AU - Shi, X.-B.

AU - Zou, J.X.

AU - Chen, H.

AU - Zhang, J.

AU - Chen, X.

AU - Luo, J.

AU - deVere White, R.W.

AU - Kung, H.-J.

AU - Evans, C.P.

AU - Gao, A.C.

N1 - 引用次數:82 Export Date: 5 March 2018 通訊地址: Nadiminty, N.; Department of Urology, University of California Davis, Sacramento, CA, United States; 電子郵件: acgao@ucdavis.edu 化學物質/CAS: Androgens; Green Fluorescent Proteins, 147336-22-9; MicroRNAs; mirnlet7 microRNA, human 參考文獻: Shi, X.-B., Tepper, C.G., deVere White, R.W., Cancerous miRNAs and their regulation Cell Cycle (2008), 7, pp. 1529-1538; Coppola, V., de Maria, R., Bonci, D., (2009) MicroRNAs and prostate cancer, pp. ER0170-ER0172. , Endocr Relat Cancer; Gandellini, P., Folini, M., Zaffaroni, N., Towards the definition of prostate cancer-related microRNAs: where are we now? (2009) Trends in Molecular Medicine, 15, pp. 381-390; Calin, G.A., Sevignani, C., Dumitru, C.D., Hyslop, T., Noch, E., Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers (2004) Proc Natl Acad Sci USA, 101, pp. 2999-3004; Lee, Y.S., Dutta, A., The tumor suppressor microRNA let-7 represses the HMGA2 oncogene (2007) Genes & Development, 21, pp. 1025-1030; Yu, F., Yao, H., Zhu, P., Zhang, Z., Pan, Q., let-7 regulates self-renewal and tumorigenicity of breast cancer cells Cell (2007), 131, pp. 1109-1123; Weidhaas, J.B., Babar, I., Nallur, S.M., Trang, P., Roush, S., MicroRNAs as Potential Agents to Alter Resistance to Cytotoxic Anticancer Therapy (2007) Cancer Res, 67, pp. 11111-11116; Takamizawa, J., Konishi, H., Yanagisawa, K., Tomida, S., Osada, H., Reduced Expression of the let-7 MicroRNAs in Human Lung Cancers in Association with Shortened Postoperative Survival (2004) Cancer Res, 64, pp. 3753-3756; Shell, S., Park, S.-M., Radjabi, A.R., Schickel, R., Kistner, E.O., Let-7 expression defines two differentiation stages of cancer (2007) Proc Natl Acad Sci USA, 104, pp. 11400-11405; Boyerinas, B., Park, S.-M., Hau, A., Murmann, A.E., Peter, M.E., The role of let-7 in cell differentiation and cancer (2010) Endocr Relat Cancer, 17, pp. F19-F36; Ozen, M., Creighton, C., Ozdemir, M., Ittmann, M., Widespread deregulation of microRNA expression in human prostate cancer (2007) Oncogene, 27, pp. 1788-1793; Jiang, J., Lee, E.J., Gusev, Y., Schmittgen, T.D., Real-time expression profiling of microRNA precursors in human cancer cell lines (2005) Nucl Acids Res, 33, pp. 5394-5403; Johnson, S., Grosshans, H., Shingara, J., Byrom, M., Jarvis, R., RAS is regulated by the let-7 microRNA family Cell (2005), 120, pp. 635-647; Kumar, M.S., Lu, J., Mercer, K.L., Golub, T.R., Jacks, T., Impaired microRNA processing enhances cellular transformation and tumorigenesis (2007) Nat Genet, 39, pp. 673-677; Barh, D., Malhotra, R., Ravi, B., Sindhurani, P., MicroRNA let-7: an emerging next-generation cancer therapeutic (2010) Current Oncology, 17 (1), pp. 70-80; Esquela-Kerscher, A., Trang, P., Wiggins, J., Patrawala, L., Cheng, A., The let-7 microRNA reduces tumor growth in mouse models of lung cancer Cell Cycle (2008), 7, pp. 759-764; Viswanathan, S.R., Powers, J.T., Einhorn, W., Hoshida, Y., Ng, T.L., Lin28 promotes transformation and is associated with advanced human malignancies (2009) Nat Genet, 41, pp. 843-848; Iliopoulos, D., Hirsch, H., Struhl, K., An epigenetic switch involving NF-kappaB, Lin28, Let-7 microRNA and IL6 links inflammation to cell transformation Cell (2009), 139, pp. 693-706; Peng, S., Maihle, N., Huang, Y., Pluripotency factors Lin28 and Oct4 identify a sub-population of stem cell-like cells in ovarian cancer (2010) Oncogene, 29, pp. 2153-2159; Viswanathan, S.R., Daley, G.Q., Gregory, R.I., Selective Blockade of MicroRNA Processing by Lin28 (2008) Science, 320, pp. 97-100; Viswanathan, S.R., Daley, G.Q., Lin28: A microRNA regulator with a macro role Cell (2010), 140, pp. 445-449; Chang, T.-C., Zeitels, L.R., Hwang, H.-W., Chivukula, R.R., Wentzel, E.A., Lin-28B transactivation is necessary for Myc-mediated let-7 repression and proliferation (2009) Proc Natl Acad Sci USA, 106, pp. 3384-3389; Dangi-Garimella, S., Yun, J., Eves, E.M., Newman, M., Erkeland, S.J., Raf kinase inhibitory protein suppresses a metastasis signalling cascade involving LIN28 and let-7 (2009) EMBO J, 28, pp. 347-358; Lu, J., Getz, G., Miska, E.A., Alvarez-Saavedra, E., Lamb, J., MicroRNA expression profiles classify human cancers (2005) Nature, 435, pp. 834-838; Nadiminty, N., Lou, W., Lee, S.O., Lin, X., Trump, D.L., Stat3 activation of NF-kappaB p100 processing involves CBP/p300-mediated acetylation (2006) Proc Natl Acad Sci USA, 103, pp. 7264-7269; Nadiminty, N., Dutt, S., Tepper, C., Gao, A.C., Microarray analysis reveals potential target genes of NF-kappaB2/p52 in LNCaP prostate cancer cells (2009) Prostate, 70, pp. 276-287; Nadiminty, N., Lou, W., Sun, M., Chen, J., Yue, J., Aberrant Activation of the Androgen Receptor by NF-kappaB2/p52 in Prostate Cancer Cells (2010) Cancer Research, 70, pp. 3309-3319; Nadiminty, N., Chun, J.Y., Lou, W., Lin, X., Gao, A.C., NF-kappaB2/p52 enhances androgen-independent growth of human LNCaP cells via protection from apoptotic cell death and cell cycle arrest induced by androgen-deprivation (2008) Prostate, 68, pp. 1725-1733; Dunn, T.A., Chen, S., Faith, D.A., Hicks, J.L., Platz, E.A., A novel role of myosin VI in human prostate cancer (2006) Am J Pathol, 169, pp. 1843-1854; Lee, S.O., Lou, W., Hou, M., de Miguel, F., Gerber, L., Interleukin-6 promotes androgen-independent growth in LNCaP human prostate cancer cells (2003) Clin Cancer Res, 9, pp. 370-376; Lee, S.O., Chun, J.Y., Nadiminty, N., Lou, W., Gao, A.C., Interleukin-6 undergoes transition from growth inhibitor associated with neuroendocrine differentiation to stimulator accompanied by androgen receptor activation during LNCaP prostate cancer cell progression (2007) The Prostate, 67, pp. 764-773; Nadiminty, N., Tummala, R., Lou, W., Zhu, Y., Zhang, J., MicroRNA let-7c suppresses androgen receptor expression and activity via regulation of Myc expression in prostate cancer cells (2011), Journal of Biological Chemistry [Epub ahead of print]; Andersen, R.J., Mawji, N.R., Wang, J., Wang, G., Haile, S., Regression of Castrate-Recurrent Prostate Cancer by a Small-Molecule Inhibitor of the Amino-Terminus Domain of the Androgen Receptor (2010) Cancer Cell, 17, pp. 535-546; Tsang, W., Kwok, T., Let-7a microRNA suppresses therapeutics-induced cancer cell death by targeting caspase-3 (2008) Apoptosis, 13, pp. 1215-1222; Guled, M., Lahti, L., Lindholm, P.M., Salmenkivi, K., Bagwan, I., CDKN2A, NF2, and JUN are dysregulated among other genes by miRNAs in malignant mesothelioma-A miRNA microarray analysis (2009) Genes, Chromosomes and Cancer, 48, pp. 615-623; Lawrie, C.H., Chi, J., Taylor, S., Tramonti, D., Ballabio, E., Expression of microRNAs in diffuse large B cell lymphoma is associated with immunophenotype, survival and transformation from follicular lymphoma (2009) J Cell Mol Med, 13, pp. 1248-1260; Dong, Q., Meng, P., Wang, T., Qin, W., Qin, W., MicroRNA Let-7a Inhibits Proliferation of Human Prostate Cancer Cells In Vitro and In Vivo by Targeting E2F2 and CCND2 (2010) PLoS ONE, 5, pp. e10147

PY - 2012/3

Y1 - 2012/3

N2 - Purpose: Prostate cancer (PCa) is characterized by deregulated expression of several tumor suppressor or oncogenic miRNAs. The objective of this study was the identification and characterization of miR-let-7c as a potential tumor suppressor in PCa. Experimental Design: Levels of expression of miR-let-7c were examined in human PCa cell lines and tissues using qRT-PCR and in situ hybridization. Let-7c was overexpressed or suppressed to assess the effects on the growth of human PCa cell lines. Lentiviral-mediated re-expression of let-7c was utilized to assess the effects on human PCa xenografts. Results: We identified miR-let-7c as a potential tumor suppressor in PCa. Expression of let-7c is downregulated in castration-resistant prostate cancer (CRPC) cells. Overexpression of let-7c decreased while downregulation of let-7c increased cell proliferation, clonogenicity and anchorage-independent growth of PCa cells in vitro. Suppression of let-7c expression enhanced the ability of androgen-sensitive PCa cells to grow in androgen-deprived conditions in vitro. Reconstitution of Let-7c by lentiviral-mediated intratumoral delivery significantly reduced tumor burden in xenografts of human PCa cells. Furthermore, let-7c expression is downregulated in clinical PCa specimens compared to their matched benign tissues, while the expression of Lin28, a master regulator of let-7 miRNA processing, is upregulated in clinical PCa specimens. Conclusions: These results demonstrate that microRNA let-7c is downregulated in PCa and functions as a tumor suppressor, and is a potential therapeutic target for PCa. © 2012 Nadiminty et al.

AB - Purpose: Prostate cancer (PCa) is characterized by deregulated expression of several tumor suppressor or oncogenic miRNAs. The objective of this study was the identification and characterization of miR-let-7c as a potential tumor suppressor in PCa. Experimental Design: Levels of expression of miR-let-7c were examined in human PCa cell lines and tissues using qRT-PCR and in situ hybridization. Let-7c was overexpressed or suppressed to assess the effects on the growth of human PCa cell lines. Lentiviral-mediated re-expression of let-7c was utilized to assess the effects on human PCa xenografts. Results: We identified miR-let-7c as a potential tumor suppressor in PCa. Expression of let-7c is downregulated in castration-resistant prostate cancer (CRPC) cells. Overexpression of let-7c decreased while downregulation of let-7c increased cell proliferation, clonogenicity and anchorage-independent growth of PCa cells in vitro. Suppression of let-7c expression enhanced the ability of androgen-sensitive PCa cells to grow in androgen-deprived conditions in vitro. Reconstitution of Let-7c by lentiviral-mediated intratumoral delivery significantly reduced tumor burden in xenografts of human PCa cells. Furthermore, let-7c expression is downregulated in clinical PCa specimens compared to their matched benign tissues, while the expression of Lin28, a master regulator of let-7 miRNA processing, is upregulated in clinical PCa specimens. Conclusions: These results demonstrate that microRNA let-7c is downregulated in PCa and functions as a tumor suppressor, and is a potential therapeutic target for PCa. © 2012 Nadiminty et al.

KW - androgen

KW - lentivirus vector

KW - microRNA

KW - microRNA let 7c

KW - regulator protein

KW - tumor suppressor protein

KW - unclassified drug

KW - green fluorescent protein

KW - mirnlet7 microRNA, human

KW - animal cell

KW - animal experiment

KW - animal tissue

KW - article

KW - cancer cell culture

KW - cancer growth

KW - cancer inhibition

KW - castration resistant prostate cancer

KW - cell growth

KW - cell proliferation

KW - clonogenesis

KW - controlled study

KW - down regulation

KW - drug targeting

KW - gene overexpression

KW - human

KW - human cell

KW - in situ hybridization

KW - in vitro study

KW - male

KW - mouse

KW - nonhuman

KW - protein expression

KW - protein function

KW - reverse transcription polymerase chain reaction

KW - RNA processing

KW - tumor volume

KW - tumor xenograft

KW - upregulation

KW - animal

KW - experimental neoplasm

KW - gene expression regulation

KW - genetics

KW - Lentivirinae

KW - metabolism

KW - Northern blotting

KW - nude mouse

KW - orchiectomy

KW - pathology

KW - prostate tumor

KW - tumor cell line

KW - tumor suppressor gene

KW - xenograft

KW - Androgens

KW - Animals

KW - Blotting, Northern

KW - Cell Line, Tumor

KW - Cell Proliferation

KW - Down-Regulation

KW - Gene Expression Regulation, Neoplastic

KW - Genes, Tumor Suppressor

KW - Green Fluorescent Proteins

KW - Humans

KW - In Situ Hybridization

KW - Lentivirus

KW - Male

KW - Mice

KW - Mice, Nude

KW - MicroRNAs

KW - Neoplasms, Experimental

KW - Orchiectomy

KW - Prostatic Neoplasms

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - Transplantation, Heterologous

KW - Tumor Burden

U2 - 10.1371/journal.pone.0032832

DO - 10.1371/journal.pone.0032832

M3 - Article

VL - 7

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 3

ER -