Top

Published in:

01-08-2012 | Preclinical Study

MicroRNA-30a inhibits cell migration and invasion by downregulating vimentin expression and is a potential prognostic marker in breast cancer

Authors: Chun-Wen Cheng, Hsiao-Wei Wang, Chia-Wei Chang, Hou-Wei Chu, Cheng-You Chen, Jyh-Cherng Yu, Jui-I Chao, Huei-Fang Liu, Shian-ling Ding, Chen-Yang Shen

Published in: Breast Cancer Research and Treatment | Issue 3/2012

Abstract

Tumor recurrence and metastasis result in an unfavorable prognosis for cancer patients. Recent studies have suggested that specific microRNAs (miRNAs) may play important roles in the development of cancer cells. However, prognostic markers and the outcome prediction of the miRNA signature in breast cancer patients have not been comprehensively assessed. The aim of this study was to identify miRNA biomarkers relating to clinicopathological features and outcome of breast cancer. A miRNA microarray analysis was performed on breast tumors of different lymph node metastasis status and with different progression signatures, indicated by overexpression of cyclin D1 and β-catenin genes, to identify miRNAs showing a significant difference in expression. The functional interaction between the candidate miRNA, miR-30a, and the target gene, Vim, which codes for vimentin, a protein involved in epithelial–mesenchymal transition, was examined using the luciferase reporter assay, western blotting, and migration and invasion assays. The association between the decreased miR-30a levels and breast cancer progression was examined in a survival analysis. miR-30a negatively regulated vimentin expression by binding to the 3′-untranslated region of Vim. Overexpression of miR-30a suppressed the migration and invasiveness phenotypes of breast cancer cell lines. Moreover, reduced tumor expression of miR-30a in breast cancer patients was associated with an unfavorable outcome, including late tumor stage, lymph node metastasis, and worse progression (mortality and recurrence) (p < 0.05). In conclusion, these findings suggest a role for miR-30a in inhibiting breast tumor invasiveness and metastasis. The finding that miR-30a downmodulates vimentin expression might provide a therapeutic target for the treatment of breast cancer.

Orlando FA, Brown KD (2009) Unraveling breast cancer heterogeneity through transcriptomic and epigenomic analysis. Ann Surg Oncol 16(8):2270–2279PubMedCrossRef

Polyak K (2007) Breast cancer: origins and evolution. J Clin Invest 117(11):3155–3163PubMedCrossRef

Guarino M, Rubino B, Ballabio G (2007) The role of epithelial–mesenchymal transition in cancer pathology. Pathology 39(3):305–318PubMedCrossRef

Micalizzi DS, Farabaugh SM, Ford HL (2010) Epithelial–mesenchymal transition in cancer: parallels between normal development and tumor progression. J Mammary Gland Biol Neoplasia 15(2):117–134PubMedCrossRef

Trimboli AJ, Fukino K, de Bruin A, Wei G, Shen L, Tanner SM, Creasap N, Rosol TJ, Robinson ML, Eng C, Ostrowski MC, Leone G (2008) Direct evidence for epithelial–mesenchymal transitions in breast cancer. Cancer Res 68(3):937–945PubMedCrossRef

Wells A, Yates C, Shepard CR (2008) E-cadherin as an indicator of mesenchymal to epithelial reverting transitions during the metastatic seeding of disseminated carcinomas. Clin Exp Metastasis 25(6):621–628PubMedCrossRef

Marsit CJ, Posner MR, McClean MD, Kelsey KT (2008) Hypermethylation of E-cadherin is an independent predictor of improved survival in head and neck squamous cell carcinoma. Cancer 113(7):1566–1571PubMedCrossRef

Prasad CP, Mirza S, Sharma G, Prashad R, DattaGupta S, Rath G, Ralhan R (2008) Epigenetic alterations of CDH1 and APC genes: relationship with activation of Wnt/beta-catenin pathway in invasive ductal carcinoma of breast. Life Sci 83(9–10):318–325PubMedCrossRef

Yates DR, Rehman I, Abbod MF, Meuth M, Cross SS, Linkens DA, Hamdy FC, Catto JW (2007) Promoter hypermethylation identifies progression risk in bladder cancer. Clin Cancer Res 13(7):2046–2053PubMedCrossRef

10.

Graziano F, Humar B, Guilford P (2003) The role of the E-cadherin gene (CDH1) in diffuse gastric cancer susceptibility: from the laboratory to clinical practice. Ann Oncol 14(12):1705–1713PubMedCrossRef

11.

Braun J, Hoang-Vu C, Dralle H, Huttelmaier S (2010) Downregulation of microRNAs directs the EMT and invasive potential of anaplastic thyroid carcinomas. Oncogene 29(29):4237–4244PubMedCrossRef

12.

Vetter G, Saumet A, Moes M, Vallar L, Le Bechec A, Laurini C, Sabbah M, Arar K, Theillet C, Lecellier CH, Friederich E (2010) miR-661 expression in SNAI1-induced epithelial to mesenchymal transition contributes to breast cancer cell invasion by targeting Nectin-1 and StarD10 messengers. Oncogene 29(31):4436–4448PubMedCrossRef

13.

Cho WC (2007) OncomiRs: the discovery and progress of microRNAs in cancers. Mol Cancer 6:60PubMedCrossRef

14.

Negrini M, Nicoloso MS, Calin GA (2009) MicroRNAs and cancer—new paradigms in molecular oncology. Curr Opin Cell Biol 21(3):470–479PubMedCrossRef

15.

Ortholan C, Puissegur MP, Ilie M, Barbry P, Mari B, Hofman P (2009) MicroRNAs and lung cancer: new oncogenes and tumor suppressors, new prognostic factors and potential therapeutic targets. Curr Med Chem 16(9):1047–1061PubMedCrossRef

16.

Shenouda SK, Alahari SK (2009) MicroRNA function in cancer: oncogene or a tumor suppressor? Cancer Metastasis Rev 28(3–4):369–378PubMedCrossRef

17.

Iwatsuki M, Mimori K, Fukagawa T, Ishii H, Yokobori T, Sasako M, Baba H, Mori M (2010) The clinical significance of vimentin-expressing gastric cancer cells in bone marrow. Ann Surg Oncol 17(9):2526–2533PubMedCrossRef

18.

Mendez MG, Kojima S, Goldman RD (2010) Vimentin induces changes in cell shape, motility, and adhesion during the epithelial to mesenchymal transition. FASEB J 24(6):1838–1851PubMedCrossRef

19.

Usami Y, Satake S, Nakayama F, Matsumoto M, Ohnuma K, Komori T, Semba S, Ito A, Yokozaki H (2008) Snail-associated epithelial–mesenchymal transition promotes oesophageal squamous cell carcinoma motility and progression. J Pathol 215(3):330–339PubMedCrossRef

20.

Yang PS, Yang TL, Liu CL, Wu CW, Shen CY (1997) A case-control study of breast cancer in Taiwan—a low-incidence area. Br J Cancer 75(5):752–756PubMedCrossRef

21.

Lo YL, Yu JC, Huang CS, Tseng SL, Chang TM, Chang KJ, Wu CW, Shen CY (1998) Allelic loss of the BRCA1 and BRCA2 genes and other regions on 17q and 13q in breast cancer among women from Taiwan (area of low incidence but early onset). Int J Cancer 79(6):580–587PubMedCrossRef

22.

Cheng TC, Chen ST, Huang CS, Fu YP, Yu JC, Cheng CW, Wu PE, Shen CY (2005) Breast cancer risk associated with genotype polymorphism of the catechol estrogen-metabolizing genes: a multigenic study on cancer susceptibility. Int J Cancer 113(3):345–353PubMedCrossRef

23.

Ming-Shiean H, Yu JC, Wang HW, Chen ST, Hsiung CN, Ding SL, Wu PE, Shen CY, Cheng CW (2010) Synergistic effects of polymorphisms in DNA repair genes and endogenous estrogen exposure on female breast cancer risk. Ann Surg Oncol 17(3):760–771PubMedCrossRef

24.

Ding SL, Sheu LF, Yu JC, Yang TL, Chen BF, Leu FJ, Shen CY (2004) Abnormality of the DNA double-strand-break checkpoint/repair genes, ATM, BRCA1 and TP53, in breast cancer is related to tumour grade. Br J Cancer 90(10):1995–2001PubMedCrossRef

25.

Hsu HM, Wang HC, Chen ST, Hsu GC, Shen CY, Yu JC (2007) Breast cancer risk is associated with the genes encoding the DNA double-strand break repair Mre11/Rad50/Nbs1 complex. Cancer Epidemiol Biomarkers Prev 16(10):2024–2032PubMedCrossRef

26.

Shen CY, Yu JC, Lo YL, Kuo CH, Yue CT, Jou YS, Huang CS, Lung JC, Wu CW (2000) Genome-wide search for loss of heterozygosity using laser capture microdissected tissue of breast carcinoma: an implication for mutator phenotype and breast cancer pathogenesis. Cancer Res 60(14):3884–3892PubMed

27.

Lo YL, Shen CY (2002) Laser capture microdissection in carcinoma analysis. Methods Enzymol 356:137–144PubMedCrossRef

28.

Petroff BK, Phillips TA, Kimler BF, Fabian CJ (2006) Detection of biomarker gene expression by real-time polymerase chain reaction using amplified ribonucleic acids from formalin-fixed random periareolar fine needle aspirates of human breast tissue. Anal Quant Cytol Histol 28(5):297–302PubMed

29.

Cheng CW, Yu JC, Wang HW, Huang CS, Shieh JC, Fu YP, Chang CW, Wu PE, Shen CY (2010) The clinical implications of MMP-11 and CK-20 expression in human breast cancer. Clin Chim Acta 411(3–4):234–241PubMedCrossRef

30.

Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29(9):e45PubMedCrossRef

31.

McInroy L, Maatta A (2007) Down-regulation of vimentin expression inhibits carcinoma cell migration and adhesion. Biochem Biophys Res Commun 360(1):109–114PubMedCrossRef

32.

Satelli A, Li S (2011) Vimentin in cancer and its potential as a molecular target for cancer therapy. Cell Mol Life Sci 68(18):3033–3046PubMedCrossRef

33.

Vuoriluoto K, Haugen H, Kiviluoto S, Mpindi JP, Nevo J, Gjerdrum C, Tiron C, Lorens JB, Ivaska J (2011) Vimentin regulates EMT induction by Slug and oncogenic H-Ras and migration by governing Axl expression in breast cancer. Oncogene 30(12):1436–1448PubMedCrossRef

34.

Franke WW, Grund C, Kuhn C, Jackson BW, Illmensee K (1982) Formation of cytoskeletal elements during mouse embryogenesis. III. Primary mesenchymal cells and the first appearance of vimentin filaments. Differentiation 23(1):43–59PubMedCrossRef

35.

Dutsch-Wicherek M, Lazar A, Tomaszewska R (2010) The potential role of MT and vimentin immunoreactivity in the remodeling of the microenvironment of parotid adenocarcinoma. Cancer Microenviron 4(1):105–113PubMedCrossRef

36.

Sarrio D, Palacios J, Hergueta-Redondo M, Gomez-Lopez G, Cano A, Moreno-Bueno G (2009) Functional characterization of E- and P-cadherin in invasive breast cancer cells. BMC Cancer 9:74PubMedCrossRef

37.

Mellios N, Huang HS, Grigorenko A, Rogaev E, Akbarian S (2008) A set of differentially expressed miRNAs, including miR-30a-5p, act as post-transcriptional inhibitors of BDNF in prefrontal cortex. Hum Mol Genet 17(19):3030–3042PubMedCrossRef

38.

Hand NJ, Master ZR, Eauclaire SF, Weinblatt DE, Matthews RP, Friedman JR (2009) The microRNA-30 family is required for vertebrate hepatobiliary development. Gastroenterology 136(3):1081–1090PubMedCrossRef

39.

Agrawal R, Tran U, Wessely O (2009) The miR-30 miRNA family regulates Xenopus pronephros development and targets the transcription factor Xlim1/Lhx1. Development 136(23):3927–3936PubMedCrossRef

40.

Kumarswamy R, Mudduluru G, Ceppi P, Muppala S, Kozlowski M, Niklinski J, Papotti M, Allgayer H (2012) MicroRNA-30a inhibits epithelial-to-mesenchymal transition by targeting Snai1 and is downregulated in non-small cell lung cancer. Int J Cancer 130(9):2044–2053PubMedCrossRef

41.

Izzotti A, Calin GA, Arrigo P, Steele VE, Croce CM, De Flora S (2009) Downregulation of microRNA expression in the lungs of rats exposed to cigarette smoke. FASEB J 23(3):806–812PubMedCrossRef

42.

Volinia S, Galasso M, Costinean S, Tagliavini L, Gamberoni G, Drusco A, Marchesini J, Mascellani N, Sana ME, Abu Jarour R, Desponts C, Teitell M, Baffa R, Aqeilan R, Iorio MV, Taccioli C, Garzon R, Di Leva G, Fabbri M, Catozzi M, Previati M, Ambs S, Palumbo T, Garofalo M, Veronese A, Bottoni A, Gasparini P, Harris CC, Visone R, Pekarsky Y, de la Chapelle A, Bloomston M, Dillhoff M, Rassenti LZ, Kipps TJ, Huebner K, Pichiorri F, Lenze D, Cairo S, Buendia MA, Pineau P, Dejean A, Zanesi N, Rossi S, Calin GA, Liu CG, Palatini J, Negrini M, Vecchione A, Rosenberg A, Croce CM (2010) Reprogramming of miRNA networks in cancer and leukemia. Genome Res 20(5):589–599PubMedCrossRef

43.

Chappell SA, Walsh T, Walker RA, Shaw JA (1997) Loss of heterozygosity at chromosome 6q in preinvasive and early invasive breast carcinomas. Br J Cancer 75(9):1324–1329PubMedCrossRef

44.

Noviello C, Courjal F, Theillet C (1996) Loss of heterozygosity on the long arm of chromosome 6 in breast cancer: possibly four regions of deletion. Clin Cancer Res 2(9):1601–1606PubMed

45.

Heinzelmann J, Henning B, Sanjmyatav J, Posorski N, Steiner T, Wunderlich H, Gajda MR, Junker K (2011) Specific miRNA signatures are associated with metastasis and poor prognosis in clear cell renal cell carcinoma. World J Urol 29(3):367–373PubMedCrossRef

46.

Li X, Zhang Y, Ding J, Wu K, Fan D (2010) Survival prediction of gastric cancer by a seven-microRNA signature. Gut 59(5):579–585PubMedCrossRef

47.

Tan X, Qin W, Zhang L, Hang J, Li B, Zhang C, Wan J, Zhou F, Shao K, Sun Y, Wu J, Zhang X, Qiu B, Li N, Shi S, Feng X, Zhao S, Wang Z, Zhao X, Chen Z, Mitchelson K, Cheng J, Guo Y, He J (2011) A 5-microRNA signature for lung squamous cell carcinoma diagnosis and hsa-miR-31 for prognosis. Clin Cancer Res 17(21):6802–6811PubMedCrossRef

48.

Brennecke J, Stark A, Russell RB, Cohen SM (2005) Principles of microRNA-target recognition. PLoS Biol 3(3):e85PubMedCrossRef

49.

Peter ME (2010) Targeting of mRNAs by multiple miRNAs: the next step. Oncogene 29(15):2161–2164PubMedCrossRef

50.

Ozcan S (2009) MiR-30 family and EMT in human fetal pancreatic islets. Islets 1(3):283–285PubMedCrossRef

51.

Kong W, Yang H, He L, Zhao JJ, Coppola D, Dalton WS, Cheng JQ (2008) MicroRNA-155 is regulated by the transforming growth factor beta/Smad pathway and contributes to epithelial cell plasticity by targeting RhoA. Mol Cell Biol 28(22):6773–6784PubMedCrossRef

52.

Wendt MK, Allington TM, Schiemann WP (2009) Mechanisms of the epithelial–mesenchymal transition by TGF-beta. Future Oncol 5(8):1145–1168PubMedCrossRef

53.

Rodriguez-Gonzalez FG, Sieuwerts AM, Smid M, Look MP, Meijer-van Gelder ME, de Weerd V, Sleijfer S, Martens JW, Foekens JA (2011) MicroRNA-30c expression level is an independent predictor of clinical benefit of endocrine therapy in advanced estrogen receptor positive breast cancer. Breast Cancer Res Treat 127(1):43–51PubMedCrossRef

Title: MicroRNA-30a inhibits cell migration and invasion by downregulating vimentin expression and is a potential prognostic marker in breast cancer
Authors: Chun-Wen Cheng
Hsiao-Wei Wang
Chia-Wei Chang
Hou-Wei Chu
Cheng-You Chen
Jyh-Cherng Yu
Jui-I Chao
Huei-Fang Liu
Shian-ling Ding
Chen-Yang Shen
Publication date: 01-08-2012
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 3/2012
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-012-2034-4

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2012

Genetic heterogeneity of HER2 in breast cancer: impact on HER2 testing and its clinicopathologic significance

Selenium intake and breast cancer mortality in a cohort of Swedish women

Cardiometabolic factors and breast cancer risk in U.S. black women

Double heterozygosity for mutations in BRCA1 and BRCA2 in German breast cancer patients: implications on test strategies and clinical management

Estrogen receptor α attenuates therapeutic efficacy of paclitaxel on breast xenograft tumors

Human breast cancer cell metastasis is attenuated by lysyl oxidase inhibitors through down-regulation of focal adhesion kinase and the paxillin-signaling pathway

Keynote webinar | Spotlight on antibody–drug conjugates in cancer