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MiR-21 overexpression in human primary squamous cell lung carcinoma is associated with poor patient prognosis

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This study compared miRNA expression patterns in primary squamous cell lung carcinoma specimens with those of matched normal lung tissue in order to determine their potential relevance to clinicopathological factors and patient postoperative survival times.


Locked nucleic acids miRNA microarray expression profiling was performed on four matched pairs of tissues. After microarray validation by quantitative real-time reverse transcription polymerase chain reaction assays (qRT-PCR) (real-time PCR), miR-21 was selected for further TaqMan real-time PCR study in 30 matched tissue pairs.


Seven miRNAs of hsa-miR-21, hsa-miR-31, hsa-miR-34a, hsa-miR-22*, hsa-miR-504, hsa-miR-18a, and hsa-miR-412 were observed to be upregulated greater than twofold in the squamous cell lung carcinoma tissues compared with normal tissues, whereas 23 miRNAs of hsa-miR-30a, hsa-miR-30d, hsa-miR-126, hsa-miR-652, hsa-miR-100, hsa-miR-143, hsa-miR-130a, hsa-miR-145, hsa-miR-30e, hsa-miR-126*, hsa-miR-181a, hsa-miR-125b, hsa-miR-886-3p, hsa-miR-451, hsa-miR-29c, hsa-miR-26b, hsa-miR-101, hsa-miR-320, hsa-miR-30b, hsa-miR-886-5p, hsa-miR-29a, hsa-miR-26a, and hsa-miR-99a were found to be downregulated greater than twofold. MiR-21 was overexpressed in 73.3% of the squamous cell lung carcinoma specimens examined (P = 0.022). The relationship between the miR-21 expression level and various clinicopathologic factors was also analyzed. High-level expression of miR-21 was significantly correlated with shortened survival time (P = 0.022, log-rank test; Kaplan–Meier). Multivariate Cox proportional hazard regression analysis revealed this significant prognostic impact (P = 0.000; HR 1.293; 95% CI 1.123–1.489) to be independent of clinical disease stage (P = 0.013; HR 2.660; 95% CI 1.229–5.758) and other clinicopathologic factors.


Expression patterns of miRNAs were found to be systematically altered in squamous cell lung carcinoma tissue. High miR-21 expression is associated with shortened survival time, indicating that miR-21 may serve as a molecular diagnostic and prognostic marker for patients with squamous cell lung carcinoma.

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  • Asangani IA, Rasheed SA, Nikolova DA, Leupold JH, Colburn NH, Post S, Allgayer H (2008) MiRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene 27:2128–2136

    Article  PubMed  CAS  Google Scholar 

  • Bartel DP (2004) MiRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297

    Article  PubMed  CAS  Google Scholar 

  • Blower PE, Chung JH, Verducci JS, Lin S, Park JK, Dai Z, Liu CG, Schmittgen TD, Reinhold WC, Croce CM, Weinstein JN, Sadee W (2008) MiRNAs modulate the chemosensitivity of tumor cells. Mol Cancer Ther 7:1–9

    Article  PubMed  CAS  Google Scholar 

  • Calin GA, Croce CM (2006a) MiRNA signatures in human cancers. Nat Rev Cancer 6:857–866

    Article  PubMed  CAS  Google Scholar 

  • Calin GA, Croce CM (2006b) MiRNA-cancer connection: the beginning of a new tale. Cancer Res 66:7390–7394

    Article  PubMed  CAS  Google Scholar 

  • Castoldi M, Schmidt S, Benes V, Noerholm M, Kulozik AE, Hentze MW, Muckenthaler MU (2006) A sensitive array for miRNA expression profiling (miChip) based on locked nucleic acids (LNA). RNA 12:913–920

    Article  PubMed  CAS  Google Scholar 

  • Chan JA, Krichevsky AM, Kosik KS (2005) MiRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res 65:6029–6033

    Article  PubMed  CAS  Google Scholar 

  • Chan SH, Wu CW, Li AF, Chi CW, Lin WC (2008) MiR-21 miRNA expression in human gastric carcinomas and its clinical association. Anticancer Res 28:907–911

    PubMed  Google Scholar 

  • Chen Y, Knösel T, Kristiansen G, Pietas A, Garber ME, Matsuhashi S, Ozaki I, Petersen I (2003) Loss of PDCD4 expression in human lung cancer correlates with tumour progression and prognosis. J Pathol 200:640–646

    Article  PubMed  CAS  Google Scholar 

  • Chen C, Ridzon DA, Broomer AJ, Zhou Z, Lee DH, Nguyen JT, Barbisin M, Xu NL, Mahuvakar VR, Andersen MR, Lao KQ, Livak KJ, Guegler KJ (2005) Real-time quantification of miRNAs by stem-loop RT-PCR. Nucleic Acids Res 33:e179

    Article  PubMed  Google Scholar 

  • Eisen MB, Spellman PT, Brown PO, Botstein D (1998) Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci USA 95:14863–14868

    Article  PubMed  CAS  Google Scholar 

  • Frankel LB, Christoffersen NR, Jacobsen A, Lindow M, Krogh A, Lund AH (2008) Programmed cell death 4 (PDCD4) is an important functional target of the miRNA miR-21 in breast cancer cells. J Biol Chem 283:1026–1033

    Article  PubMed  CAS  Google Scholar 

  • Fulci V, Chiaretti S, Goldoni M, Azzalin G, Carucci N, Tavolaro S, Castellano L, Magrelli A, Citarella F, Messina M, Maggio R, Peragine N, Santangelo S, Mauro FR, Landgraf P, Tuschl T, Weir DB, Chien M, Russo JJ, Ju J, Sheridan R, Sander C, Zavolan M, Guarini A, Foà R, Macino G (2007) Quantitative technologies establish a novel miRNA profile of chronic lymphocytic leukemia. Blood 109:4944–4951

    Article  PubMed  CAS  Google Scholar 

  • Gabriely G, Wurdinger T, Kesari S, Esau CC, Burchard J, Linsley PS, Krichevsky AM (2008) MiRNA 21 promotes glioma invasion by targeting matrix metalloproteinase regulators. Mol Cell Biol 28:5369–5380

    Article  PubMed  CAS  Google Scholar 

  • Gao W, Yu Y, Cao HL, Shen H, Li XD, Pan SY, Shu YQ (2010) Deregulated expression of miR-21,miR-143 and miR-181a in non small cell lung cancer is related to clinicopathologic characteristics or patient prognosis. Biomed Pharmacother (in press, accepted on Jan 29, 2010)

  • Greene FL, Page DL, Fleming ID et al (2002) AJCC cancer staging handbook—TNM classification of malignant tumors, 6th edn. Springer, New York

    Book  Google Scholar 

  • Iorio MV, Visone R, Di Leva G, Donati V, Petrocca F, Casalini P, Taccioli C, Volinia S, Liu CG, Alder H, Calin GA, Ménard S, Croce CM (2007) MiRNA signatures in human ovarian cancer. Cancer Res 67:8699–8707

    Article  PubMed  CAS  Google Scholar 

  • Johnson SM, Grosshans H, Shingara J, Byrom M, Jarvis R, Cheng A, Labourier E, Reinert KL, Brown D, Slack FJ (2005) RAS is regulated by the let-7 miRNA family. Cell 120:635–647

    Article  PubMed  CAS  Google Scholar 

  • Karube Y, Tanaka H, Osada H, Tomida S, Tatematsu Y, Yanagisawa K, Yatabe Y, Takamizawa J, Miyoshi S, Mitsudomi T, Takahashi T (2005) Reduced expression of dicer associated with poor prognosis in lung cancer patients. Cancer Sci 96:111–115

    Article  PubMed  CAS  Google Scholar 

  • Laskin JJ, Sandler AB (2005) State of the art in therapy for non-small cell lung cancer. Cancer Invest 23:427–442

    PubMed  Google Scholar 

  • Lawrie CH, Soneji S, Marafioti T, Cooper CD, Palazzo S, Paterson JC, Cattan H, Enver T, Mager R, Boultwood J, Wainscoat JS, Hatton CS (2007) MiRNA expression distinguishes between germinal center B cell-like and activated B cell-like subtypes of diffuse large B cell lymphoma. Int J Cancer 121:1156–1161

    Article  PubMed  CAS  Google Scholar 

  • Lawrie CH, Gal S, Dunlop HM, Pushkaran B, Liggins AP, Pulford K, Banham AH, Pezzella F, Boultwood J, Wainscoat JS, Hatton CS, Harris AL (2008) Detection of elevated levels of tumour associated miRNAs in serum of patients with diffuse large B-cell lymphoma. Br J Haematol 141:672–675

    Article  PubMed  Google Scholar 

  • Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, Sweet-Cordero A, Ebert BL, Mak RH, Ferrando AA, Downing JR, Jacks T, Horvitz HR, Golub TR (2005) MiRNA expression profiles classify human cancers. Nature 435:834–838

    Article  PubMed  CAS  Google Scholar 

  • Meng F, Henson R, Lang M, Wehbe H, Maheshwari S, Mendell JT, Jiang J, Schmittgen TD, Patel T (2006) Involvement of human micro-RNA in growth and response to chemotherapy in human cholangiocarcinoma cell lines. Gastroenterology 130:2113–2129

    Article  PubMed  CAS  Google Scholar 

  • Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST, Patel T (2007) MiRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology 133:647–658

    Article  PubMed  CAS  Google Scholar 

  • Murakami Y, Yasuda T, Saigo K, Urashima T, Toyoda H, Okanoue T, Shimotohno K (2006) Comprehensive analysis of microRNA expression patterns in hepatocellular carcinoma and non-tumorous tissues. Oncogene 25:2537–2545

    Article  PubMed  CAS  Google Scholar 

  • Neely LA, Rieger-Christ KM, Neto BS, Eroshkin A, Garver J, Patel S, Phung NA, McLaughlin S, Libertino JA, Whitney D, Summerhayes IC (2010) A microRNA expression ratio defining the invasive phenotype in bladder tumors. Urol Oncol 28:39–48

    PubMed  CAS  Google Scholar 

  • Ribas J, Ni X, Haffner M, Wentzel EA, Salmasi AH, Chowdhury WH, Kudrolli TA, Yegnasubramanian S, Luo J, Rodriguez R, Mendell JT, Lupold SE (2009) MiR-21: an androgen receptor-regulated microRNA that promotes hormone-dependent and hormone-independent prostate cancer growth. Cancer Res 69:7165–7169

    Article  PubMed  CAS  Google Scholar 

  • Schetter AJ, Leung SY, Sohn JJ, Zanetti KA, Bowman ED, Yanaihara N, Yuen ST, Chan TL, Kwong DL, Au GK, Liu CG, Calin GA, Croce CM, Harris CC (2008) MiRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. JAMA 299:425–436

    Article  PubMed  CAS  Google Scholar 

  • Si ML, Zhu S, Wu H, Lu Z, Wu F, Mo YY (2007) MiR-21-mediated tumor growth. Oncogene 26:2799–2803

    Article  PubMed  CAS  Google Scholar 

  • Slaby O, Svoboda M, Fabian P, Smerdova T, Knoflickova D, Bednarikova M, Nenutil R, Vyzula R (2007) Altered expression of miR-21, miR-31, miR-143 and miR-145 is related to clinicopathologic features of colorectal cancer. Oncology 72:397–402

    Article  PubMed  CAS  Google Scholar 

  • Sobin LH, Wittekind C (2002) UICC TNM classification of malignant tumours, 6th edn. Wiley, New York

    Google Scholar 

  • Takamizawa J, Konishi H, Yanagisawa K, Tomida S, Osada H, Endoh H, Harano T, Yatabe Y, Nagino M, Nimura Y, Mitsudomi T, Takahashi T (2004) Reduced expression of the let-7 miRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res 64:3753–3756

    Article  PubMed  CAS  Google Scholar 

  • Thomson JM, Newman M, Parker JS, Morin-Kensicki EM, Wright T, Hammond SM (2006) Extensive post-transcriptional regulation of miRNAs and its implications for cancer. Genes Dev 20:2202–2207

    Article  PubMed  CAS  Google Scholar 

  • Yan LX, Huang XF, Shao Q, Huang MY, Deng L, Wu QL, Zeng YX, Shao JY (2008) MiRNA miR-21 overexpression in human breast cancer is associated with advanced clinical stage, lymph node metastasis and patient poor prognosis. RNA 14:2348–2360

    Article  PubMed  CAS  Google Scholar 

  • Yanaihara N, Caplen N, Bowman E, Seike M, Kumamoto K, Yi M, Stephens RM, Okamoto A, Yokota J, Tanaka T, Calin GA, Liu CG, Croce CM, Harris CC (2006) Unique miRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell 9:189–198

    Article  PubMed  CAS  Google Scholar 

  • Yi Z, Fu Y, Zhao S, Zhang X, Ma C (2009, Nov 17) Differential expression of miRNA patterns in renal cell carcinoma and nontumorous tissues. J Cancer Res Clin Oncol [Epub ahead of print]

  • Yu SL, Chen HY, Chang GC, Chen CY, Chen HW, Singh S, Cheng CL, Yu CJ, Lee YC, Chen HS, Su TJ, Chiang CC, Li HN, Hong QS, Su HY, Chen CC, Chen WJ, Liu CC, Chan WK, Chen WJ, Li KC, Chen JJ, Yang PC (2007) MiRNA signature predicts survival and relapse in lung cancer. Cancer Cell 13:48–57

    Article  Google Scholar 

  • Zhu S, Si ML, Wu H, Mo YY (2007) MiRNA-21 targets the tumor suppressor gene tropomyosin 1 (TPM1). J Biol Chem 282:14328–14336

    Article  PubMed  CAS  Google Scholar 

  • Zhu S, Wu H, Wu F, Nie D, Sheng S, Mo YY (2008) MiRNA-21 targets tumor suppressor genes in invasion and metastasis. Cell Res 18:350–359

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Yongqian Shu.

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Gao, W., Shen, H., Liu, L. et al. MiR-21 overexpression in human primary squamous cell lung carcinoma is associated with poor patient prognosis. J Cancer Res Clin Oncol 137, 557–566 (2011).

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