The non-coding RNAs of the H19-IGF2 imprinted loci: A focus on biological roles and therapeutic potential in Lung Cancer

Journal of Translational Medicine

Abraham Hochberg¹  Michal Gilon¹  David Halle¹  Imad J Matouk¹ 

[1] Department of Biological Chemistry, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel

关键词: Imprinted cluster;    Lung cancer;    Oncomirs;    IGF2;    miR-675;    H19;   

Others  :  1207764
DOI  :  10.1186/s12967-015-0467-3

 received in 2014-11-30, accepted in 2015-03-18,  发布年份 2015

【 摘 要 】

Since it was first described, the imprinted cluster 11p15.5 has been reported to be deregulated in a variety of pediatric and adult cancers including that of the lung. Both protein coding and non-coding genes functioning as oncogenes or as tumor suppressor genes reside within this cluster. Oncomirs that can function as oncogenes or as tumor suppressors have also been reported. While a complete account of the role played by the 11p15.5 imprinted cluster in lung cancer is beyond the scope of this review, we will focus on the role of the non-coding RNAs processed from the H19-IGF2 loci. A special emphasis will be given to the H19/miR-675 gene locus. Their potential diagnostic and therapeutic use in lung cancer will be described.

【 授权许可】

   
2015 Matouk et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

【 参考文献 】

• [1]Lima AB, Macedo LT, Sasse AD. Addition of bevacizumab to chemotherapy in advanced non-small cell lung cancer: a systematic review and meta-analysis. PLoS One. 2011; 6:e22681.
• [2]Amit L, Ben-Aharon I, Vidal L, Leibovici L, Stemmer S. The impact of Bevacizumab (Avastin) on survival in metastatic solid tumors–a meta-analysis and systematic review. PLoS One. 2013; 8:e51780.
• [3]Gutschner T, Diederichs S. The hallmarks of cancer: a long non-coding RNA point of view. RNA Biol. 2012; 9:703-19.
• [4]Prensner JR, Chinnaiyan AM. The emergence of lncRNAs in cancer biology. Cancer Discov. 2011; 1:391-407.
• [5]Calin GA, Croce CM. MicroRNA-cancer connection: the beginning of a new tale. Cancer Res. 2006; 66:7390-4.
• [6]Enfield KS, Pikor LA, Martinez VD, Lam WL. Mechanistic Roles of Noncoding RNAs in Lung Cancer Biology and Their Clinical Implications. Genet Res Int. 2012; 2012:737416.
• [7]Gutschner T, Hämmerle M, Eissmann M, Hsu J, Kim Y, Hung G et al.. The noncoding RNA MALAT1 is a critical regulator of the metastasis phenotype of lung cancer cells. Cancer Res. 2013; 73:1180-9.
• [8]Thai P, Statt S, Chen CH, Liang E, Campbell C, Wu R. Characterization of a novel long noncoding RNA, SCAL1, induced by cigarette smoke and elevated in lung cancer cell lines. Am J Respir Cell Mol Biol. 2013; 49:204-11.
• [9]Chen W, Böcker W, Brosius J, Tiedge H. Mechanistic Roles of Noncoding RNAs in Lung Cancer Biology and Their Clinical Implications. J Pathol. 1997; 183:345-51.
• [10]Yang Y, Li H, Hou S, Hu B, Liu J, Wang J. The noncoding RNA expression profile and the effect of lncRNA AK126698 on cisplatin resistance in non-small-cell lung cancer cell. PLoS One. 2013; 8:e65309.
• [11]Yang F, Huo XS, Yuan SX, Zhang L, Zhou WP, Wang F et al.. Repression of the long noncoding RNA-LET by histone deacetylase 3 contributes to hypoxia-mediated metastasis. Mol Cell. 2013; 49:1083-96.
• [12]Khalil AM, Guttman M, Huarte M, Garber M, Raj A, Rivea Morales D et al.. Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc Natl Acad Sci U S A. 2009; 106:11667-72.
• [13]Nakagawa T, Endo H, Yokoyama M, Abe J, Tamai K, Tanaka N et al.. Large noncoding RNA HOTAIR enhances aggressive biological behavior and is associated with short disease-free survival in human non-small cell lung cancer. Biochem Biophys Res Commun. 2013; 436:319-24.
• [14]Liu Z, Sun M, Lu K, Liu J, Zhang M, Wu W et al.. The long noncoding RNA HOTAIR contributes to cisplatin resistance of human lung adenocarcinoma cells via downregualtion of p21(WAF1/CIP1) expression. PLoS One. 2013; 8:e77293.
• [15]Rodriguez A, Griffiths-Jones S, Ashurst JL, Bradley A. Identification of mammalian microRNA host genes and transcription units. Genome Res. 2004; 14:1902-10.
• [16]Kim VN. MicroRNA biogenesis: Coordinated cropping and dicing. Nat Rev Mol Cell Biol. 2005; 6:376-85.
• [17]Hagan JP, O’Neill BL, Stewart CL, Kozlov SV, Croce CM. At least ten genes define the imprinted Dlk1–Dio3 cluster on mouse chromosome 12qF1. PLoS One. 2009; 4:e4352.
• [18]Cai X, Cullen BR. The imprinted H19 noncoding RNA is a primary microRNA precursor. RNA. 2007; 13:313-6.
• [19]Xia T, Liao Q, Jiang X, Shao Y, Xiao B, Xi Y et al.. Long noncoding RNA associated-competing endogenous RNAs in gastric cancer. Sci Rep. 2014; 4:6088.
• [20]Zhao W, Luo J, Jiao S. Comprehensive characterization of cancer subtype associated long non-coding RNAs and their clinical implications. Sci Rep. 2014; 4:6591.
• [21]Mattick JS, Makunin IV. Non-coding RNA. Hum Mol Genet. 2006; 1:R17-29.
• [22]Pauli A, Valen E, Lin MF, Garber M, Vastenhouw NL, Levin JZ et al.. Systematic identification of long noncoding RNAs expressed during zebrafish embryogenesis. Genome Res. 2012; 22:577-91.
• [23]Monnier P, Martinet C, Pontis J, Stancheva I, Ait-Si-Ali S, Dandolo L. H19 lncRNA controls gene expression of the Imprinted Gene Network by recruiting MBD1. Proc Natl Acad Sci U S A. 2013; 110:20693-8.
• [24]Yang J, Lin J, Liu T, Chen T, Pan S, Huang W et al.. Analysis of lncRNA expression profiles in non-small cell lung cancers (NSCLC) and their clinical subtypes. Lung Cancer. 2014; 85:110-5.
• [25]Zhang L, Zhou XF, Pan GF, Zhao JP. Enhanced expression of long non-coding RNA ZXF1 promoted the invasion and metastasis in lung adenocarcinoma. Biomed Pharmacother. 2014; 68:401-7.
• [26]White NM, Cabanski CR, Silva-Fisher JM, Dang HX, Govindan R, Maher CA. Transcriptome sequencing reveals altered long intergenic non-coding RNAs in lung cancer. Genome Biol. 2014; 15:429. BioMed Central Full Text
• [27]Flynt AS, Lai EC. Biological principles of microRNA-mediated regulation: shared themes amid diversity. Nat Rev Genet. 2008; 9:831-42.
• [28]Ortholan C, Puissegur MP, Ilie M, Barbry P, Mari B, Hofman P. MicroRNAs and lung cancer: new oncogenes and tumor suppressors, new prognostic factors and potential therapeutic targets. Curr Med Chem. 2009; 16:1047-61.
• [29]Kumar MS, Armenteros-Monterroso E, East P, Chakravorty P, Matthews N, Winslow MM et al.. HMGA2 functions as a competing endogenous RNA to promote lung cancer progression. Nature. 2014; 505:212-7.
• [30]Zhao B, Han H, Chen J, Zhang Z, Li S, Fang F et al.. MicroRNA let-7c inhibits migration and invasion of human non-small cell lung cancer by targeting ITGB3 and MAP4K3. Cancer Lett. 2014; 342:43-51.
• [31]Fabbri M, Garzon R, Cimmino A, Liu Z, Zanesi N, Callegari E et al.. MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B. Proc Natl Acad Sci U S A. 2007; 104:15805-10.
• [32]Wiggins JF, Ruffino L, Kelnar K, Omotola M, Patrawala L, Brown D et al.. Development of a lung cancer therapeutic based on the tumor suppressor microRNA-34. Cancer Res. 2010; 70:5923-30.
• [33]Esquela-Kerscher A, Trang P, Wiggins JF, Patrawala L, Cheng A, Ford L et al.. The let-7 microRNA reduces tumor growth in mouse models of lung cancer. Cell Cycle. 2008; 7:759-64.
• [34]Qiao Y, Ma N, Wang X, Hui Y, Li F, Xiang Y et al.. MiR-483-5p controls angiogenesis in vitro and targets serum response factor. FEBS Lett. 2011; 585:3095-4000.
• [35]Song Q, Xu Y, Yang C, Chen Z, Jia C, Chen J et al.. miR-483-5p promotes invasion and metastasis of lung adenocarcinoma by targeting RhoGDI1 and ALCAM. Cancer Res. 2014; 74:3031-42.
• [36]Matouk IJ, Raveh E, Abu-lail R, Mezan S, Gilon M, Gershtain E et al.. Oncofetal H19 RNA promotes tumor metastasis. Biochim Biophys Acta. 1843; 2014:1414-26.
• [37]Dudek KA, Lafont JE, Martinez-Sanchez A, Murphy CL. Type II collagen expression is regulated by tissue-specific miR-675 in human articular chondrocytes. J Biol Chem. 2010; 285:24381-7.
• [38]Keniry A, Oxley D, Monnier P, Kyba M, Dandolo L, Smits G et al.. The H19 lincRNA is a developmental reservoir of miR-675 that suppresses growth and Igf1r. Nat Cell Biol. 2012; 14:659-65.
• [39]Tsang WP, Ng EK, Ng SS, Jin H, Yu J, Sung JJ et al.. Oncofetal H19-derived miR-675 regulates tumor suppressor RB in human colorectal cancer. Carcinogenesis. 2010; 31:350-8.
• [40]Zhuang M, Gao W, Xu J, Wang P, Shu Y. The long non-coding RNA H19-derived miR-675 modulates human gastric cancer cell proliferation by targeting tumor suppressor RUNX1. Biochem Biophys Res Commun. 2014; 448:315-22.
• [41]Shi Y, Wang Y, Luan W, Wang P, Tao T, Zhang J et al.. Long non-coding RNA H19 promotes glioma cell invasion by deriving miR-675. PLoS One. 2014; 9:e86295.
• [42]Kubo T, Yamamoto H, Ichimura K, Jida M, Hayashi T, Otani H et al.. DNA methylation in small lung adenocarcinoma with bronchioloalveolar carcinoma components. Lung Cancer. 2009; 65:328-32.
• [43]Wang J, Zhao YC, Lu YD, Ma CP. Integrated bioinformatics analyses identify dysregulated miRNAs in lung cancer. Eur Rev Med Pharmacol Sci. 2014; 18:2270-4.
• [44]Puisségur MP, Mazure NM, Bertero T, Pradelli L, Grosso S, Robbe-Sermesant K et al.. miR-210 is overexpressed in late stages of lung cancer and mediates mitochondrial alterations associated with modulation of HIF-1 activity. Cell Death Differ. 2011; 18:465-78.
• [45]Grosso S, Doyen J, Parks SK, Bertero T, Paye A, Cardinaud B et al.. MiR-210 promotes a hypoxic phenotype and increases radioresistance in human lung cancer cell lines. Cell Death Dis. 2013; 4:e544.
• [46]Devlin C, Greco S, Martelli F, Ivan M. miR-210: More than a silent player in hypoxia. IUBMB Life. 2011; 63:94-100.
• [47]Eilertsen M, Andersen S, Al-Saad S, Richardsen E, Stenvold H, Hald SM et al.. Positive prognostic impact of miR-210 in non-small cell lung cancer. Lung Cancer. 2014; 83:272-8.
• [48]Camps C, Buffa FM, Colella S, Moore J, Sotiriou C, Sheldon H et al.. hsa-miR-210 Is induced by hypoxia and is an independent prognostic factor in breast cancer. Clin Cancer Res. 2008; 14:1340-8.
• [49]Pachnis V, Belayew A, Tilghman SM. Locus unlinked to alpha-fetoprotein under the control of the murine raf and Rif genes. Proc Natl Acad Sci U S A. 1984; 81:5523-7.
• [50]Matouk I, Ayesh B, Schneider T, Ayesh S, Ohana P, De-Groot N et al.. Oncofetal splice-pattern of the human H19 gene. Biochem Biophys Res Commun. 2004; 318:916-9.
• [51]Matouk I, Raveh E, Ohana P, Lail RA, Gershtain E, Gilon M et al.. The increasing complexity of the oncofetal h19 gene locus: functional dissection and therapeutic intervention. Int J Mol Sci. 2013; 14:4298-316.
• [52]Lustig O, Ariel I, Ilan J, Lev-Lehman E, De-Groot N, Hochberg A. Expression of the imprinted gene H19 in the human fetus. Mol Reprod Dev. 1994; 38:239-46.
• [53]Berteaux N, Lottin S, Monté D, Pinte S, Quatannens B, Coll J et al.. H19 mRNA-like noncoding RNA promotes breast cancer cell proliferation through positive control by E2F1. J Biol Chem. 2005; 280:29625-36.
• [54]Matouk IJ, Mezan S, Mizrahi A, Ohana P, Abu-Lail R, Fellig Y et al.. The oncofetal H19 RNA connection: hypoxia, p53 and cancer. Biochim Biophys Acta. 1803; 2010:443-51.
• [55]Dugimont T, Montpellier C, Adriaenssens E, Lottin S, Dumont L, Iotsova V et al.. The H19 TATA-less promoter is efficiently repressed by wild-type tumor suppressor gene product p53. Oncogene. 1998; 16:2395-401.
• [56]Barsyte-Lovejoy D, Lau SK, Boutros PC, Khosravi F, Jurisica I, Andrulis IL et al.. The c-Myc oncogene directly induces the H19 noncoding RNA by allele-specific binding to potentiate tumorigenesis. Cancer Res. 2006; 66:5330-7.
• [57]Chan LH, Wang W, Yeung W, Deng Y, Yuan P, Mak KK. Hedgehog signaling induces osteosarcoma development through Yap1 and H19 overexpression. Oncogene. 2014; 33:4857-66.
• [58]Guo G, Kang Q, Chen Q, Chen Z, Wang J, Tan L et al.. High expression of long non-coding RNA H19 is required for efficient tumorigenesis induced by Bcr-Abl oncogene. FEBS Lett. 2014; 588:1780-6.
• [59]Adriaenssens E, Lottin S, Berteaux N, Hornez L, Fauquette W, Fafeur V et al.. Cross-talk between mesenchyme and epithelium increases H19 gene expression during scattering and morphogenesis of epithelial cells. Exp Cell Res. 2002; 275:215-29.
• [60]Luo M, Li Z, Wang W, Zeng Y, Liu Z, Qiu J. Long non-coding RNA H19 increases bladder cancer metastasis by associating with EZH2 and inhibiting E-cadherin expression. Cancer Lett. 2013; 333:213-21.
• [61]Kallen AN, Zhou XB, Xu J, Qiao C, Ma J, Yan L et al.. The imprinted H19 lncRNA antagonizes let-7 microRNAs. Mol Cell. 2013; 52:101-12.
• [62]Ma C, Nong K, Zhu H, Wang W, Huang X, Yuan Z et al.. H19 promotes pancreatic cancer metastasis by derepressing let-7′s suppression on its target HMGA2-mediated EMT. Tumour Biol. 2014; 35:9163-9.
• [63]Dey BK, Pfeifer K, Dutta A. The H19 long noncoding RNA gives rise to microRNAs miR-675-3p and miR-675-5p to promote skeletal muscle differentiation and regeneration. Genes Dev. 2014; 28:491-501.
• [64]Gao Y, Wu F, Zhou J, Yan L, Jurczak MJ, Lee HY et al.. The H19/let-7 double-negative feedback loop contributes to glucose metabolism in muscle cells. Nucleic Acids Res. 2014; 2:13799-811.
• [65]Yan L, Zhou J, Gao Y, Ghazal S, Lu L, Bellone S, et al. Regulation of tumor cell migration and invasion by the H19/let-7 axis is antagonized by metformin-induced DNA methylation. Oncogene. 2014. doi:10.1038/onc.2014.236.
• [66]Runge S, Nielsen FC, Nielsen J, Lykke-Andersen J, Wewer UM, Christiansen J. H19 RNA binds four molecules of insulin-like growth factor II mRNA-binding protein. J Biol Chem. 2000; 275:29562-9.
• [67]Matouk IJ, DeGroot N, Mezan S, Ayesh S, Abu-lail R, Hochberg A et al.. The H19 non-coding RNA is essential for human tumor growth. PLoS One. 2007; 2:e845.
• [68]Ayesh S, Matouk I, Schneider T, Ohana P, Laster M, Al-Sharef W et al.. Possible physiological role of H19 RNA. Mol Carcinog. 2002; 35:63-74.
• [69]Dugimont T, Curgy JJ, Wernert N, Delobelle A, Raes MB, Joubel A et al.. The H19 gene is expressed within both epithelial and stromal components of human invasive adenocarcinomas. Biol Cell. 1995; 85:117-24.
• [70]Sadiq AA, Salgia R. MET as a possible target for non-small-cell lung cancer. J Clin Oncol. 2013; 31:1089-96.
• [71]Kondo M, Suzuki H, Ueda R, Osada H, Takagi K, Takahashi T et al.. Frequent loss of imprinting of the H19 gene is often associated with its overexpression in human lung cancers. Oncogene. 1995; 10:1193-8.
• [72]Kaplan R, Luettich K, Heguy A, Hackett NR, Harvey BG, Crystal RG. Monoallelic up-regulation of the imprinted H19 gene in airway epithelium of phenotypically normal cigarette smokers. Cancer Res. 2003; 63:1475-82.
• [73]Chen B, Yu M, Chang Q, Lu Y, Thakur C, Ma D et al.. Mdig de-represses H19 large intergenic non-coding RNA (lincRNA) by down-regulating H3K9me3 and heterochromatin. Oncotarget. 2013; 4:1427-37.
• [74]Berteaux N, Aptel N, Cathala G, Genton C, Coll J, Daccache A et al.. A novel H19 antisense RNA overexpressed in breast cancer contributes to paternal IGF2 expression. Mol Cell Biol. 2008; 28:6731-45.
• [75]Deng Q, He B, Gao T, Pan Y, Sun H, Xu Y et al.. Up-regulation of 91H promotes tumor metastasis and predicts poor prognosis for patients with colorectal cancer. PLoS One. 2014; 9:e103022.
• [76]Vu TH, Chuyen NV, Li T, Hoffman AR. Loss of imprinting of IGF2 sense and antisense transcripts in Wilms’ tumor. Cancer Res. 2003; 63:1900-5.
• [77]Rabinowits G, Gerçel-Taylor C, Day JM, Taylor DD, Kloecker GH. Exosomal microRNA: a diagnostic marker for lung cancer. Clin Lung Cancer. 2009; 10:42-6.
• [78]Heegaard NH, Schetter AJ, Welsh JA, Yoneda M, Bowman ED, Harris CC. Circulating micro-RNA expression profiles in early stage nonsmall cell lung cancer. Int J Cancer. 2012; 130:1378-86.
• [79]Zandberga E, Kozirovskis V, Abols A, Andrējeva D, Purkalne G, Linē A. Cell-free microRNAs as diagnostic, prognostic, and predictive biomarkers for lung cancer. Genes Chromosomes Cancer. 2013; 52:356-69.
• [80]Yu L, Todd NW, Xing L, Xie Y, Zhang H, Liu Z et al.. Early detection of lung adenocarcinoma in sputum by a panel of microRNA markers. Int J Cancer. 2010; 127:2870-8.
• [81]Xie Y, Todd NW, Liu Z, Zhan M, Fang H, Peng H et al.. Altered miRNA expression in sputum for diagnosis of non-small cell lung cancer. Lung Cancer. 2010; 67:170-6.
• [82]Kim NH, Choi SH, Kim CH, Lee CH, Lee TR, Lee AY. Reduced MiR-675 in exosome in H19 RNA-related melanogenesis via MITF as a direct target. J Invest Dermatol. 2014; 134:1075-82.
• [83]Gofrit ON, Benjamin S, Halachmi S, Leibovitch I, Dotan Z, Lamm DL et al.. DNA Based Therapy with Diphtheria Toxin-A BC-819: A Phase 2b Marker Lesion Trial in Patients with Intermediate Risk Nonmuscle Invasive Bladder Cancer. J Urol. 2014; 191:1697-702.
• [84]Matouk I, Evantal N, Amit D, Ohana P, Gofrit O, Sorin V, Birman T, Gershtain E, Hochberg A. The H19-IGF2 Role in Bladder Cancer Biology and DNA-Based Therapy, Bladder Cancer - From Basic Science to Robotic Surgery. ISBN: 978-953-307-839-7, intech, doi:10.5772/29236.
• [85]Ohana P, Matouk I, Amit D, Gilon M, Hochberg A. Toxin-based cancer gene therapy under the control of oncofetal H19 regulatory sequences. 3rd. edition. gene therapy of cancer. 2014; 107–122. ISBN: 978-0-12-394295-1.
• [86]Hasenpusch G, Pfeifer C, Aneja MK, Wagner K, Reinhardt D, Gilon M et al.. Aerosolized BC-819 inhibits primary but not secondary lung cancer growth. PLoS One. 2011; 6:e20760.
• [87]Amit D, Tamir S, Hochberg A. Development of targeted therapy for a broad spectrum of solid tumors mediated by a double promoter plasmid expressing diphtheria toxin under the control of IGF2-P4 and IGF2-P3 regulatory sequences. Int J Clin Exp Med. 2013; 6:110-8.
• [88]Amit D, Matouk IJ, Lavon I, Birman T, Galula J, Abu-Lail R et al.. Transcriptional targeting of glioblastoma by diphtheria toxin-A driven by both H19 and IGF2-P4 promoters. Int J Clin Exp Med. 2012; 5:124-35.
• [89]Amit D, Hochberg A. Development of targeted therapy for bladder cancer mediated by a double promoter plasmid expressing diphtheria toxin under the control of H19 and IGF2-P4 regulatory sequences. J Transl Med. 2010; 8:134. BioMed Central Full Text
• [90]Amit D, Hochberg A. Development of targeted therapy for a broad spectrum of cancers (pancreatic cancer, ovarian cancer, glioblastoma and HCC) mediated by a double promoter plasmid expressing diphtheria toxin under the control of H19 and IGF2-P4 regulatory sequences. Int J Clin Exp Med. 2012; 5:296-305.
• [91]Ganesh S, Iyer AK, Weiler J, Morrissey DV, Amiji MM. Combination of siRNA-directed Gene Silencing With Cisplatin Reverses Drug Resistance in Human Non-small Cell Lung Cancer. Mol Ther Nucleic Acids. 2013; 2:e110.
• [92]Chen G, Kronenberger P, Teugels E, Umelo IA, De Grève J. Targeting the epidermal growth factor receptor in non-small cell lung cancer cells: the effect of combining RNA interference with tyrosine kinase inhibitors or cetuximab. BMC Med. 2012; 10:28. BioMed Central Full Text
• [93]Tsang WP, Kwok TT. Riboregulator H19 induction of MDR1-associated drug resistance in human hepatocellular carcinoma cells. Oncogene. 2007; 26:4877-81.
• [94]Shim G, Choi HW, Lee S, Choi J, Yu YH, Park DE et al.. Enhanced intrapulmonary delivery of anticancer siRNA for lung cancer therapy using cationic ethylphosphocholine-based nanolipoplexes. Mol Ther. 2013; 21:816-24.
• [95]Xu CX, Jere D, Jin H, Chang SH, Chung YS, Shin JY et al.. Poly(ester amine)-mediated, aerosol-delivered Akt1 small interfering RNA suppresses lung tumorigenesis. Am J Respir Crit Care Med. 2008; 178:60-73.
• [96]Beyerle A, Braun A, Merkel O, Koch F, Kissel T, Stoeger T. Comparative in vivo study of poly(ethylene imine)/siRNA complexes for pulmonary delivery in mice. J Control Release. 2011; 151:51-6.
• [97]Li YJ, Zhang YX, Wang PY, Chi YL, Zhang C, Ma Y et al.. Regression of A549 lung cancer tumors by anti-miR-150 vector. Oncol Rep. 2012; 27:129-34.
• [98]Fiori ME, Barbini C, Haas TL, Marroncelli N, Patrizii M, Biffoni M et al.. Antitumor effect of miR-197 targeting in p53 wild-type lung cancer. Cell Death Differ. 2014; 21:774-82.
• [99]Shi Y, Liu C, Liu X, Tang DG, Wang J. The microRNA miR-34a inhibits non-small cell lung cancer (NSCLC) growth and the CD44hi stem-like NSCLC cells. PLoS One. 2014; 9:e90022.