MicroRNA-21 versus microRNA-34: Lung cancer promoting and inhibitory microRNAs analysed in silico and in vitro and their clinical impact

MicroRNAs are well-known strong RNA regulators modulating whole functional units in complex signaling networks. Regarding clinical application, they have potential as biomarkers for prognosis, diagnosis, and therapy. In this review, we focus on two microRNAs centrally involved in lung cancer progression. MicroRNA-21 promotes and microRNA-34 inhibits cancer progression. We elucidate here involved pathways and imbed these antagonistic microRNAs in a network of interactions, stressing their cancer microRNA biology, followed by experimental and bioinformatics analysis of such microRNAs and their targets. This background is then illuminated from a clinical perspective on microRNA-21 and microRNA-34 as general examples for the complex microRNA biology in lung cancer and its diagnostic value. Moreover, we discuss the immense potential that microRNAs such as microRNA-21 and microRNA-34 imply by their broad regulatory effects. These should be explored for novel therapeutic strategies in the clinic.

[1]  J. Gu,et al.  Induction of p53-regulated genes and tumor regression in lung cancer patients after intratumoral delivery of adenoviral p53 (INGN 201) and radiation therapy. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[2]  Patrick Maisonneuve,et al.  A serum circulating miRNA diagnostic test to identify asymptomatic high-risk individuals with early stage lung cancer , 2011, EMBO molecular medicine.

[3]  Ugo Pastorino,et al.  MicroRNA signatures in tissues and plasma predict development and prognosis of computed tomography detected lung cancer , 2011, Proceedings of the National Academy of Sciences.

[4]  Li Lin,et al.  Effect of microRNA-21 on multidrug resistance reversal in A549/DDP human lung cancer cells. , 2015, Molecular medicine reports.

[5]  C. Croce,et al.  miR-130a targets MET and induces TRAIL-sensitivity in NSCLC by downregulating miR-221 and 222 , 2012, Oncogene.

[6]  K. Wiman,et al.  Strategies for therapeutic targeting of the p53 pathway in cancer , 2006, Cell Death and Differentiation.

[7]  M. Waterfield,et al.  Signalling through phosphoinositide 3-kinases: the lipids take centre stage. , 1999, Current opinion in cell biology.

[8]  William Pao,et al.  AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. , 2014, Cancer discovery.

[9]  M. Brighenti.  MicroRNA and MET in lung cancer. , 2015, Annals of translational medicine.

[10]  Patricia L. Harris,et al.  Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. , 2004, The New England journal of medicine.

[11]  S. Novello,et al.  Lung cancer in never smokers: a different disease , 2014, Current Respiratory Care Reports.

[12]  A. Menssen,et al.  miR-34 and SNAIL form a double-negative feedback loop to regulate epithelial-mesenchymal transitions , 2011, Cell cycle.

[13]  Molly Hammell,et al.  Computational methods to identify miRNA targets. , 2010, Seminars in cell & developmental biology.

[14]  C. Croce,et al.  Cross-talk between MET and EGFR in non-small cell lung cancer involves miR-27a and Sprouty2 , 2013, Proceedings of the National Academy of Sciences.

[15]  Y. Zhuang,et al.  Post‐transcriptional up‐regulation of miR‐21 by type I collagen , 2011, Molecular carcinogenesis.

[16]  W. Cho,et al.  Restoration of tumour suppressor hsa-miR-145 inhibits cancer cell growth in lung adenocarcinoma patients with epidermal growth factor receptor mutation. , 2009, European journal of cancer.

[17]  A. Hatzigeorgiou,et al.  A guide through present computational approaches for the identification of mammalian microRNA targets , 2006, Nature Methods.

[18]  Sylvain Pradervand,et al.  Impact of normalization on miRNA microarray expression profiling. , 2009, RNA.

[19]  B. Li,et al.  MiR-155 inhibits the sensitivity of lung cancer cells to cisplatin via negative regulation of Apaf-1 expression , 2012, Cancer Gene Therapy.

[20]  T. Speed,et al.  A positive feedback between p53 and miR-34 miRNAs mediates tumor suppression , 2014, Genes & development.

[21]  D. Tang,et al.  Identification of plasma microRNAs as novel noninvasive biomarkers for early detection of lung cancer , 2013, European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation.

[22]  Xiao-guang Liu,et al.  miRNAs expression profiling to distinguish lung squamous-cell carcinoma from adenocarcinoma subtypes , 2012, Journal of Cancer Research and Clinical Oncology.

[23]  P. Hainaut,et al.  TP53 and KRAS mutation load and types in lung cancers in relation to tobacco smoke: distinct patterns in never, former, and current smokers. , 2005, Cancer research.

[24]  Erik Vassella,et al.  miR-34a and miR-15a/16 are co-regulated in non-small cell lung cancer and control cell cycle progression in a synergistic and Rb-dependent manner , 2011, Molecular Cancer.

[25]  Christopher J. Cheng,et al.  Nanoparticle-based therapy in an in vivo microRNA-155 (miR-155)-dependent mouse model of lymphoma , 2012, Proceedings of the National Academy of Sciences.

[26]  M. Tsao,et al.  Molecular predictive and prognostic markers in non-small-cell lung cancer. , 2009, The Lancet. Oncology.

[27]  Jane J. Sohn,et al.  MicroRNA expression and clinical outcomes in patients treated with adjuvant chemotherapy after complete resection of non-small cell lung carcinoma. , 2010, Cancer research.

[28]  F. Slack,et al.  miRNA-34 prevents cancer initiation and progression in a therapeutically resistant K-ras and p53-induced mouse model of lung adenocarcinoma. , 2012, Cancer research.

[29]  H. Ji,et al.  MicroRNA-143 (miR-143) Regulates Cancer Glycolysis via Targeting Hexokinase 2 Gene* , 2012, The Journal of Biological Chemistry.

[30]  Shuhang Wang,et al.  Identification of plasma microRNA profiles for primary resistance to EGFR-TKIs in advanced non-small cell lung cancer (NSCLC) patients with EGFR activating mutation , 2015, Journal of Hematology & Oncology.

[31]  R. Stephens,et al.  Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. , 2006, Cancer cell.

[32]  R. Herbst,et al.  Bevacizumab and erlotinib: a promising new approach to the treatment of advanced NSCLC. , 2008, The oncologist.

[33]  J. Castle,et al.  Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs , 2005, Nature.

[34]  Yingdong Zhao,et al.  MicroRNA Expression Differentiates Histology and Predicts Survival of Lung Cancer , 2010, Clinical Cancer Research.

[35]  C. Harris,et al.  p53 and K-ras mutations in lung cancers from former and never-smoking women. , 2001, Cancer research.

[36]  Thomas Thum,et al.  Bioinformatics of cardiovascular miRNA biology. , 2015, Journal of molecular and cellular cardiology.

[37]  K. Wiman,et al.  Mutant p53 reactivation by small molecules makes its way to the clinic , 2014, FEBS letters.

[38]  W. Bshara,et al.  MiR-205 and MiR-375 MicroRNA Assays to Distinguish Squamous Cell Carcinoma from Adenocarcinoma in Lung Cancer Biopsies , 2015, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[39]  N. Rajewsky.  microRNA target predictions in animals , 2006, Nature Genetics.

[40]  L. Lim,et al.  A microRNA component of the p53 tumour suppressor network , 2007, Nature.

[41]  Zhenyu Xuan,et al.  A biochemical approach to identifying microRNA targets , 2007, Proceedings of the National Academy of Sciences.

[42]  W. Sellers,et al.  Regulation of G1 progression by the PTEN tumor suppressor protein is linked to inhibition of the phosphatidylinositol 3-kinase/Akt pathway. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[43]  M. Kiebler,et al.  Faculty Opinions recommendation of Argonaute HITS-CLIP decodes microRNA-mRNA interaction maps. , 2009 .

[44]  Y. Mo,et al.  MicroRNA-145 suppresses cell invasion and metastasis by directly targeting mucin 1. , 2010, Cancer research.

[45]  Soo Young Lee,et al.  Combining microRNA-449a/b with a HDAC inhibitor has a synergistic effect on growth arrest in lung cancer. , 2012, Lung cancer.

[46]  C. Croce,et al.  MicroRNA-cancer connection: the beginning of a new tale. , 2006, Cancer research.

[47]  T. Iwakuma,et al.  Targeting Oncogenic Mutant p53 for Cancer Therapy , 2015, Front. Oncol..

[48]  A. Schetter,et al.  Circulating micro‐RNA expression profiles in early stage nonsmall cell lung cancer , 2012, International journal of cancer.

[49]  W. Cavenee,et al.  Therapeutic resistance in cancer: microRNA regulation of EGFR signaling networks , 2013, Cancer biology & medicine.

[50]  H. Allgayer,et al.  MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer , 2008, Oncogene.

[51]  M. Dobbelstein,et al.  MicroRNA-449 in cell fate determination , 2011, Cell cycle.

[52]  Richard J Stephens,et al.  Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[53]  Wei Wang,et al.  MicroRNA-34b and MicroRNA-34c are targets of p53 and cooperate in control of cell proliferation and adhesion-independent growth. , 2007, Cancer research.

[54]  Christopher A. Maher,et al.  A p53/miRNA-34 axis regulates Snail1-dependent cancer cell epithelial–mesenchymal transition , 2011 .

[55]  B. Jiang,et al.  Alteration in Mir-21/PTEN Expression Modulates Gefitinib Resistance in Non-Small Cell Lung Cancer , 2014, PloS one.

[56]  K. Yoon,et al.  The prognostic impact of microRNA sequence polymorphisms on the recurrence of patients with completely resected non-small cell lung cancer. , 2012, The Journal of thoracic and cardiovascular surgery.

[57]  F. Slack,et al.  RAS Is Regulated by the let-7 MicroRNA Family , 2005, Cell.

[58]  Michael Kertesz,et al.  The role of site accessibility in microRNA target recognition , 2007, Nature Genetics.

[59]  D. Takai,et al.  Genome structure‐based screening identified epigenetically silenced microRNA associated with invasiveness in non‐small‐cell lung cancer , 2012, International journal of cancer.

[60]  George A Calin,et al.  Downregulation of microRNA expression in the lungs of rats exposed to cigarette smoke , 2009, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[61]  H. Hermeking.  p53 enters the microRNA world. , 2007, Cancer cell.

[62]  Yue Yu,et al.  Deregulated expression of miR-21, miR-143 and miR-181a in non small cell lung cancer is related to clinicopathologic characteristics or patient prognosis. , 2010, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[63]  Vidar Skaug,et al.  The Association of MicroRNA Expression with Prognosis and Progression in Early-Stage, Non–Small Cell Lung Adenocarcinoma: A Retrospective Analysis of Three Cohorts , 2011, Clinical Cancer Research.

[64]  Ying Feng,et al.  Supplemental Data P53-mediated Activation of Mirna34 Candidate Tumor-suppressor Genes , 2022 .

[65]  T. Betsuyaku,et al.  Identification of microRNAs differentially expressed between lung squamous cell carcinoma and lung adenocarcinoma. , 2013, Molecular medicine reports.

[66]  E. Olson,et al.  Modulation of K-Ras-dependent lung tumorigenesis by MicroRNA-21. , 2010, Cancer cell.

[67]  N. Colburn,et al.  MicroRNA-21 promotes cell transformation by targeting the programmed cell death 4 gene , 2008, Oncogene.

[68]  V. Velculescu,et al.  Implications of micro-RNA profiling for cancer diagnosis , 2006, Oncogene.

[69]  Xiaoping Liu,et al.  MicroRNA-486 as a Biomarker for Early Diagnosis and Recurrence of Non-Small Cell Lung Cancer , 2015, PloS one.

[70]  Masahiro Fukuoka,et al.  Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected]. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[71]  J. Minna,et al.  Focus on lung cancer. , 2002, Cancer cell.

[72]  A. Marchetti,et al.  EGFR mutations in non-small-cell lung cancer: analysis of a large series of cases and development of a rapid and sensitive method for diagnostic screening with potential implications on pharmacologic treatment. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[73]  Dan Li,et al.  Meta-Analysis of Microarrays: Diagnostic value of microRNA-21 as a Biomarker for Lung Cancer , 2015, The International journal of biological markers.

[74]  Patricia Soteropoulos,et al.  MicroRNA let-7a down-regulates MYC and reverts MYC-induced growth in Burkitt lymphoma cells. , 2007, Cancer research.

[75]  Xing Chen,et al.  MicroRNA-34a overcomes HGF-mediated gefitinib resistance in EGFR mutant lung cancer cells partly by targeting MET. , 2014, Cancer letters.

[76]  M. Ceccarelli,et al.  Upregulation of miR-21 by Ras in vivo and its role in tumor growth , 2011, Oncogene.

[77]  T. Dønnem,et al.  Prognostic Impact of MiR-155 in Non-Small Cell Lung Cancer Evaluated by in Situ Hybridization , 2011, Journal of Translational Medicine.

[78]  김남희,et al.  A p53/miRNA-34 axis regulates Snail1-dependent cancer cell epithelial-mesenchymal transition , 2011 .

[79]  F. López-Ríos,et al.  MicroRNA-Dependent Regulation of Transcription in Non-Small Cell Lung Cancer , 2014, PloS one.

[80]  F. Khuri,et al.  Adenovirus-mediated p53 gene transfer in sequence with cisplatin to tumors of patients with non-small-cell lung cancer. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[81]  Yu Wang,et al.  MicroRNA-143 Inhibits Migration and Invasion of Human Non-Small-Cell Lung Cancer and Its Relative Mechanism , 2013, International journal of biological sciences.

[82]  Massimo Bellomi,et al.  miR-Test: a blood test for lung cancer early detection. , 2015, Journal of the National Cancer Institute.

[83]  David Cella,et al.  Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. , 2003, JAMA.

[84]  Akira Mogi,et al.  TP53 Mutations in Nonsmall Cell Lung Cancer , 2011, Journal of biomedicine & biotechnology.

[85]  Anne-Marie C. Dingemans,et al.  MicroRNA Expression and Clinical Outcome of Small Cell Lung Cancer , 2011, PloS one.

[86]  R. Chen,et al.  Quantification and Dynamic Monitoring of EGFR T790M in Plasma Cell-Free DNA by Digital PCR for Prognosis of EGFR-TKI Treatment in Advanced NSCLC , 2014, PloS one.

[87]  Ming Liu,et al.  MicroRNA-21 Regulates Non-Small Cell Lung Cancer Cell Invasion and Chemo-Sensitivity through SMAD7 , 2016, Cellular Physiology and Biochemistry.

[88]  D. Mu,et al.  MicroRNAs and lung cancers: from pathogenesis to clinical implications , 2012, Frontiers of Medicine.

[89]  Naoto Tsuchiya,et al.  Tumor-suppressive miR-34a induces senescence-like growth arrest through modulation of the E2F pathway in human colon cancer cells , 2007, Proceedings of the National Academy of Sciences.

[90]  M. Kayani,et al.  Role of miRNAs in breast cancer. , 2011, Asian Pacific journal of cancer prevention : APJCP.

[91]  A. Krogh,et al.  Programmed Cell Death 4 (PDCD4) Is an Important Functional Target of the MicroRNA miR-21 in Breast Cancer Cells* , 2008, Journal of Biological Chemistry.

[92]  J. Nikliński,et al.  Validation for histology‐driven diagnosis in non‐small cell lung cancer using hsa‐miR‐205 and hsa‐miR‐21 expression by two different normalization strategies , 2016, International journal of cancer.

[93]  R. Aharonov,et al.  MicroRNAs accurately identify cancer tissue origin , 2008, Nature Biotechnology.

[94]  N. Hanna,et al.  MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling , 2008 .

[95]  S. Lippman,et al.  Lung cancer. , 2008, The New England journal of medicine.

[96]  Jian-An Huang,et al.  Expression profile analysis of microRNAs and downregulated miR-486-5p and miR-30a-5p in non-small cell lung cancer. , 2015, Oncology reports.

[97]  Kun Wang,et al.  Foxo3a Regulates Apoptosis by Negatively Targeting miR-21* , 2010, The Journal of Biological Chemistry.

[98]  A. Hatzigeorgiou,et al.  A combined computational-experimental approach predicts human microRNA targets. , 2004, Genes & development.

[99]  C. Burge,et al.  Prediction of Mammalian MicroRNA Targets , 2003, Cell.

[100]  Wun-Jae Kim,et al.  Downregulation of cell‐free miR‐198 as a diagnostic biomarker for lung adenocarcinoma‐associated malignant pleural effusion , 2013, International journal of cancer.

[101]  M. Zavolan,et al.  Identification and consequences of miRNA–target interactions — beyond repression of gene expression , 2014, Nature Reviews Genetics.

[102]  David Atlan,et al.  Non-Coding RNAs in Lung Cancer: Contribution of Bioinformatics Analysis to the Development of Non-Invasive Diagnostic Tools , 2016, Genes.

[103]  A. E. Erson,et al.  miRNAs and cancer: New research developments and potential clinical applications , 2009, Cancer biology & therapy.

[104]  J. Woodburn,et al.  The epidermal growth factor receptor and its inhibition in cancer therapy. , 1999, Pharmacology & therapeutics.

[105]  W. Grizzle,et al.  miR-155 promotes macroscopic tumor formation yet inhibits tumor dissemination from mammary fat pads to the lung by preventing EMT , 2011, Oncogene.

[106]  Yuriy Gusev,et al.  Computational analysis of biological functions and pathways collectively targeted by co-expressed microRNAs in cancer , 2007, BMC Bioinformatics.

[107]  Anindya Dutta,et al.  The tumor suppressor microRNA let-7 represses the HMGA2 oncogene. , 2007, Genes & development.

[108]  Zhiwei Wang,et al.  Delta‐tocotrienol suppresses Notch‐1 pathway by upregulating miR‐34a in nonsmall cell lung cancer cells , 2012, International journal of cancer.

[109]  F. Slack,et al.  Combinatorial Action of MicroRNAs let-7 and miR-34 Effectively Synergizes with Erlotinib to Suppress Non-small Cell Lung Cancer Cell Proliferation , 2015, Cell cycle.

[110]  F. Khuri,et al.  A randomized phase II study of ganetespib, a heat shock protein 90 inhibitor, in combination with docetaxel in second-line therapy of advanced non-small cell lung cancer (GALAXY-1). , 2015, Annals of oncology : official journal of the European Society for Medical Oncology.

[111]  J. Minna,et al.  Lung cancer • 9: Molecular biology of lung cancer: clinical implications , 2003, Thorax.

[112]  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.

[113]  C. Burge,et al.  Most mammalian mRNAs are conserved targets of microRNAs. , 2008, Genome research.

[114]  Sung-Liang Yu,et al.  MicroRNA signature predicts survival and relapse in lung cancer. , 2008, Cancer cell.

[115]  Xuan Huang,et al.  miR‑96 functions as a tumor suppressor gene by targeting NUAK1 in pancreatic cancer. , 2014, International journal of molecular medicine.

[116]  Reuven Agami,et al.  Regulation of the p27Kip1 tumor suppressor by miR‐221 and miR‐222 promotes cancer cell proliferation , 2007 .

[117]  H. Horvitz,et al.  MicroRNA expression profiles classify human cancers , 2005, Nature.

[118]  R. Nicholson,et al.  EGFR and cancer prognosis. , 2001, European journal of cancer.

[119]  Michael A. Beer,et al.  Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. , 2007, Molecular cell.

[120]  C. Croce,et al.  EGFR and MET receptor tyrosine kinase-altered microRNA expression induces tumorigenesis and gefitinib resistance in lung cancers , 2011, Nature medicine.

[121]  J. Sun,et al.  EGFR and MET receptor tyrosine kinase-altered microRNA expression induces tumorigenesis and gefitinib resistance in lung cancers , 2011, Nature Medicine.

[122]  Hansjuerg Alder,et al.  miR-221&222 regulate TRAIL resistance and enhance tumorigenicity through PTEN and TIMP3 downregulation. , 2009, Cancer cell.

[123]  J. Minna,et al.  Molecular genetics of lung cancer. , 1988, Annual review of medicine.

[124]  J. Minna,et al.  Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. , 2006, Journal of the National Cancer Institute.

[125]  S. Rai,et al.  Housekeeping genes for studies of plasma microRNA: A need for more precise standardization. , 2015, Surgery.

[126]  G. Daley,et al.  Selective Blockade of MicroRNA Processing by Lin28 , 2008, Science.

[127]  J. Lieberman,et al.  Desperately seeking microRNA targets , 2010, Nature Structural &Molecular Biology.

[128]  Huazong Zeng,et al.  miRNA-145 inhibits non-small cell lung cancer cell proliferation by targeting c-Myc , 2010, Journal of experimental & clinical cancer research : CR.

[129]  R. Govindan,et al.  Use of MicroRNA Expression Levels to Predict Outcomes in Resected Stage I Non-small Cell Lung Cancer , 2010, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[130]  H. Hermeking.  The miR-34 family in cancer and apoptosis , 2010, Cell Death and Differentiation.

[131]  C. la Vecchia,et al.  Clinical utility of a plasma-based miRNA signature classifier within computed tomography lung cancer screening: a correlative MILD trial study. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[132]  S. Ren,et al.  MiR-21 overexpression is associated with acquired resistance of EGFR-TKI in non-small cell lung cancer. , 2014, Lung cancer.

[133]  C. Ficorella,et al.  EGFR genomic alterations in cancer: prognostic and predictive values. , 2011, Frontiers in bioscience.

[134]  Xi-rong Guo,et al.  microRNA-145 suppresses lung adenocarcinoma-initiating cell proliferation by targeting OCT4. , 2011, Oncology reports.

[135]  Lin Wang,et al.  Identification of A Panel of Serum microRNAs as Biomarkers for Early Detection of Lung Adenocarcinoma , 2017, Journal of Cancer.

[136]  John McAnally,et al.  MicroRNAs miR-143 and miR-145 modulate cytoskeletal dynamics and responsiveness of smooth muscle cells to injury. , 2009, Genes & development.

[137]  R. Ramesh,et al.  Cancer stem cells: progress and challenges in lung cancer. , 2014, Stem cell investigation.

[138]  A. Lund,et al.  MicroRNA and cancer , 2012, Molecular oncology.

[139]  Wei Sun,et al.  MiR-130a overcomes gefitinib resistance by targeting met in non-small cell lung cancer cell lines. , 2014, Asian Pacific journal of cancer prevention : APJCP.

[140]  Y. Yatabe,et al.  The sensitivity of lung cancer cell lines to the EGFR-selective tyrosine kinase inhibitor ZD1839 ('Iressa') is not related to the expression of EGFR or HER-2 or to K-ras gene status. , 2003, Lung cancer.

[141]  W. Dong,et al.  High expression of miR-21 and miR-155 predicts recurrence and unfavourable survival in non-small cell lung cancer. , 2013, European journal of cancer.

[142]  Heidi J. Peltier,et al.  Normalization of microRNA expression levels in quantitative RT-PCR assays: identification of suitable reference RNA targets in normal and cancerous human solid tissues. , 2008, RNA.

[143]  A. Børresen-Dale,et al.  Unique microRNA-profiles in EGFR-mutated lung adenocarcinomas , 2014, International journal of cancer.

[144]  Phillip A Sharp,et al.  Suppression of non-small cell lung tumor development by the let-7 microRNA family , 2008, Proceedings of the National Academy of Sciences.

[145]  Y. Yatabe,et al.  Reduced Expression of the let-7 MicroRNAs in Human Lung Cancers in Association with Shortened Postoperative Survival , 2004, Cancer Research.

[146]  C. Croce,et al.  MicroRNA signatures in human cancers , 2006, Nature Reviews Cancer.

[147]  Zhiguo Wang.  MicroRNA: A matter of life or death. , 2010, World journal of biological chemistry.

[148]  I. Faraoni,et al.  miR-155 gene: a typical multifunctional microRNA. , 2009, Biochimica et biophysica acta.

[149]  Jiuyong Li,et al.  Identifying miRNAs, targets and functions , 2012, Briefings Bioinform..

[150]  Edward S. Kim,et al.  Implication of the Insulin-like Growth Factor-IR Pathway in the Resistance of Non–small Cell Lung Cancer Cells to Treatment with Gefitinib , 2007, Clinical Cancer Research.

[151]  Tsung-Cheng Chang,et al.  Widespread microRNA repression by Myc contributes to tumorigenesis , 2008, Nature Genetics.

[152]  Yu Liang.  An expression meta-analysis of predicted microRNA targets identifies a diagnostic signature for lung cancer , 2008, BMC Medical Genomics.

[153]  F. Slack,et al.  A combinatorial microRNA therapeutics approach to suppressing non-small cell lung cancer , 2014, Oncogene.

[154]  Wei Yan,et al.  Tissue-dependent paired expression of miRNAs , 2007, Nucleic acids research.

[155]  C. Caldas,et al.  Micro‐RNAs and breast cancer , 2010, Molecular oncology.

[156]  Mohsen Khorshid,et al.  PAR-CliP - A Method to Identify Transcriptome-wide the Binding Sites of RNA Binding Proteins , 2010, Journal of visualized experiments : JoVE.

[157]  K. Gunsalus,et al.  Combinatorial microRNA target predictions , 2005, Nature Genetics.

[158]  E. Kroh,et al.  Blood Cell Origin of Circulating MicroRNAs: A Cautionary Note for Cancer Biomarker Studies , 2011, Cancer Prevention Research.

[159]  Frank J. Slack,et al.  The multiple roles of microRNA-155 in oncogenesis , 2013, Journal of Clinical Bioinformatics.

[160]  T. Elton,et al.  Regulation of the MIR155 host gene in physiological and pathological processes. , 2013, Gene.

[161]  R. Kolde,et al.  Meta‐analysis of microRNA expression in lung cancer , 2013, International journal of cancer.

[162]  S. De Flora,et al.  Smoke‐induced microRNA and related proteome alterations. Modulation by chemopreventive agents , 2012, International journal of cancer.

[163]  W. Cho,et al.  MiR-145 inhibits cell proliferation of human lung adenocarcinoma by targeting EGFR and NUDT1 , 2011, RNA biology.

[164]  D. Bartel,et al.  The impact of microRNAs on protein output , 2008, Nature.

[165]  Vassilis Georgoulias,et al.  Prognostic value of mature microRNA-21 and microRNA-205 overexpression in non-small cell lung cancer by quantitative real-time RT-PCR. , 2008, Clinical chemistry.