Paxillin predicts survival and relapse in non-small cell lung cancer by microRNA-218 targeting.

Paxillin (PXN) gene mutations are associated with lung adenocarcinoma progression and PXN is known to be a target gene of microRNA-218 (miR-218). On this basis, we hypothesized that PXN overexpression via miR-218 suppression may promote tumor progression and metastasis and that PXN may predict survival and relapse in non-small cell lung cancer (NSCLC). Expression of miR-218 and PXN in 124 surgically resected lung tumors were evaluated by real-time PCR and immunohistochemical analysis. The prognostic value of miR-218 and PXN expression on overall survival (OS) and relapse-free survival (RFS) was analyzed by the Kaplan-Meier test and Cox regression analysis. miR-218 expression in lung tumors was negatively associated with PXN expression. Multivariate analyses showed that PXN and miR-218 might independently predict OS and RFS, respectively, in NSCLC. Moreover, patients with low miR-218 combined with PXN-positive had the worst OS and RFS among the 4 combinations. In a cell model, PXN was negatively regulated by miR-218 and cell proliferation, invasion, and soft agar colony formation were enhanced by PXN overexpression induced by miR-218 suppression. Taken together, our findings suggest that PXN overexpression induced by miR-218 suppression is an independent predictor of survival and relapse in NSCLC, highlighting PXN as a potential therapeutic target to improve clinical outcomes in this disease.

[1]  Y. Cheng,et al.  Subcellular localization of apurinic endonuclease 1 promotes lung tumor aggressiveness via NF-κB activation , 2010, Oncogene.

[2]  D. Fan,et al.  MiR-218 Inhibits Invasion and Metastasis of Gastric Cancer by Targeting the Robo1 Receptor , 2010, PLoS genetics.

[3]  Hong Lu,et al.  Reduced microRNA‐218 expression is associated with high nuclear factor kappa B activation in gastric cancer , 2009, Cancer.

[4]  Bernat Gel,et al.  miR-34a as a prognostic marker of relapse in surgically resected non-small-cell lung cancer. , 2009, Carcinogenesis.

[5]  Gideon Rechavi,et al.  Diagnostic assay based on hsa-miR-205 expression distinguishes squamous from nonsquamous non-small-cell lung carcinoma. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  George A. Calin,et al.  MicroRNAs — the micro steering wheel of tumour metastases , 2009, Nature Reviews Cancer.

[7]  Avrum Spira,et al.  MicroRNAs as modulators of smoking-induced gene expression changes in human airway epithelium , 2009, Proceedings of the National Academy of Sciences.

[8]  Ya‐Wen Cheng,et al.  Human Telomerase Reverse Transcriptase Activated by E6 Oncoprotein Is Required for Human Papillomavirus-16/18-Infected Lung Tumorigenesis , 2008, Clinical Cancer Research.

[9]  M. Malumbres,et al.  Control of cell proliferation pathways by microRNAs , 2008, Cell cycle.

[10]  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.

[11]  Igor Jurisica,et al.  Gene expression–based survival prediction in lung adenocarcinoma: a multi-site, blinded validation study , 2008, Nature Medicine.

[12]  F. Monzon,et al.  Human papillomavirus type 16 reduces the expression of microRNA-218 in cervical carcinoma cells , 2008, Oncogene.

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

[14]  Ya‐Wen Cheng,et al.  Human papillomavirus 16/18 E6 oncoprotein is expressed in lung cancer and related with p53 inactivation. , 2007, Cancer research.

[15]  J. Massagué,et al.  Cancer Metastasis: Building a Framework , 2006, Cell.

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

[17]  F. Slack,et al.  Oncomirs — microRNAs with a role in cancer , 2006, Nature Reviews Cancer.

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

[19]  R. Pillai.  MicroRNA function: multiple mechanisms for a tiny RNA? , 2005, RNA.

[20]  Phillip D. Zamore,et al.  Ribo-gnome: The Big World of Small RNAs , 2005, Science.

[21]  I. Bièche,et al.  Epigenetic inactivation of SLIT3 and SLIT1 genes in human cancers , 2004, British Journal of Cancer.

[22]  C. Turner,et al.  Paxillin: adapting to change. , 2004, Physiological reviews.

[23]  Z. Nawaz,et al.  Tamoxifen induces the expression of maspin through estrogen receptor-alpha. , 2004, Cancer letters.

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

[25]  D. Bartel.  MicroRNAs Genomics, Biogenesis, Mechanism, and Function , 2004, Cell.

[26]  M. Kizaki,et al.  In vitro and in vivo growth suppression of human papillomavirus 16-positive cervical cancer cells by E6 siRNA. , 2003, Molecular therapy : the journal of the American Society of Gene Therapy.

[27]  J. Minna,et al.  SLIT2, a human homologue of the Drosophila Slit2 gene, has tumor suppressor activity and is frequently inactivated in lung and breast cancers. , 2002, Cancer research.

[28]  J. Milner,et al.  Selective silencing of viral gene expression in HPV-positive human cervical carcinoma cells treated with siRNA, a primer of RNA interference , 2002, Oncogene.

[29]  Michael D Schaller,et al.  Paxillin: a focal adhesion-associated adaptor protein , 2001, Oncogene.

[30]  G. Sheu,et al.  The association of human papillomavirus 16/18 infection with lung cancer among nonsmoking Taiwanese women. , 2001, Cancer research.

[31]  C. Turner.  Paxillin and focal adhesion signalling , 2000, Nature Cell Biology.

[32]  K. Kerr,et al.  Expression of CD44v6 but not E‐cadherin or β‐catenin influences prognosis in primary pulmonary adenocarcinoma , 2000, The Journal of pathology.

[33]  M. Hendrix,et al.  Molecular biology of breast cancer metastasis Molecular expression of vascular markers by aggressive breast cancer cells , 2000, Breast Cancer Research.

[34]  B. Rollins,et al.  Expression of the focal adhesion protein paxillin in lung cancer and its relation to cell motility , 1999, Oncogene.

[35]  B. Werness,et al.  Activation of the focal adhesion kinase signal transduction pathway in cervical carcinoma cell lines and human genital epithelial cells immortalized with human papillomavirus type 18 , 1997, Oncogene.

[36]  M. Hendrix,et al.  Maspin acts at the cell membrane to inhibit invasion and motility of mammary and prostatic cancer cells. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[37]  S. Lo,et al.  Increased tyrosine phosphorylation of focal adhesion proteins in myeloid cell lines expressing p210BCR/ABL. , 1995, Oncogene.

[38]  S. Yousem,et al.  Prognostic significance of CD44 expression in adenocarcinoma of the lung , 1995, Clinical molecular pathology.

[39]  E. Danen,et al.  Expression of cd44 splice variants in human cutaneous melanoma and melanoma cell lines is related to tumor progression and metastatic potential , 1995, International journal of cancer.

[40]  W. Eisterer,et al.  CD44 variant isoforms in non-Hodgkin's lymphoma: a new independent prognostic factor. , 1995, Blood.

[41]  J. Parsons,et al.  pp125FAK-dependent tyrosine phosphorylation of paxillin creates a high-affinity binding site for Crk , 1995, Molecular and cellular biology.

[42]  P. Herrlich,et al.  CD44 variant exon epitopes in primary breast cancer and length of survival , 1995, The Lancet.

[43]  J. Brugge,et al.  Detection of Src homology 3-binding proteins, including paxillin, in normal and v-Src-transformed Balb/c 3T3 cells. , 1993, The Journal of biological chemistry.

[44]  S. Knudsen,et al.  Evaluation of microRNA expression profiles that may predict recurrence of localized stage I non-small cell lung cancer after surgical resection. , 2010, Cancer research.

[45]  Stuart Schwartz,et al.  Paxillin is a target for somatic mutations in lung cancer: implications for cell growth and invasion. , 2008, Cancer research.

[46]  T. Yamada,et al.  Progression in gastric carcinoma relative to the ratio of CD44 epithelial variant transcript to CD44 hematopoietic variant transcript , 1996, Cancer.

[47]  D. Parker.  Colorectal cancer prognosis and expression of exon-v6-containing CD44 proteins. , 1995, Lancet.