Expression of SIRT1 and cortactin is associated with progression of non-small cell lung cancer.

Cortactin is an F-actin binding protein involved in cell migration and tumor metastasis. Recent reports suggest that silent mating-type information regulation 2 homologue 1 (sirtuin1; SIRT1) enhances the function of cortactin and promotes cell migration. We investigated SIRT1 and cortactin expression in 144 invasive non-small cell lung cancers (NSCLC) and 19 adenocarcinomas in situ (AIS) by immunohistochemistry and evaluated their clinicopathological significance in NSCLC. Positive SIRT1 and cortactin expression was observed in 67% (96 of 144) and 58% (84 of 144) of patients with invasive NSCLC, respectively. SIRT1 and cortactin expression was significantly associated with unfavorable clinicopathological factors, including high pathological T stage, lymph node metastasis, and advanced tumor invasion (AIS vs. invasive adenocarcinoma). Cortactin was significantly associated with high pathological T stage and lymph node metastasis in SIRT1-positive tumors. Cytoplasmic SIRT1 was significantly associated with high pathological T stage and large tumor size compared to that of nuclear SIRT1. Large tumor size, high pathological T stage, lymph node metastasis, and cytoplasmic SIRT1 expression were significantly associated with shorter overall survival in a univariate analysis. Our findings suggest that SIRT1 and cortactin may play a role in the progression of NSCLC and may cooperate during tumor progression in NSCLC.

[1]  P. Kruk,et al.  Deacetylation of cortactin by SIRT1 promotes cell migration , 2009, Oncogene.

[2]  K. Jang,et al.  Expressions of E-cadherin, Cortactin and MMP-9 in Pseudoepitheliomatous Hyperplasia and Squamous Cell Carcinoma of the Head and Neck: Their Relationships with Clinicopathologic Factors and Prognostic Implication , 2012, Korean journal of pathology.

[3]  D. Yamazaki,et al.  Regulation of cancer cell motility through actin reorganization , 2005, Cancer science.

[4]  Delin Chen,et al.  Mammalian SIRT1 Represses Forkhead Transcription Factors , 2004, Cell.

[5]  L. Forman,et al.  Aberrant Cytoplasm Localization and Protein Stability of SIRT1 is Regulated by PI3K/IGF-1R Signaling in Human Cancer Cells , 2010, International journal of biological sciences.

[6]  L. Guarente,et al.  Sir2 links chromatin silencing, metabolism, and aging. , 2000, Genes & development.

[7]  B. Tang.  Sirt1 and cell migration , 2010, Cell adhesion & migration.

[8]  E. Berg,et al.  World Health Organization Classification of Tumours , 2002 .

[9]  J. Forbes,et al.  EMS1 gene expression in primary breast cancer: relationship to cyclin D1 and oestrogen receptor expression and patient survival , 1998, Oncogene.

[10]  Q. Zhan,et al.  Amplification and overexpression of CTTN (EMS1) contribute to the metastasis of esophageal squamous cell carcinoma by promoting cell migration and anoikis resistance. , 2006, Cancer research.

[11]  J. Weber,et al.  Deacetylation of the retinoblastoma tumour suppressor protein by SIRT1. , 2007, The Biochemical journal.

[12]  R. Weinberg,et al.  hSIR2SIRT1 Functions as an NAD-Dependent p53 Deacetylase , 2001, Cell.

[13]  C. Tzao,et al.  Distinct HIC1-SIRT1-p53 loop deregulation in lung squamous carcinoma and adenocarcinoma patients. , 2009, Neoplasia.

[14]  Delin Chen,et al.  Negative Control of p53 by Sir2α Promotes Cell Survival under Stress , 2001, Cell.

[15]  D. Zimonjic,et al.  Amplification and overexpression of the EMS 1 oncogene, a possible prognostic marker, in human hepatocellular carcinoma. , 2003, The Journal of molecular diagnostics : JMD.

[16]  S. Baylin,et al.  Tumor Suppressor HIC1 Directly Regulates SIRT1 to Modulate p53-Dependent DNA-Damage Responses , 2005, Cell.

[17]  K. Jang,et al.  SIRT1 Expression is Associated With Poor Prognosis of Diffuse Large B-Cell Lymphoma , 2008, The American journal of surgical pathology.

[18]  K. Jang,et al.  Expression of DBC1 and SIRT1 Is Associated with Poor Prognosis of Gastric Carcinoma , 2009, Clinical Cancer Research.

[19]  D. Reinberg,et al.  Composition and histone substrates of polycomb repressive group complexes change during cellular differentiation. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[20]  Alissa M. Weaver.  Cortactin in tumor invasiveness. , 2008, Cancer letters.

[21]  S. Knuutila,et al.  Specificity, selection and significance of gene amplifications in cancer. , 2007, Seminars in cancer biology.

[22]  Masahiro Tsuboi,et al.  International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society International Multidisciplinary Classification of Lung Adenocarcinoma , 2011, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[23]  E. Schuuring.  The involvement of the chromosome 11q13 region in human malignancies: cyclin D1 and EMS1 are two new candidate oncogenes--a review. , 1995, Gene.

[24]  M. Mayo,et al.  Modulation of NF‐κB‐dependent transcription and cell survival by the SIRT1 deacetylase , 2004, The EMBO journal.

[25]  Xianglin Shi,et al.  Cytoplasm‐localized SIRT1 enhances apoptosis , 2007, Journal of cellular physiology.

[26]  Steven P. Gygi,et al.  Stress-Dependent Regulation of FOXO Transcription Factors by the SIRT1 Deacetylase , 2004, Science.

[27]  K. Jang,et al.  Expression and prognostic significance of SIRT1 in ovarian epithelial tumours , 2009, Pathology.

[28]  J. Rodrigo,et al.  EMS1 gene amplification correlates with poor prognosis in squamous cell carcinomas of the head and neck. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[29]  M. Fresno,et al.  Distinctive clinicopathological associations of amplification of the cortactin gene at 11q13 in head and neck squamous cell carcinomas , 2009, Journal of Pathology.

[30]  Jun Liu,et al.  microRNA-182 inhibits the proliferation and invasion of human lung adenocarcinoma cells through its effect on human cortical actin-associated protein. , 2011, International journal of molecular medicine.

[31]  L. Guarente,et al.  Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase , 2000, Nature.

[32]  S. Minucci,et al.  Human SIR2 deacetylates p53 and antagonizes PML/p53‐induced cellular senescence , 2002, The EMBO journal.