Adenovirus-mediated SOCS 3 gene transfer inhibits the growth and enhances the radiosensitivity of human non-small cell lung cancer cells

The Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway is one of the most important components of cytokine signaling cascades. JAK-STAT signaling pathway modulates various fundamental biological processes and cancer pathogenesis. JAK-STAT is controlled by negative regulators that include suppressors of cytokine signaling (SOCS) proteins. Failure of feedback suppression by SOCS proteins may result in activated JAK-STAT signaling. Methylation-mediated silencing of SOCS3 has been reported in non-small lung cancer (NSCLC) and other human cancers. In this study, we restored SOCS3 expression using adenovirus-mediated gene transfer in NSCLC cells. Infection with a SOCS3-expressing vector inhibited the growth of lung cancer cells, with or without SOCS3 expression, at 2-3 days after infection. The growth inhibition of lung cancer cells was associated with suppressing entry into the S-phase. Restoration of SOCS3 expression induced apoptosis of NSCLC cells that did not express SOCS3. In addition, over-expression of SOCS3 by adenoviral transfer enhanced the radiosensitivity of treated NSCLC cells. In conclusion, our findings may provide insights into the development of applications of SOCS3 gene therapy for lung cancer and, possibly, other human cancers. Introduction Suppressors of cytokine signaling (SOCS) proteins comprise a family of eight cytoplasmic proteins: cytokine-inducible SH2-domain-containing protein (CIS) and SOCS1-7 (1,2). SOCS proteins contain a central SH2 domain, a conserved C-terminus (the SOCS box) and a unique N-terminus (1,2). Expression of SOCS proteins can be stimulated by activating Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathways. SOCS can inhibit JAK activity via a feedback loop by binding to both a cytokine receptor and JAK itself (3-5). JAK-STAT pathway mediates cytokine signaling, which control immune functions, cell growth, differentiation and hematopoiesis (6). Aberrant activation of JAK-STAT pathway has been implicated in many human cancers. Constitutively activated JAK leads to persistent activation of STAT3. Constitutive activation of JAK2 was found in T-cell acute lymphoblastic leukemia of childhood (7). An activating somatic JAK2 mutation that encodes a V617F substitution, which promotes JAK2 catalytic activation and cytokine-independent signaling, was identified in the majority of patients with myeloproliferative neoplasms (8,9). In addition, STAT3 is a well-known oncogene (10). Transfection with constitutively activated STAT3 results in tumorigenesis in nude mice (10). Constitutively active STAT3 has been found in various human cancers, including non-small cell lung cancer (NSCLC) (11-13). Aberrant SOCS feedback inhibition of JAK-STAT signaling can also result in carcinogenesis. Abnormal STAT3 activation after SOCS3 genetic ablation has been demonstrated (14-16). In addition, deletion of the SOCS3 gene promoted hepatitis-induced hepatocarcinogenesis (17). Down-regulation of SOCS3 in both lung adenocarcinoma and squamous cell carcinoma was demonstrated by cDNA microarrays (18,19). SOCS3 silencing by promoter hypermethylation with enhanced STAT3 activation has been reported in human NSCLC (11) and various other human ONCOLOGY REPORTS 24: 1605-1612, 2010 Adenovirus-mediated SOCS3 gene transfer inhibits the growth and enhances the radiosensitivity of human non-small cell lung cancer cells YU-CHING LIN1,2,6, CHIN-KUO LIN1,2,6, YING-HUANG TSAI1,4, HSU-HUEI WENG3,6, YA-CHIN LI1, LIANG YOU8, JAN-KAN CHEN5, DAVID M. JABLONS8 and CHENG-TA YANG4,7 1Division of Pulmonary and Critical Care Medicine, Departments of 2Respiratory Care, and 3Diagnostic Radiology, Chang Gung Memorial Hospital, Chiayi; Departments of 4Respiratory Care, and 5Physiology, College of Medicine, Chang Gung University, Taoyuan; 6Chang Gung Institute of Technology, Chiayi; 7Department of Thoracic Medicine, Chang Gung Memorial Hospital, Taipei, Taiwan, R.O.C.; 8Thoracic Oncology Laboratory, Department of Surgery, University of California, San Francisco, CA 94115, USA Received July 14, 2010; Accepted September 2, 2010 DOI: 10.3892/or_00001024 _________________________________________ Correspondence to: Dr Cheng-Ta Yang, Department of Thoracic Medicine, Chang Gung Memorial Hospital 199, Tung-Hwa North Road, Taipei 10507, Taiwan, R.O.C. E-mail: yang1946@adm.cgmh.org.tw