ERp57 modulates STAT3 activity in radioresistant laryngeal cancer cells and serves as a prognostic marker for laryngeal cancer

Abstract

// Min Ho Choe 1 , Joong Won Min 1 , Hong Bae Jeon 2 , Dong-Hyung Cho 3 , Jeong Su Oh 4 , Hyun Gyu Lee 5 , Sang-Gu Hwang 1 , Sungkwan An 6 , Young-Hoon Han 1 and Jae-Sung Kim 1 1 Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, Korea 2 Biomedical Research Institute, MEDIPOST Co., Ltd., Seoul, Korea 3 Graduate School of East-West Medical Science, Kyung Hee University, Suwon, Korea 4 Department of Genetic Engineering, Sungkyunkwan University, Suwon, Korea 5 Department of Microbiology and Immunology, College of Medicine, Yonsei University, Seoul, Korea 6 Molecular-Targeted Drug Research Center and Korea Institute for Skin and Clinical Sciences, Konkuk University, Seoul, Korea Correspondence: Jae-Sung Kim, email: // Keywords : ERp57, STAT3, Mcl-1, Laryngeal cancer, Radioresistance Received : August 18, 2014 Accepted : December 12, 2014 Published : January 08, 2015 Abstract Although targeting radioresistant tumor cells is essential for enhancing the efficacy of radiotherapy, the signals activated in resistant tumors are still unclear. This study shows that ERp57 contributes to radioresistance of laryngeal cancer by activating STAT3. Increased ERp57 was associated with the radioresistant phenotype of laryngeal cancer cells. Interestingly, increased interaction between ERp57 and STAT3 was observed in radioresistant cells, compared to the control cells. This physical complex is required for the activation of STAT3 in the radioresistant cells. Among STAT3-regulatory genes, Mcl-1 was predominantly regulated by ERp57. Inhibition of STAT3 activity with a chemical inhibitor or siRNA-mediated depletion of Mcl-1 sensitized radioresistant cells to irradiation, suggesting that the ERp57-STAT3-Mcl-1 axis regulates radioresistance of laryngeal cancer cells. Furthermore, we observed a positive correlation between ERp57 and phosphorylated STAT3 or Mcl-1 and in vivo interactions between ERp57 and STAT3 in human laryngeal cancer. Importantly, we also found that increased ERp57-STAT3 complex was associated with poor prognosis in human laryngeal cancer, indicating the prognostic role of ERp57-STAT3 regulation. Overall, our data suggest that ERp57-STAT3 regulation functions in radioresistance of laryngeal cancer, and targeting the ERp57-STAT3 pathway might be important for enhancing the efficacy of radiotherapy in human laryngeal cancer.