title: SERPINB2 down-regulation contributes to chemoresistance in head and neck cancer.
abstract: Resistance to cisplatin-based chemotherapy is responsible for the majority of deaths from head and neck squamous cell carcinoma (HNSCC). In this study, using genome-wide gene expression analysis to investigate potential molecular mediators of HNSCC chemoresistance, we identified SERPINB2, a known inhibitor of extracellular serine proteinase urokinase-type plasminogen activator (uPA), as an important candidate. Whereas SERPINB2 is known to function as a suppressor of uPA molecular cascades, many of which play important roles in tumor invasion and metastasis, a role for SERPINB2 in cancer drug resistance has not been examined. By using quantitative real-time PCR and Western blot analysis, we determined that SERPINB2 mRNA and protein levels correlated with chemoresistance in HNSCC cell lines, and significantly lower SERPINB2 expression levels were observed in two cisplatin resistant HNSCC subclones compared to their isogenic drug-sensitive parental lines. Immunohistochemical analysis of HNSCC tumor tissues from patients treated with neoadjuvant cisplatin-based chemotherapy (n = 67 cases) revealed a significant association between SERPINB2 protein levels, tumor differentiation and patient relapse. Moreover, SERPINB2 down-regulation was a strong predictor of reduced overall survival in patients with HNSCC who received cisplatin-based chemotherapy (P = 0.001, log rank test). Studies using either siRNA-mediated down-regulation or forced over-expression of SERPINB2 in HNSCC cell lines confirmed a functional role for SERPINB2 in drug resistance. The findings were further supported using chemical inhibitors of STAT3 activity (a downstream effecter of uPAR signaling pathway), showing that STAT3 suppression altered HNSCC cell line cisplatin sensitivity. This is the first report on a role for SERPINB2 in acquired resistance to cisplatin in patients with HNSCC.
authors: Medical Sciences Program, Indiana University School of Medicine, Bloomington, Indiana; Department of Oral and Maxillofacial Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, P.R., China; Department of Cellular and Integrative Physiology and Indiana University Simon Cancer Center, Indianapolis, Indiana.
authors: Zhiquan
authors: Z
authors: Huang
authors: Haigang
authors: H
authors: Li
authors: Qi
authors: Q
authors: Huang
authors: Dan
authors: D
authors: Chen
authors: Jingjing
authors: J
authors: Han
authors: Lili
authors: L
authors: Wang
authors: Chanbin
authors: C
authors: Pan
authors: Weiliang
authors: W
authors: Chen
authors: Michael G
authors: MG
authors: House
authors: Kenneth P
authors: KP
authors: Nephew
authors: Zhongmin
authors: Z
authors: Guo
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002945:Cisplatin / Q000494:pharmacology; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D006801:Humans; D020128:Inhibitory Concentration 50; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D017396:Plasminogen Activator Inhibitor 2 / Q000235:genetics* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D017396:Plasminogen Activator Inhibitor 2; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D002945:Cisplatin
keywords: chemoresistance; chemotherapy; head and neck cancer; serpin peptidase inhibitor B2(SERPINB2); uPAR signaling