HSP27-Mediated Extracellular and Intracellular Signaling Pathways Synergistically Confer Chemoresistance in Squamous Cell Carcinoma of Tongue

• Published in: Clinical cancer research 2018-03, Vol.24 (5), p.1163-1175
• Main Authors: Zheng, Guopei, Zhang, Zhijie, Liu, Hao, Xiong, Yan, Luo, Liyun, Jia, Xiaoting, Peng, Cong, Zhang, Qiong, Li, Nan, Gu, Yixue, Lu, Minying, Song, Ying, Pan, Hao, Liu, Jinbao, Liu, Wanqing, He, Zhimin
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis; BAX protein; BIM protein; Biomarkers; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Cell culture; Cell Line, Tumor; Cell survival; Chemoresistance; Chemotherapy; Cohort Studies; Cytochrome; Cytochrome c; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Experimental design; Female; Gene Expression Regulation, Neoplastic - drug effects; Gene Knockdown Techniques; HSP27 Heat-Shock Proteins - genetics; HSP27 Heat-Shock Proteins - metabolism; Hsp27 protein; Humans; In vivo methods and tests; Intracellular; Intracellular signalling; Kaplan-Meier Estimate; Male; Mice, Nude; Middle Aged; Mitochondria; Multidrug resistance; NF-kappa B - metabolism; NF-κB protein; Oral cavity; Patients; Precision Medicine - methods; Prognosis; Proteins; Signal Transduction; Squamous cell carcinoma; Squamous Cell Carcinoma of Head and Neck - blood; Squamous Cell Carcinoma of Head and Neck - drug therapy; Squamous Cell Carcinoma of Head and Neck - mortality; Squamous Cell Carcinoma of Head and Neck - pathology; Therapeutic applications; Tissues; TLR5 protein; Toll-like receptors; Tongue; Tongue - pathology; Tongue Neoplasms - blood; Tongue Neoplasms - drug therapy; Tongue Neoplasms - mortality; Tongue Neoplasms - pathology; Translocation; Up-Regulation - drug effects; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-17-2619

Squamous cell carcinoma of tongue (SCCT) is the most common type of oral cavity carcinoma. Chemoresistance in SCCT is common, and the underlying mechanism remains largely unknown. We aimed to identify key molecules and signaling pathways mediating chemoresistance in SCCT. Using a proteomic approach, we found that the HSP27 was a potential mediator for chemoresistance in SCCT cells. To further validate this role of HSP27, we performed various mechanistic studies using and models as well as serum and tissue samples from SCCT patients. The HSP27 protein level was significantly increased in the multidrug-resistant SCCT cells and cell culture medium. Both HSP27 knockdown and anti-HSP27 antibody treatment reversed chemoresistance. Inversely, both HSP27 overexpression and recombinant human HSP27 protein treatment enhanced chemoresistance. Moreover, chemotherapy significantly induced HSP27 protein expression in both SCCT cells and their culture medium, as well as in tumor tissues and serum of SCCT patients. HSP27 overexpression predicts a poor outcome for SCCT patients receiving chemotherapy. Mechanically, extracellular HSP27 binds to TLR5 and then activates NF-κB signaling to maintain SCCT cell survival. TLR5 knockdown or restored IκBα protein level disrupts extracellular HSP27-induced NF-κB transactivation and chemoresistance. Moreover, intracellular HSP27 binds to BAX and BIM to repress their translocation to mitochondrion and subsequent cytochrome C release upon chemotherapy, resulting in inhibition of the mitochondrial apoptotic pathway. HSP27 plays a pivotal role in chemoresistance of SCCT cells via a synergistic extracellular and intracellular signaling. HSP27 may represent a potential biomarker and therapeutic target for precision SCCT treatment. .