HSP27-mediated Extracellular and Intracellular Signaling Pathways Synergistically Confer Chemo-Resistance in Squamous Cell Carcinoma of Tongue

Purpose: Squamous cell carcinoma of tongue (SCCT) is the most common type of the oral cavity carcinoma. Chemo-resistance in SCCT is common and the underlying mechanism remains largely unknown. We aim to identify key molecules and signaling pathways mediating chemo-resistance in SCCT. Experimental Design: Using a proteomic approach we identify that the HSP27 was a potential mediator for chemo-resistance in SCCT cells. To further validate this role of HSP27, we performed various mechanistic studies using in vitro and in vivo models as well as serum and tissue samples of SCCT patients. Results: 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 chemo-resistance. Inversely, both HSP27 overexpression and recombinant human HSP27 protein treatment enhanced chemo-resistance. Moreover, chemotherapy significantly induced HSP27 protein expression in both SCCT cells and their culture medium, so is that in tumor tissues and serum of SCCT patients. HSP27 overexpression predicts a poor outcome of SCCT patients receiving chemotherapy. Mechanically, extracellular HSP27 binds to TLR5 and then activates NF-B signaling to maintain SCCT cells survival. TLR5 knockdown or restored IBα protein level disrupts extracellular HSP27-induced NF-B transactivation and chemo-resistance. Moreover, Intracellular HSP27 binds to BAX and BIM to repress their translocation to mitochondrion and subsequent cytochrome C release upon chemotherapy, resulting into inhibition of the mitochondrial apoptotic pathway. Conclusions: HSP27 plays pivotal role in chemo-resistance of SCCT cells via a synergistic extracellular and intracellular signaling. HSP27 may represent a potential biomarker and therapeutic target for precision SCCT treatment.

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