Poly(I:C) signaling induces robust CXCL10 production and apoptosis in human esophageal squamous cell carcinoma cells

We previously reported that high tumoral expression of Toll-like receptor 3 (TLR3) and CXCL10, a member of the CXC chemokine family, was an independent positive prognostic factor in patients with advanced thoracic esophageal squamous cell carcinoma (ESCC). However, the direct relationships between TLR3 and CXCL10 in ESCC cells was not fully understood. Here, we analyzed TLR3 mRNA and protein expression in two ESCC lines (TE8 and KYSE180) and one esophageal adenocarcinoma (EAC) line (OE19). We also assessed the effect of the TLR3 agonist poly(I:C) on production of downstream adapter proteins and cytokines, including CXCL10, and further tested its effects on cell viability and caspase 3/7 activity with and without siRNA-induced knockdown of TLR3 and the TICAM-1 or MAVS adapter protein. Both ESCC lines, but not the EAC line, showed high expression of TLR3 mRNA and protein. TICAM-1 and MAVS were also expressed, and their knockdown suppressed responsiveness to poly(I:C) in the ESCC lines. Poly(I:C) induced strong CXCL10 production, resulting in significantly upregulated caspase3/7 activity and downregulated cell proliferation in both ESCC lines but not the EAC line. The effect of poly(I:C) on CXCL10 production was attenuated after transfecting the cells with siRNAs targeting TICAM-1 or MAVS. TLR3 is thus highly expressed in ESCC cells, where it induces strong CXCL10 production and significantly upregulates caspase3/7 activity and downregulates cell proliferation. TLR3 signaling and the resultant downstream CXCL10 production have the potential to serve as useful prognostic markers and therapeutic targets for the treatment of ESCC.