Effect of TALEN-mediated IL-6 knockout on cell proliferation, apoptosis, invasion and anti-cancer therapy in hepatocellular carcinoma (HCC-LM3) cells

PURPOSE: To determine the exact effect of Interleukin-6 (IL-6) on tumor cell proliferation, apoptosis, invasion, and anti-cancer therapy in hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN: IL-6 was disrupted by transcription activator-like effector nucleases (TALEN) in HCCLM3 cells, and was used to evaluate the role of IL-6 on tumor cell proliferation, apoptosis, invasion and key signaling pathways involved in sorafenib and/or IFNα therapy. RESULTS: IL-6 has no direct effect on cell proliferation and invasion but promotes cell apoptosis and up-regulate IL-33 and VEGF-A expression. IL-6 could attenuate the anti-proliferation effect by sorafenib and combination therapy but facilitate the pro-apoptosis of the combination therapy and augment the pro-invasive effect induced by single treatment. IL-6 could down-regulate p-STAT3, however up-regulate the p-MEK/p-ERK and NF-kB/iNOS expression, and it also facilitated the promotion on p-JAK2 and p-MEK/p-ERK by either sorafenib or IFN-α. in vivo study, IL-6 significantly promotes tumor growth. The combination treatment showed the highest inhibition on tumor growth which is derived from HCCLM3-IL6(-) cells. CONCLUSIONS: IL-6 has no direct effect on cell proliferation and invasion but promotes tumor cell apoptosis in vitro study. Sorafenib and combination therapies are suitable for HCC cells with low or no IL-6 expression confirmed in vivo study.