Inhibition Of Stat3 By NSC 74859 Increases Cetuximab's Anti-proliferation Activity In HCC

BackgroundHCC is a troublesome tumor with a poor prognosis due to late diagnoses and a lack of effective treatment options. Cetuximab(an Epidermal growth factor receptor inhibitor) is an effective drug in other cancers such as rectal cancer which shown only modest efficacy in clinical trials of HCC. Signal transducers and activators of transcription (STAT) family of transcriptional factors were originally identified as the critical mediators of cytokine responses and subsequently implicated in diverse external stimuli-initiated cellular signaling. Stat3 is a member of STAT family which has been considered as an oncogene based on its ability to transactivate a number of genes whose products are involved in cell proliferation and survival, invasion, metastasis and angiogenesis. Previous studies have shown that the level of Stat3 in hepatic tumor tissue was higher than in normal tissue and expression of Stat3 may be as a determinant of sensitivity of HCC to antitumor drugs. But the relationship of Stat3 and the mechanism of resistance to Cetuximab in liver cancer patients has not been reported.Materials and MethodsWe compared the tolerance for Cetuximab between two HCC cell lines, Hep G2 and SK-HEP 1 by MTT. We used the Stat3 pathway specific blocker NSC 74859 to block the Stat3 pathway. And we compared the percentage of resistance to Cetuximab of the two cell lines with or without NSC 74859. Hep G2 and SK-HEP 1 cells were transfected with Nagative SiRNA, Stat3 SiRNA and wild type stat3. EGFR, Stat3, and p-Stat3 expression in different levels of treatment group were estimated by RT-PCR and Western blot.ResultIn our study, we found that Hep G2 was more sensitive to cetuximab than Sk-Hep-1. We also found that the expression of p-stat3 in Sk-Hep-1 cell line was higher than that in Hep G2 cell line. Blocking p-stat3 using NSC 74859 or an small interfere RNA(stat3 SiRNA) boost the cetuximab's effect in both cell lines especially in Sk-Hep-1 while transfection stat3 cDNA plasmid into Hep G2 lost the sensitivity to cetuximab compared to control Hep G2.ConclusionOur study first found that p-stat3 inhibition by NSC74859 mediate sensitivity to cetuximab, suggesting that the combined NSC74859 with cetuximab would be an effective therapy for HCC.