High expression levels of IKKα and IKKβ are necessary for the malignant properties of liver cancer

Abstract

IKK-NF-kappaB signaling is regarded as an important factor in hepatocarcinogenesis and a potential target for liver cancer therapy. Therefore, in this study, we analyzed the expression of mRNAs encoding components and targets of NF-kappaB signaling including IKKalpha, IKKbeta, RANK, RANKL, OPG, CyclinD3, mammary serine protease inhibitor (Maspin), CyclinD1, c-FLIP, Bcl-xl, Stat3, Cip1 and Cip2 by real-time PCR in 40 patients with liver cancer. After statistical analysis, 7 indices including IKKalpha, IKKbeta, RANK, Maspin, c-FLIP, Cip2 and cyclinD1 were found to show significant differences between tumor tissue and its corresponding adjacent tissue. When IKKalpha and IKKbeta were downregulated in the hepatocellular carcinoma (HCC) cell lines of MHCC-97L and MHCC-97H in vitro, the numbers of BrdU positive cells were decreased in both IKKalpha and IKKbeta knockdown cells. Levels of apoptosis were also investigated in IKKalpha and IKKbeta knockdown cells. The growth of HCC was inhibited in the subcutaneous implantation model, and lung metastatogenesis was also significantly inhibited in the kidney capsule transplantation model. Downregulation of IKKalpha and IKKbeta in HCC cultured in vitro revealed that increased Maspin, OPG and RANKL expression was associated with metastasis of HCC. These findings were associated with downregulation of Bcl-XL and c-FLIP, which may be the reason for increased apoptosis. The therapeutic effect of IKKalpha and IKKbeta downregulation depends on extent of NF-kappaB inhibition and the malignant nature of the HCC. We anticipate that IKK-targeted gene therapy can be used in the treatment of HCC, a cancer that is notoriously resistant to radiation and chemotherapy.