Abnormal expression of circulating nuclear factor-κB in hepatocellular carcinoma and reversal of multidrug resistance through intervening its gene transcription

Abstract

To investigate the expressions of nuclear factor-κB (NF-κB) and P-glycoprotein (P-gp) in patients with liver diseases and the effects and mechanism of intervening NF-κB activation on multiple drug resistance (MDR) reversal. The levels of circulating NF-κB and P-gp expression were quantitatively detected in 294 patients with liver diseases by using enzyme-linked immunosorbent assay. NF-κB gene transcription in human HepG2 cells was intervened by specific siRNA with/without doxorubicin treatment. Levels of protein or gene expression were analyzed by Western blotting or fluorescence quantitative polymerase chain reaction (PCR). The dynamic increase of circulating NF-κB and P-gp expressions were observed during patients from chronic hepatitis to cirrhosis to hepatocellular carcinoma (HCC) development. The levels of serum NF-κB and P-gp expression in HCC were significantly higher (P<0.001) than those in cirrhosis, chronic hepatitis, and normal controls. The expression levels of serum NF-κB and P-gp were significantly associated with HBV infection (P<0.05), elevated after interventional chemotherapy with higher frequency or prolonged therapy, and significantly decreased in the post-operative HCC (P<0.001). Both expressions in HepG2 cells were significantly higher after adding doxorubicin in the cell cultures. After the cells were transfected with siRNA, the NF-κB expression was down-regulated at mRNA or protein level with higher sensitivity to doxorubicin. The over-expressions of NF-κB and P-gp are closely associated with MDR formation; intervention of NF-κB activation can inhibit P-gp expression, and enhance the sensitivity to anti-cancer drug and reverse MDR of HCC.