Silencing of the ABCC4 gene by RNA interference reverses multidrug resistance in human gastric cancer.

ABSTRACT

The identification of genes associated with recurrent drug resistance in gastric cancer and the elucidation of the underlying molecular mechanisms associated with recurrent drug resistance in gastric cancer are important for the effective treatment and prognosis of this cancer. Variations in the expression level of the ATP-binding cassette subfamily C member 4 (ABCC4) gene are correlated with the recurrence, development and chemotherapeutic susceptibility of various types of cancers. In the present study, we demonstrated that the ABCC4 gene was highly expressed in multiple types of gastric cancer cells, and ABCC4 expression was even more prominent in the drug-resistant gastric cancer cells. Conversely, in normal gastric mucosal cells, ABCC4 expression was very low or undetectable. We used RNA interference to decrease the expression of ABCC4 in drug-resistant gastric cancer cells, which resulted in an increase in apoptosis and cell cycle arrest in the G1 phase. In addition, we found that ABCC4 knockdown in 5-fluorouracil (5-FU)-resistant cancer cells restored 5-FU sensitivity, resulting in the inhibition of cell proliferation and tumour growth in nude mice. Our results showed that inhibition of ABCC4 gene expression can inhibit the proliferation of multidrug-resistant gastric cancer cells and can enhance gastric cancer cell sensitivity to chemotherapeutic drugs.