Downregulation of δ opioid receptor by RNA interference enhances the sensitivity of BEL/FU drug-resistant human hepatocellular carcinoma cells to 5-FU

Abstract

δ opioid receptor (DOR) was the first opioid receptor of the G protein-coupled receptor family to be cloned. Our previous studies demonstrated that DOR is involved in regulating the development and progression of human hepatocellular carcinoma (HCC), and is involved in the regulation of the processes of invasion and metastasis of HCC cells. However, whether DOR is involved in the development and progression of drug resistance in HCC has not been reported and requires further elucidation. The aim of the present study was to investigate the expression levels of DOR in the drug-resistant HCC BEL-7402/5-fluorouracil (BEL/FU) cell line, and its effects on drug resistance, in order to preliminarily elucidate the effects of DOR in HCC drug resistance. The results of the present study demonstrated that DOR was expressed at high levels in the BEL/FU cells, and the expression levels were higher, compared with those in normal liver cells. When the expression of DOR was silenced, the proliferation of the drug-resistant HCC cells were unaffected. However, when the cells were co-treated with a therapeutic dose of 5-FU, the proliferation rate of the BEL/FU cells was significantly inhibited, a large number of cells underwent apoptosis, cell cycle progression was arrested and changes in the expression levels of drug-resistant proteins were observed. Overall, the expression of DOR was upregulated in the drug-resistant HCC cells, and its functional status was closely associated with drug resistance in HCC. Therefore, DOR may become a recognized target molecule with important roles in the clinical treatment of drug-resistant HCC.

microRNA-874 suppresses tumor proliferation and metastasis in hepatocellular carcinoma by targeting the DOR/EGFR/ERK pathway

“…Particularly in liver cancer, our previous study showed that upregulation of the DOR promotes liver cancer proliferation and metastasis both in vitro and in vivo 6 . Downregulation of the DOR enhances the sensitivity of drug-resistant HCC cells to 5‑FU 18 . We also found that activated DOR inhibits hydrogen peroxide-induced apoptosis in liver cancer cells 7 , suggesting that the DOR is involved in the proliferation, metastasis, and apoptosis of HCC.…”

Down-regulation of the tumour suppressor κ-opioid receptor predicts poor prognosis in hepatocellular carcinoma patients

“…Although the reports in the literature are inconsistent, opioid receptors expressed in tumour cells may have an implication in tumour progression [ 16 , 17 ]. KOR expression has been reported in various cancer cells, such as small lung cancer cell and oesophageal cancer cell [ 18 , 19 ].…”