Opsin3 sensitizes hepatocellular carcinoma cells to 5-fluorouracil treatment by regulating the apoptotic pathway

Hepatocellular carcinoma (HCC) is the third most common cancer worldwide, causing over 0.5 million deaths per year, with approximately half of these in China. Chemotherapy is the optimal treatment for patients with advanced HCC, although chemoresistance has become a significant obstacle to successful anti-cancer therapy. The expression of opsin3 (OPN3), also called encephalopsin or panopsin, is lower in 5-fluorouracil (5-FU)-resistant Bel74025-FU cells compared to 5-FU-sensitive Bel7402 cells. To explore the role of OPN3 in 5-FU resistance, OPN3 overexpressing (Bel74025-FU–OPN3) and knockdown (Bel7402–RNAi–OPN3) cell lines were generated. Bel74025-FU–OPN3 cells were more sensitive to 5-FU treatment than controls, while OPN3 knockdown resulted in a significant increase in 5-FU resistance. This result was replicated in a second HCC cell line, HepG2. Further investigation of the mechanism revealed that decreased OPN3 levels in Bel74025-FU cells activated the anti-apoptotic pathway through increasing phospho-Akt and the Bcl2/Bax ratio, while overexpression of OPN3 inactivated this pathway. Taken together, these results suggest that OPN3 depletion is involved in 5-FU resistance, and that therapeutic strategies targeting OPN3 may improve HCC sensitivity to chemotherapy.