CircNOX4 promotes proliferation and resistance by regulating the hsa-miR-6884-5p/YWHAG Axis and ERK signaling pathway in cholangiocarcinoma

Abstract

The biological function of circular RNAs (circRNAs) has been increasingly implicated in tumor drug resistance. However, their role in intrahepatic cholangiocarcinoma (ICC) remains poorly understood, and the underlying mechanisms are largely unexplored. In this study, we identified a key circRNA, circNOX4, through data mining and experimental validation in ICC. We found that circNOX4 was significantly upregulated in ICC tissues and its expression correlated with advanced clinicopathological features. Functional assays demonstrated that circNOX4 promoted ICC cell proliferation and tumor growth both in vitro and in vivo. Mechanistically, circNOX4 acted as a molecular sponge for hsa-miR-6884-5p, thereby upregulating YWHAG expression. YWHAG, in turn, interacted with RAF1, enhancing its phosphorylation and activating the ERK signaling pathway. This led to the nuclear translocation of phosphorylated ERK and subsequent promotion of ICC progression. Furthermore, we found that circNOX4 attenuated the anti-tumor efficacy of Trametinib. In summary, circNOX4 contributes to ICC progression and drug resistance through the hsa-miR-6884-5p/YWHAG/ERK axis, and may serve as a potential diagnostic marker, prognostic indicator, and therapeutic target in ICC.

Keywords: Cholangiocarcinoma; CircNOX4; RAF/MEK/ERK signaling; Resistance; YWHAG.