IL‐6–induced cGGNBP2 encodes a protein to promote cell growth and metastasis in intrahepatic cholangiocarcinoma

Abstract

Background and Aims IL‐6–induced tumor progression has been well established through the induction of antiapoptotic and proliferative genes. However, whether other mechanisms such as IL‐6 regulation of circular RNAs (circRNAs) may also contribute to tumor development remains unknown. Approach and Results High‐throughput RNA sequencing was used to identify the differentially expressed circRNAs on IL‐6 stimulation in intrahepatic cholangiocarcinoma (ICC) cells. CircRNA GGNBP2 (derived from ggnbp2 gene, termed as cGGNBP2) was up‐regulated by IL‐6 treatment in a time and concentration‐dependent manner. The biogenesis of cGGNBP2 was regulated by RNA‐binding protein DEx‐H Box Helicase 9, which was also mediated by IL‐6 exposure. Mass spectrometry and western blotting identified a protein cGGNBP2‐184aa encoded by cGGNBP2. cGGNBP2‐184aa promoted ICC cell proliferation and metastasis in vitro and in vivo. Mechanistically, cGGNBP2‐184aa directly interacted with signal transducers and activators of transduction‐3 (STAT3), phosphorylated STAT3Tyr705, and played a positive regulatory role in modulating IL‐6/STAT3 signaling. IL‐6/cGGNBP2‐184aa/STAT3 formed a positive feedback loop to sustain constitutive activation of IL‐6/STAT3 signaling. Elevated cGGNBP2 expression was correlated with poor prognosis of patients with ICC and was identified as an independent risk factor for patient prognosis. Conclusions Our study demonstrates that cGGNBP2‐184aa, a protein encoded by IL‐6–induced cGGNBP2, formed a positive feedback loop to facilitate ICC progression and may serve as an auxiliary target for clinical IL‐6/STAT3‐targeting treatments in ICC.

Tumor Burden Score Stratifies Prognosis of Patients With Intrahepatic Cholangiocarcinoma After Hepatic Resection: A Retrospective, Multi-Institutional Study

“…Intrahepatic cholangiocarcinoma (ICC) is cholangiocellular carcinoma originated from intrahepatic bile duct cells, accounting for 5%–20% of primary liver malignancies ( 2 ). The risk factors of ICC mainly include intrahepatic bile duct stones, hepatitis B or C infection, primary sclerosing cholangitis, hepatobiliary parasites, and diabetes ( 3 , 4 ). The incidence of ICC demonstrates a geological difference, with the highest incidence rate in Asia, while a noticeable increase was also observed in western countries in recent years ( 5 , 6 ).…”

Role of Immune Cells in Biliary Repair

“…IL-6 is a pleiotropic inflammatory cytokine and plays an important role in tumorigenesis and cancer progression. IL-6 is highly expressed in human iCCA ( 179 ) and contributes to CCA cell proliferation and invasion through the IL-6/STAT3 signaling pathway ( 180 , 181 ). Furthermore, loss of c-Jun N-terminal kinases (JNKs) in hepatocytes affects cholesterol metabolism and bile acid synthesis, conjugation, and transportation ( 182 ), leading to overexpression of IL-6.…”

An m6A-Related lncRNA Signature Predicts the Prognosis of Hepatocellular Carcinoma

“…Hepatocellular carcinoma (HCC), the primary common type of liver cancer, ranks third among cancer-related deaths worldwide ( Bray et al, 2018 ; Li et al, 2021 ). Despite advancements in current medical treatments, including liver resection (LR), transhepatic arterial chemotherapy and embolization (TACE), radiofrequency ablation (RFA), liver transplantation (LT), and targeted molecular therapy, the overall survival (OS) rate of liver cancer patients is still unsatisfactory ( Omata et al, 2017 ).…”