Researchers identified another mechanism in which interleukin-6 (IL-6) contributes to tumor development: by inducing the expression of cGGNBP2, a circular RNA (circRNA), to form a positive feedback loop to facilitate the progression of intrahepatic cholangiocarcinoma (ICC).

“IL-6 induced tumor progression has been well established via the induction of anti-apoptotic and proliferative genes,” the research team said in a study published in Hepatology. “However, whether other mechanisms such as IL-6 regulation of circRNAs may also contribute to tumor development remains unknown.”

To investigate whether these other mechanisms exist, they conducted high-throughput RNA sequencing to identify differentially expressed circRNAs that were stimulated by IL-6 in ICC cells. Tumor tissues were obtained from archives of the surgical specimens of 136 patients with ICC who were treated at the West China Hospital in Chengdu.

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They discovered that the circRNA cGGNBP2 was upregulated by IL-6 treatment in a manner that was time- and concentration-dependent. Elevated expression of cGGNBP2 was identified as an independent risk factor for worsening prognosis in patients with ICC. 

The researchers went a step further to determine the clinical relevance of cGGNBP2 by evaluating the expression levels of cGGNBP2 in 136 matched ICC and nontumor samples. They discovered that the expression of cGGNBP2 was much higher in tumor tissue than in nontumor tissue. 

The circRNA cGGNBP2 encoded cGGNBP2-184aa, a novel protein that physically interacted with signal transducer and activator of transcription 3 (STAT3) and enhanced its phosphorylation. The researchers also discovered that cGNBP2-184aa facilitated the growth and metastasis of ICC cells in vitro and in vivo.

“Our findings uncovered a novel mechanism underlying IL-6 induced tumor progression and might suggest an auxiliary target for clinical IL-6/STAT3-targeting treatments in ICC,” the research team concluded. 


Li H, Lan T, Liu H, et al. IL-6 induced cGGNBP2 encodes a novel protein to promote cell growth and metastasis in intrahepatic cholangiocarcinomaHepatology. 2021;10. doi:10.1002/hep.32232