The mitochondrial protein called circular RNA reticulon 4 interacting protein 1 (circRTN4IP1) may play a role in the progression of intrahepatic cholangiocarcinoma, according to a new study published in the journal Pathology – Research and Practice. This protein could therefore be a therapeutic target for the disease.

Recent studies have shown that circRTN4IP1 is upregulated in cholangiocarcinoma tissues compared to adjacent nontumor tissues. However, the role of the protein in the progression of intrahepatic cholangiocarcinoma had not been explored in detail so far.

In the present study, a team of researchers from China quantified the expression of circRTN4IP1 in intrahepatic cholangiocarcinoma tissues and cells and analyzed its role in cell proliferation and apoptosis. They also explored the effect of the protein on glycolysis, since glucose metabolism plays an important role in cancer cell proliferation. 

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The team also investigated the potential role of the circRTN4IP1, miR-541-5p, and hypoxia inducible factor 1 subunit alpha (HIF1A) signaling cascade in the development of the disease. Since circRTN4IP1 carries the complementary sites of miR-541-5p, which can target HIF1A, it’s known to contribute to tumorigenesis in intrahepatic cholangiocarcinoma.

The results showed that intrahepatic cholangiocarcinoma tissues and cells highly expressed circRTN4IP1 and HIF1A. However, the expression of miR-541-5p was low.

When they knocked down the expression of circRTN4IP1 in this tissue, the researchers found that cell proliferation and glucose metabolism were repressed while apoptosis was promoted. In contrast, when circRTN4IP1 was overexpressed, cell proliferation and glucose metabolism were induced and apoptosis was repressed. 

The researchers also showed that miR-541-5p inhibitors could cancel out the effect of knocking down circRTN4IP1, suggesting that circRTN4IP1 acted as a sponge for miR-541-5p.

“CircRTN4IP1 knockdown inhibited [intrahepatic cholangiocarcinoma] cell malignancy by miR-541-5p/HIF1A axis, providing us with a reliable target for the therapy of [intrahepatic cholangiocarcinoma],” the researchers concluded.


Tang J, Wang R, Tang R, Gu P, Han J, Huang W. CircRTN4IP1 regulates the malignant progression of intrahepatic cholangiocarcinoma by sponging miR-541-5p to induce HIF1A production. Pathol Res Pract. Published online December 5, 2021. doi:10.1016/j.prp.2021.153732