A novel mechanism could explain the action of antitumor proteins in intrahepatic cholangiocarcinoma (CCA), according to a study recently published in Hepatology International.

“Our study uncovered a rare mechanism of [microRNA (miR)]-122-5p and provided a new possibility to study the function of miR-122-5p in the future,” the authors wrote.

The research used 4 different cell lines of CCA, including CCLP1, HuCCT1, RBE, and 9810, as well as bile duct epithelial cell lines. The investigators evaluated the levels of insulin-like growth factor-binding protein 4 (IGFBP4) and miR-122-5p, while further chromatin isolation by RNA purification and dual luciferase reporter assays helped understand the regulation of these proteins.

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First, the investigators confirmed the effects of miR-122-5p as a tumor suppressor and its ability to impair metastasis and invasion. Moreover, the study identified IGFBP4 as a potential target of miR-122-5p through transcriptome sequencing.

Subsequent experiments using RNA purification technology yielded a newly described mechanism through which miR-122-5p increases the transcription of IGFBP4 messenger RNA (mRNA). This upregulating effect occurs by first binding to its promoter region.

The researchers obtained confirmation of these findings in a later experiment in a mouse orthotopic metastasis model, in which miR-122-5p successfully suppressed the invasion of CCA.

Previous literature has reported that losing liver-enriched transcription factors could lead to decreased levels of miR-122-5p. Similarly, long noncoding RNA (lncRNA) also inhibits the expression of miR-122-5p.

Regardless, previous studies regarding the antitumor activity of miR-122-5p have been performed in vitro, making it challenging to extrapolate such results into human beings.

This study suggests that miR-122-5p could become a potential target for future therapeutic options for patients with CCA.

“In our study, an orthotopic [patient-derived xenograft (PDX)] model was used to simulate the actual situation of [intrahepatic CCA] metastasis in the human body as much as possible, and PDX could better simulate the heterogeneity of [intrahepatic CCA],” Tao and colleagues concluded.


Tao L, Wang Y, Shen Z, et al. Activation of IGFBP4 via unconventional mechanism of miRNA attenuates metastasis of intrahepatic cholangiocarcinoma. Hepatol Int. Published online June 22, 2023. doi:10.1007/s12072-023-10552-7