Circ_0084927 promotes progression of intrahepatic cholangiocarcinoma by sponging miR-4725-5p to activate the PDPK1/AKT/mTOR signaling pathway

Chenxi Xie; Gengping Zhou; Taiyang Chen; Qingshan Li; Hao Yuan; Yang Xu; Kai Zhang; Chunmei Wang; Xiaopei Hao; Haibo Yu

doi:10.1016/j.cellsig.2025.111965

Circ_0084927 promotes progression of intrahepatic cholangiocarcinoma by sponging miR-4725-5p to activate the PDPK1/AKT/mTOR signaling pathway

Cell Signal. 2025 Jun 26:111965. doi: 10.1016/j.cellsig.2025.111965. Online ahead of print.

Authors

Chenxi Xie¹, Gengping Zhou¹, Taiyang Chen¹, Qingshan Li¹, Hao Yuan¹, Yang Xu¹, Kai Zhang¹, Chunmei Wang², Xiaopei Hao³, Haibo Yu⁴

Affiliations

¹ Hepatobiliary Center, Department of Hepatobiliary Surgery, People's Hospital of Zhengzhou University, Zhengzhou, China.
² Department of Oncology, Sir Run Run Hospital, Nanjing Medical University, Nanjing 211166, China. Electronic address: ye-lucky@163.com.
³ The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, People's Republic of China. Electronic address: hxp11297536@163.com.
⁴ Hepatobiliary Center, Department of Hepatobiliary Surgery, People's Hospital of Zhengzhou University, Zhengzhou, China; Zhengzhou Key Laboratory of Minimally Invasive Treatment of Liver Cancer, Zhengzhou, China. Electronic address: yhb2101661@zzu.edu.cn.

PMID: 40581264
DOI: 10.1016/j.cellsig.2025.111965

Abstract

Background: Numerous studies have indicated that circular RNAs (circRNA) are involved in the regulation of various malignant tumors, including intrahepatic cholangiocarcinoma (ICC). However, the exact role of circRNA in the progression of ICC and their underlying regulatory mechanisms remain to be further elucidated.

Methods: We investigated the dysregulation of circRNA expression profiles in five pairs of ICC tissues and adjacent normal tissues through RNA sequencing, revealing a significant upregulation of circ_0084927. Next, the levels of circ_0084927 in ICC cell lines and tissues were assessed by qRT-PCR. Then, we analyzed the relationship between circ_0084927 and the prognosis of ICC based on clinical indicators. Then, we investigated the effects by constructing circ_0084927 knockdown and overexpression ICC cell lines in vitro and in vivo. Subsequently, bioinformatics analysis and mechanistic experiments were used to explore the downstream regulatory mechanisms of circ_0084927. Exosomes isolated from gemcitabine-resistant ICC cell lines were used to assess the relationship between exosomal circ_0084927 and gemcitabine resistance.

Results: Circ_0084927 is significantly upregulated in ICC cell lines and tissues. High levels of circ_0084927 expression is associated with poorer prognosis in ICC patients. Functionally, circ_0084927 notably promotes ICC proliferation, invasion, and migration while inhibiting apoptosis in vitro and in vivo. Mechanistically, circ_0084927 upregulates its downstream target PDPK1 by competitively binding with miR-4725-5p, thereby activating the downstream AKT/mTOR signaling pathway. Moreover, circ_0084927 can be transferred from gemcitabine-resistant cells to sensitive cells via exosomes, leading to the induction of drug resistance in the recipient cells previously sensitive to gemcitabine.

Conclusion: Circ_0084927 promotes the expression of PDPK1 by sponging miR-4725-5p, activating the downstream AKT/mTOR signaling pathway. Additionally, circ_0084927 mediates the transfer of gemcitabine resistance in ICC cells through exosomes. Therefore, circ_0084927 not only serves as a promising prognostic indicator but also as a viable therapeutic target for ICC.

Keywords: Circ_0084927; Exosome; Gemcitabine resistance; Intrahepatic cholangiocarcinoma.