Xie Chenxi, Zhou Gengping, Chen Taiyang, Li Qingshan, Yuan Hao, Xu Yang, Zhang Kai, Wang Chunmei, Hao Xiaopei, Yu Haibo
Hepatobiliary Center, Department of Hepatobiliary Surgery, People's Hospital of Zhengzhou University, Zhengzhou, China.
Department of Oncology, Sir Run Run Hospital, Nanjing Medical University, Nanjing 211166, China.
Cell Signal. 2025 Oct;134:111965. doi: 10.1016/j.cellsig.2025.111965. Epub 2025 Jun 26.
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.
We investigated the dysregulation of circRNA expression profiles in five pairs of ICC tissues and adjacent normal tissues through high-throughput 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.
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.
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.
大量研究表明，环状RNA（circRNA）参与包括肝内胆管癌（ICC）在内的多种恶性肿瘤的调控。然而，circRNA在ICC进展中的具体作用及其潜在调控机制仍有待进一步阐明。
我们通过高通量测序研究了5对ICC组织和癌旁正常组织中circRNA表达谱的失调情况，发现circ_0084927显著上调。接下来，通过qRT-PCR评估了circ_0084927在ICC细胞系和组织中的水平。然后，基于临床指标分析了circ_0084927与ICC预后的关系。随后，我们通过构建circ_0084927敲低和过表达的ICC细胞系在体外和体内研究其作用。随后，利用生物信息学分析和机制实验探索circ_0084927的下游调控机制。从吉西他滨耐药的ICC细胞系中分离外泌体，以评估外泌体circ_0084927与吉西他滨耐药性之间的关系。
circ_0084927在ICC细胞系和组织中显著上调。高水平的circ_0084927表达与ICC患者较差的预后相关。在功能上，circ_0084927在体外和体内显著促进ICC的增殖、侵袭和迁移，同时抑制细胞凋亡。机制上，circ_0084927通过与miR-4725-5p竞争性结合上调其下游靶点PDPK1，从而激活下游AKT/mTOR信号通路。此外，circ_0084927可以通过外泌体从吉西他滨耐药细胞转移到敏感细胞，导致先前对吉西他滨敏感的受体细胞产生耐药性。
circ_0084927通过海绵吸附miR-4725-5p促进PDPK1的表达，激活下游AKT/mTOR信号通路。此外，circ_0084927通过外泌体介导ICC细胞中吉西他滨耐药性的转移。因此，circ_0084927不仅是一个有前景的预后指标，也是ICC的一个可行治疗靶点。
