Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, Fujian Province, People's Republic of China.
Department of Hepatobiliary Surgery, Jinshan Branch of Fujian Province Hospital, Fuzhou, 350007, Fujian Province, People's Republic of China.
J Exp Clin Cancer Res. 2022 Apr 23;41(1):153. doi: 10.1186/s13046-022-02343-z.
Chemoresistance of pancreatic cancer is the main reason for the poor treatment effect of pancreatic cancer patients. Exploring chemotherapy resistance-related genes has been a difficult and hot topic of oncology. Numerous studies implicate the key roles of circular RNAs (circRNAs) in the development of pancreatic cancer. However, the regulation of circRNAs in the process of pancreatic ductal adenocarcinoma (PDAC) chemotherapy resistance is not yet fully clear.
Based on the cross-analysis of the Gene Expression Omnibus (GEO) database and the data of our center, we explored a new molecule, hsa_circ_0078297 (circ-MTHFD1L), related to chemotherapy resistance. QRT-PCR was used to detect the expression of circRNAs, miRNAs, and mRNAs in human PDAC tissues and their matched normal tissues. The interaction between circ-MTHFD1L and miR-615-3p/RPN6 signal axis was confirmed by a series of experiments such as Dual-luciferase reporter assay, fluorescence in situ hybridization (FISH) RNA immunoprecipitation (RIP) assays.
Circ-MTHFD1L was significantly increased in PDAC tissues and cells. And in PDAC patients, the higher the expression level of circ-MTHFD1L, the worse the prognosis. Mechanism analysis showed that circ-MTHFD1L, as an endogenous miR-615-3p sponge, upregulates the expression of RPN6, thereby promoting DNA damage repair and exerting its effect on enhancing gemcitabine chemotherapy resistance. More importantly, we also found that Silencing circ-MTHFD1L combined with olaparib can increase the sensitivity of pancreatic cancer to gemcitabine.
Circ-MTHFD1L maintains PDAC gemcitabine resistance through the miR-615-3p/RPN6 signal axis. Circ-MTHFD1L may be a molecular marker for the effective treatment of PDAC.
胰腺癌的化疗耐药性是导致胰腺癌患者治疗效果不佳的主要原因。探索化疗耐药相关基因一直是肿瘤学的一个难点和热点。大量研究表明环状 RNA（circRNAs）在胰腺癌的发生发展中起关键作用。然而，circRNAs 在胰腺导管腺癌（PDAC）化疗耐药过程中的调控作用尚不完全清楚。
基于基因表达综合数据库（GEO）数据库和本中心数据的交叉分析，我们探讨了一个与化疗耐药相关的新分子 hsa_circ_0078297（circ-MTHFD1L）。采用 QRT-PCR 检测人 PDAC 组织及其配对正常组织中 circRNAs、miRNAs 和 mRNAs 的表达。通过双荧光素酶报告基因实验、荧光原位杂交（FISH）、RNA 免疫沉淀（RIP）等一系列实验证实 circ-MTHFD1L 与 miR-615-3p/RPN6 信号轴的相互作用。
circ-MTHFD1L 在 PDAC 组织和细胞中显著上调。在 PDAC 患者中，circ-MTHFD1L 表达水平越高，预后越差。机制分析表明，circ-MTHFD1L 作为内源性 miR-615-3p 海绵，上调 RPN6 的表达，从而促进 DNA 损伤修复，发挥增强吉西他滨化疗耐药的作用。更重要的是，我们还发现沉默 circ-MTHFD1L 联合奥拉帕利可以增加胰腺癌对吉西他滨的敏感性。
circ-MTHFD1L 通过 miR-615-3p/RPN6 信号轴维持 PDAC 对吉西他滨的耐药性。circ-MTHFD1L 可能是 PDAC 有效治疗的分子标志物。
