最近，越来越多的研究揭示了环状RNA在各种肿瘤生物学过程中发挥重要作用，包括化疗抵抗。我们之前的研究发现，在获得性吉西他滨（GEM）耐药的胰腺癌（PC）细胞中，circACTR2明显下调，而这一点尚未得到充分探讨。我们的研究旨在研究circACTR2在PC化疗抵抗中的功能和分子机制。利用qRT-PCR和Western blot分析检测基因表达情况。通过CCK-8和流式细胞法检查circACTR2对PC GEM耐药性的影响。生物信息学分析、RNA pull-down和双荧光素酶报告分析法确定circACTR2是否能作为miR-221-3p的海绵体，并调节PTEN的表达。circACTR2在一系列GEM耐药PC细胞系中明显下调，并与PC的侵袭性表型和恶性预后呈负相关。circACTR2的下调促进了PC细胞的GEM化疗耐药性，通过体外增加和降低circACTR2功能的实验得到证实，其使细胞周期S期减少和细胞凋亡。另外，circACTR2在体内能减缓GEM耐药性。进一步的研究表明，circACTR2作为ceRNA与miR-221-3p相互作用，直接靶向PTEN。机械研究表明，通过miR-221-3p下调PTEN表达引起的PI3K/AKT通路的激活，circACTR2的丧失促进了PC的GEM耐药性。circACTR2通过海绵miR-221-3p并上调PTEN表达抑制PI3K/AKT信号通路，逆转了PC细胞对GEM的化疗耐药性。©2023. 作者。

Recently, accumulating studies have unveiled that circRNAs exert critical function in a variety of tumor biological processes including chemoresistance. Our previous study has found circACTR2 is significantly down-regulated in acquired gemcitabine (GEM)- resistant pancreatic cancer (PC) cells, which has not been well-explored. Our study aimed to research the function and molecular mechanism of circACTR2 in PC chemoresistance.qRT-PCR and western blot analysis was performed to detect gene expression. The effect of circACTR2 on PC GEM resistance were examined by CCK-8 and flow cytometry assays. Whether circACTR2 could sponge miR-221-3p and regulate PTEN expression were determined by bioinformatics analysis, RNA pull-down, and Dual-luciferase reporter assay.circACTR2 was notably down-regulated in a panel of GEM-resistant PC cells lines, and negatively associated with aggressive phenotype and poor prognosis of PC. circACTR2 downregulation contributed to GEM chemoresistance of PC cells with decreased S phase ratio of cell cycle and cell apoptosis, as confirmed by gain- and loss-of-function assays in vitro. In addition, circACTR2 overexpression retarded GEM resistance in vivo. Further, circACTR2 acted as a ceRNA against miR-221-3p, which directly targeted PTEN. The mechanistic studies revealed that loss of circACTR2 promoted GEM resistance in PC through activating the PI3K/AKT signaling pathway by downregulating PTEN expression in a miR-221-3p dependent manner.circACTR2 reversed the chemoresistance of PC cells to GEM through inhibiting PI3K/AKT signaling pathway by sponging miR-221-3p and upregulating PTEN expression.© 2023. The Author(s).