Chen Yuli, Yang Xin, Li Qiang
Health Management Center, The Third People's Hospital of Chengdu, Sichuan, Chengdu, 610014, China.
School of Clinical Medicine, Chengdu Medical College, Department of Pediatrics, The First Affiliated Hospital of Chengdu Medical College, Chengdu, 610500, China.
Recent Pat Anticancer Drug Discov. 2025;20(2):260-273. doi: 10.2174/0115748928307544240502064448.
Current cisplatin (CDDP) resistance remains a major challenge in the treatment of advanced gastric cancer. To address the issue of drug resistance, we explored the regulatory functions of PDZ and LIM structural domain protein 1 (PDLIM1) in CDDP chemotherapy for gastric cancer.
In this study, we analyzed PDLIM1 expression and prognosis using bioinformatics on publicly available data. PDLIM1 expression in a gastric mucosal epithelial cell line (GSE-1), CDDP- sensitive (SGC7901, BGC823) and CDDP-resistant gastric cancer cells was detected by RTqPCR and Western blotting. Cell proliferative capacity was assessed by knockdown of PDLIM1 and overexpression of PDLIM1 in cells administered in combination with cisplatin, and apoptotic levels were measured by CCK-8 and colony formation assay and by flow cytometry. Expression of breast cancer susceptibility gene 1 (BRCA1) and γH2AX was determined by Western blotting or immunofluorescence staining.
Downregulation of PDLIM1 was found in tumor tissues and cells, which was associated with poor clinical outcomes. Knockdown of PDLIM1 enhanced proliferation and attenuated apoptosis in gastric cancer cells. In addition, the therapeutic effects of CDDP on proliferation, apoptosis, and DNA damage repair were attenuated by PDLIM1 deletion.PDLIM1 expression was downregulated in CDDP-resistant tumor cells. Overexpression of PDLIM1 overcomes CDDP resistance in tumor cells as BRCA1 expression decreases and γH2AX expression increases.
Our findings demonstrate that PDLIM1 enables to alleviate gastric cancer progression and resistance to cisplatin via impeding DNA damage repair.
目前顺铂（CDDP）耐药仍是晚期胃癌治疗中的主要挑战。为解决耐药问题，我们探讨了PDZ和LIM结构域蛋白1（PDLIM1）在胃癌顺铂化疗中的调控作用。
在本研究中，我们利用生物信息学对公开可用数据进行分析，以研究PDLIM1的表达及预后情况。通过RTqPCR和蛋白质免疫印迹法检测胃黏膜上皮细胞系（GSE-1）、顺铂敏感（SGC7901、BGC823）及顺铂耐药胃癌细胞中PDLIM1的表达。通过敲低和过表达PDLIM1，并联合顺铂处理细胞，评估细胞增殖能力，采用CCK-8法、集落形成试验及流式细胞术检测细胞凋亡水平。通过蛋白质免疫印迹法或免疫荧光染色法检测乳腺癌易感基因1（BRCA1）和γH2AX的表达。
在肿瘤组织和细胞中发现PDLIM1表达下调，这与不良临床预后相关。敲低PDLIM1可增强胃癌细胞的增殖能力并减弱其凋亡。此外，PDLIM1缺失会削弱顺铂对细胞增殖、凋亡及DNA损伤修复的治疗效果。在顺铂耐药肿瘤细胞中，PDLIM1表达下调。过表达PDLIM1可克服肿瘤细胞的顺铂耐药性，此时BRCA1表达降低，γH2AX表达增加。
我们的研究结果表明，PDLIM1可通过阻碍DNA损伤修复来缓解胃癌进展及顺铂耐药。
