Wei Xiaoli, Zhu Jiejie, Zhang Yiyin, Zhao Qihong, Wang Hua, Gu Kangsheng
Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230032, P.R. China.
Department of Food and Nutrition Hygiene, School of Public Health, Anhui Medical University, Hefei, Anhui 230032, P.R. China.
J Cancer. 2021 Sep 23;12(22):6756-6772. doi: 10.7150/jca.58249. eCollection 2021.
MiRNAs have been widely reported to be involved in the occurrence and development of cancers. So far, some studies have revealed that miR-338-5p has the functions of tumorigenesis and tumor suppression. However, the role of miR-338-5p in the pathogenesis, progression and treatment of gastric cancer (GC) has not been reported. MiRNAs microarray analysis showed for the first time that miR-338-5p was significantly lower-expression in cisplin-resistant GC cells SGC7901/DDP, and cell viability assay and flow cytometry confirmed that overexpression of miR-338-5p could significantly increase cisplatin-sensitivity of SGC7901/DDP and BGC823 cells. Subsequently, we found that the expression of miR-338-5p in postoperative cancer tissues of GC patients was also significantly lower than the corresponding paracancer tissues. The expression of miR-338-5p in peripheral blood serum of GC patients is generally lower than that of healthy people. Moreover, the low expression of miR-338-5p in the cancer tissues and serum of GC patients was closely associated with larger tumor volume, lymph node metastasis, later stage, and even poorer survival, which was confirmed by close 5-year cases follow-up. ZEB2, as a predictive target of miR-338-5p, its expression was negatively regulated by miR-338-5p and can promote cisplatin-resistance in SGC7901/DDP and BGC823 cells. The expression of ZEB2 in cisplatin-resistant SGC7901/DDP cells and GC tissues were significantly higher than SGC7901 cells and paracancer tissues, respectively. Moreover, the expression of ZEB2 in tumor tissues was negatively correlated with miR-338-5p in tumor tissues and peripheral blood serum of GC patients, and the abnormally high expression of ZEB2 in prospective case studies is positively related with more serious clinical pathology and worse survival. More meaningfully, in a retrospective case study, we found that high ZEB2 expression predicts worse clinical efficacy of platinum chemotherapy. Thus, miR-338-5p-ZEB2 axis have novel diagnostic, therapeutic predictive, and prognostic value in GC patients.
已有广泛报道称，微小RNA（miRNA）参与癌症的发生和发展。到目前为止，一些研究表明miR-338-5p具有肿瘤发生和肿瘤抑制功能。然而，miR-338-5p在胃癌（GC）发病机制、进展及治疗中的作用尚未见报道。微小RNA芯片分析首次显示，miR-338-5p在顺铂耐药的GC细胞SGC7901/DDP中表达显著降低，细胞活力测定和流式细胞术证实，miR-338-5p过表达可显著增加SGC7901/DDP和BGC823细胞对顺铂的敏感性。随后，我们发现GC患者术后癌组织中miR-338-5p的表达也显著低于相应癌旁组织。GC患者外周血血清中miR-338-5p的表达普遍低于健康人。此外，GC患者癌组织和血清中miR-338-5p的低表达与肿瘤体积较大、淋巴结转移、分期较晚以及生存率较差密切相关，这一点通过对5年病例的密切随访得到证实。ZEB2作为miR-338-5p的预测靶点，其表达受miR-338-5p负调控，并可促进SGC7901/DDP和BGC823细胞的顺铂耐药性。顺铂耐药的SGC7901/DDP细胞和GC组织中ZEB2的表达分别显著高于SGC7901细胞和癌旁组织。此外，GC患者肿瘤组织中ZEB2的表达与肿瘤组织及外周血血清中miR-338-5p呈负相关，前瞻性病例研究中ZEB2的异常高表达与更严重的临床病理及更差的生存率呈正相关。更有意义的是，在一项回顾性病例研究中，我们发现ZEB2高表达预示铂类化疗的临床疗效较差。因此，miR-338-5p-ZEB2轴在GC患者中具有新的诊断、治疗预测和预后价值。
