Department of Anorectal Section, Shanghai Baoshan District Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai 201999, P.R. China.
Department of Anorectal Section, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China.
Mol Med Rep. 2021 Dec;24(6). doi: 10.3892/mmr.2021.12507. Epub 2021 Oct 22.
Intestinal mucositis is a common side effect of cancer chemotherapy and it limits the dose of chemotherapy given to a patient. Tripartite motif family (TRIM) proteins have been reported to be implicated in the regulation of cancer chemotherapy. The present study aimed to investigate the effect of TRIM9 on irinotecan‑induced intestinal mucositis in the rat intestinal epithelial cell line IEC‑6. The expression of several TRIMs, such as TRIM1, TRIM9, TRIM18, TRIM36, TRIM46 and TRIM67, was examined. After TRIM9 knockdown or overexpression by lentivirus infection, cell proliferation and apoptosis, epithelial barrier tight‑junction proteins, inflammatory cytokines, transepithelial electrical resistance (TEER) and FITC dextran were measured. Treatment with irinotecan significantly inhibited cell proliferation and induced cell apoptosis, TRIM9 expression, intestinal mucosal barrier impairment, the levels of inflammatory cytokines and P38 phosphorylation in IEC‑6 cells, while the expression levels of epithelial barrier tight‑junction protein ZO‑1 and Claudin‑4 were decreased. Knockdown of TRIM9 partly counteracted the effect of irinotecan treatment, and inhibition of P38 potently reversed the effect of TRIM9 overexpression in IEC‑6 cells. Moreover, co‑immunoprecipitation showed an interaction between TRIM9 and DUSP6 in IEC‑6 cells, and overexpression of DUSP6 notably counteracted the effect of TRIM9 overexpression. The results demonstrated that TRIM9 knockdown may benefit patients with intestinal mucositis by inhibiting inflammatory cytokine expression and repairing intestinal barrier functions, which was probably due to inhibition of the activation of the P38 pathway via targeting DUSP6.
肠黏膜炎是癌症化疗的常见副作用，它限制了给予患者的化疗剂量。三结构域家族（TRIM）蛋白已被报道参与癌症化疗的调节。本研究旨在探讨 TRIM9 对伊立替康诱导的大鼠肠上皮细胞系 IEC-6 肠黏膜炎的影响。检测了几种 TRIMs 的表达，如 TRIM1、TRIM9、TRIM18、TRIM36、TRIM46 和 TRIM67。通过慢病毒感染进行 TRIM9 敲低或过表达后，测量细胞增殖和凋亡、上皮屏障紧密连接蛋白、炎症细胞因子、跨上皮电阻（TEER）和 FITC 葡聚糖。伊立替康处理显著抑制细胞增殖并诱导细胞凋亡、TRIM9 表达、肠黏膜屏障损伤、IEC-6 细胞中炎症细胞因子和 P38 磷酸化水平升高，而上皮屏障紧密连接蛋白 ZO-1 和 Claudin-4 的表达水平降低。TRIM9 敲低部分抵消了伊立替康处理的效果，而 P38 抑制强烈逆转了 IEC-6 细胞中 TRIM9 过表达的效果。此外，共免疫沉淀显示 TRIM9 和 DUSP6 之间在 IEC-6 细胞中有相互作用，而过表达 DUSP6 显著抵消了 TRIM9 过表达的效果。结果表明，TRIM9 敲低可能通过抑制炎症细胞因子表达和修复肠屏障功能有益于肠黏膜炎患者，这可能是通过靶向 DUSP6 抑制 P38 通路的激活所致。
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