Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China.
Department of Health Management Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China.
Curr Med Chem. 2024;31(22):3397-3411. doi: 10.2174/0109298673255498231117100421.
Chemotherapy resistance is one of the main causes of clinical chemotherapy failure. Current cancer research explores the drug resistance mechanism and new therapeutic targets. This work aims to elucidate the mechanism of thyroid hormone receptor interactor 13 (TRIP13) affecting doxorubicin (DOX) resistance in colorectal cancer (CRC).
Bioinformatics analyses were employed to clarify TRIP13 expression in CRC tissues and predict the correlation of the TRIP13 enrichment pathway with glycolysis-related genes and stemness index mRNAsi. Quantitative real-time polymerase chain reaction and western blot were adopted to analyze the expression of TRIP13 and glycolysis- related genes. Cell Counting Kit-8 was utilized to determine the cell viability and IC value. Western blot was employed to measure the expression of stemness-related factors. Cell function assays were performed to detect cells' sphere-forming ability and glycolysis level. Animal models were constructed to determine the effects of TRIP13 expression on CRC tumor growth.
TRIP13 was significantly overexpressed in CRC, concentrated in the glycolysis signaling pathway, and positively correlated with stemness index mRNAsi. High expression of TRIP13 facilitated DOX resistance in CRC. Further mechanistic studies revealed that overexpression of TRIP13 could promote cell stemness through glycolysis, which was also confirmed in animal experiments.
TRIP13 was highly expressed in CRC, which enhanced the DOX resistance of CRC cells by activating glycolysis to promote cell stemness. These findings offer new insights into the pathogenesis of DOX resistance in CRC and suggest that TRIP13 may be a new target for reversing DOX resistance in CRC.
化疗耐药是临床化疗失败的主要原因之一。目前的癌症研究探索了耐药机制和新的治疗靶点。本工作旨在阐明甲状腺激素受体相互作用蛋白 13（TRIP13）影响结直肠癌（CRC）多柔比星（DOX）耐药的机制。
采用生物信息学分析方法阐明 TRIP13 在 CRC 组织中的表达，并预测 TRIP13 富集途径与糖酵解相关基因和干性指数 mRNAsi 的相关性。采用定量实时聚合酶链反应和 Western blot 分析 TRIP13 和糖酵解相关基因的表达。细胞计数试剂盒-8 用于测定细胞活力和 IC 值。Western blot 用于测量干性相关因子的表达。细胞功能测定用于检测细胞的球体形成能力和糖酵解水平。构建动物模型以确定 TRIP13 表达对 CRC 肿瘤生长的影响。
TRIP13 在 CRC 中显著过表达，集中在糖酵解信号通路中，与干性指数 mRNAsi 呈正相关。TRIP13 高表达促进 CRC 对 DOX 的耐药性。进一步的机制研究表明，TRIP13 的过表达可以通过糖酵解促进细胞干性，这在动物实验中也得到了证实。
TRIP13 在 CRC 中高表达，通过激活糖酵解促进细胞干性，增强 CRC 细胞对 DOX 的耐药性。这些发现为 CRC 中 DOX 耐药的发病机制提供了新的见解，并表明 TRIP13 可能是逆转 CRC 中 DOX 耐药的新靶点。
