Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, 200 Hui He Road, Wuxi, Jiangsu, 214062, China.
Laboratory of Cancer Epigenetics, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, 214122, China.
Mol Cancer. 2024 Jan 24;23(1):23. doi: 10.1186/s12943-024-01939-7.
Colorectal cancer (CRC) is a major cause of cancer-related deaths worldwide, and chemoresistance is a major obstacle in its treatment. Despite advances in therapy, the molecular mechanism underlying chemoresistance in CRC is not fully understood. Recent studies have implicated the key roles of long noncoding RNAs (lncRNAs) in the regulation of CRC chemoresistance.
In this study, we investigated the role of the lncRNA LINC01852 in CRC chemoresistance. LINC01852 expression was evaluated in multiple CRC cohorts using quantitative reverse transcription PCR. We conducted in vitro and in vivo functional experiments using cell culture and mouse models. RNA pull-down, RNA immunoprecipitation, chromatin immunoprecipitation, and dual luciferase assays were used to investigate the molecular mechanism of LINC01852 in CRC.
Our findings revealed that a lncRNA with tumor-inhibiting properties, LINC01852, was downregulated in CRC and inhibited cell proliferation and chemoresistance both in vitro and in vivo. Further mechanistic investigations revealed that LINC01852 increases TRIM72-mediated ubiquitination and degradation of SRSF5, inhibiting SRSF5-mediated alternative splicing of PKM and thereby decreasing the production of PKM2. Overexpression of LINC01852 induces a metabolic switch from aerobic glycolysis to oxidative phosphorylation, which attenuates the chemoresistance of CRC cells by inhibiting PKM2-mediated glycolysis.
Our results demonstrate that LINC01852 plays an important role in repressing CRC malignancy and chemoresistance by regulating SRSF5-mediated alternative splicing of PKM, and that targeting the LINC01852/TRIM72/SRSF5/PKM2 signaling axis may represent a potential therapeutic strategy for CRC.
结直肠癌（CRC）是全球癌症相关死亡的主要原因，而化疗耐药是其治疗的主要障碍。尽管治疗取得了进展，但 CRC 化疗耐药的分子机制尚未完全阐明。最近的研究表明，长链非编码 RNA（lncRNA）在调节 CRC 化疗耐药中起着关键作用。
在本研究中，我们研究了 lncRNA LINC01852 在 CRC 化疗耐药中的作用。使用定量逆转录 PCR 评估了多个 CRC 队列中 LINC01852 的表达。我们使用细胞培养和小鼠模型进行了体外和体内功能实验。RNA 下拉、RNA 免疫沉淀、染色质免疫沉淀和双荧光素酶报告基因实验用于研究 LINC01852 在 CRC 中的分子机制。
我们的研究结果表明，一种具有肿瘤抑制特性的 lncRNA，LINC01852，在 CRC 中下调，并在体外和体内均抑制细胞增殖和化疗耐药。进一步的机制研究表明，LINC01852 增加了 TRIM72 介导的 SRSF5 的泛素化和降解，抑制了 SRSF5 介导的 PKM 的可变剪接，从而减少了 PKM2 的产生。LINC01852 的过表达诱导有氧糖酵解向氧化磷酸化的代谢转变，通过抑制 PKM2 介导的糖酵解，减轻 CRC 细胞的化疗耐药性。
我们的研究结果表明，LINC01852 通过调节 SRSF5 介导的 PKM 的可变剪接，在抑制 CRC 恶性肿瘤和化疗耐药中发挥重要作用，靶向 LINC01852/TRIM72/SRSF5/PKM2 信号轴可能代表 CRC 的一种潜在治疗策略。
