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.

中文翻译：

---

LINC01852 通过抑制 SRSF5 介导的 PKM 选择性剪接来抑制结直肠癌的肿瘤发生和化疗耐药

结直肠癌（CRC）是全世界癌症相关死亡的主要原因，化疗耐药是其治疗的主要障碍。尽管治疗取得了进展，但结直肠癌化疗耐药的分子机制尚不完全清楚。最近的研究表明长链非编码 RNA (lncRNA) 在调节 CRC 化疗耐药性中发挥着关键作用。在这项研究中，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 在多个 CRC 队列中评估 LINC01852 表达。我们使用细胞培养物和小鼠模型进行了体外和体内功能实验。使用 RNA Pull-down、RNA 免疫沉淀、染色质免疫沉淀和双荧光素酶测定来研究 LINC01852 在 CRC 中的分子机制。我们的研究结果表明，具有肿瘤抑制特性的 lncRNA LINC01852 在 CRC 中表达下调，并在体外和体内抑制细胞增殖和化疗耐药性。进一步的机制研究表明，LINC01852 增加 TRIM72 介导的 SRSF5 泛素化和降解，抑制 SRSF5 介导的 PKM 选择性剪接，从而减少 PKM2 的产生。LINC01852 的过度表达会诱导从有氧糖酵解到氧化磷酸化的代谢转变，从而通过抑制 PKM2 介导的糖酵解来减弱 CRC 细胞的化疗耐药性。我们的结果表明，LINC01852通过调节SRSF5介导的PKM选择性剪接在抑制CRC恶性肿瘤和化疗耐药中发挥重要作用，并且靶向LINC01852/TRIM72/SRSF5/PKM2信号轴可能代表CRC的潜在治疗策略。