Department of Oncology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Department of Oncology, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China.
J Gene Med. 2023 Aug;25(8):e3506. doi: 10.1002/jgm.3506. Epub 2023 Apr 12.
Long non-coding RNAs (lncRNAs) play a critical role in regulating various human diseases including cancer. In colorectal cancer (CRC), there are still some undervalued lncRNAs with potential functions and mechanisms that need to be clarified. The present study aimed to investigate the role of linc02231 in the progression of CRC.
The proliferation of CRC cells was evaluated using Cell Counting Kit-8, colony formation, and 5-ethynyl-2'-deoxyuridine (EdU) assays. Cell migration was examined through wound healing and Transwell analyses. The impact of linc02231 on angiogenesis was determined through a tube formation assay. Western blotting was used to detect the expression of specific proteins. A mouse xenograft model is established to observe the effect of linc02231 on the in vivo growth of CRC cells. Target genes of linc02231 are screened using high-throughput sequencing. The transcriptional activity of STAT2 on linc02231 and the binding activity between linc02231/miR-939-5p/hnRNPA1 were analyzed by a luciferase assay.
Based on public databases and comprehensive bioinformatics analysis, we found that lncRNA linc02231 was upregulated in CRC tumor tissues, which is consistent with our clinical results. linc02231 promoted the proliferation and migration of CRC cells in vitro and their tumorigenicity in vivo. Furthermore, linc02231 promotes the angiogenic ability of human umbilical vein endothelial cells. Mechanistically, the transcription factor STAT2 binds to the promoter region of linc02231 and activates its transcription. linc02231 also competes with miR-939-5p for binding to the pro-oncogenic target gene hnRNPA1, preventing its degradation. hnRNPA1 prevents the maturation of angiopoietin-like protein 4 (ANGPTL4) messenger RNA, leading to impaired tumor angiogenesis and increased metastasis of CRC.
The expression of linc02231, which is induced by STAT2, has been found to enhance the proliferation, metastasis, and angiogenesis of CRC by binding to miR-939-5p and increasing the expression of hnNRPA1 at the same time as suppressing ANGPTL4. These findings suggest that linc02231 could serve as a potential biomarker and therapeutic target for CRC.
长链非编码 RNA（lncRNA）在调控包括癌症在内的各种人类疾病中起着关键作用。在结直肠癌（CRC）中，仍然有一些被低估的 lncRNA 具有潜在的功能和机制需要阐明。本研究旨在探讨 linc02231 在 CRC 进展中的作用。
使用细胞计数试剂盒-8、集落形成和 5-乙炔基-2'-脱氧尿苷（EdU）检测评估 CRC 细胞的增殖。通过划痕愈合和 Transwell 分析检测细胞迁移。通过管形成测定评估 linc02231 对血管生成的影响。使用 Western blot 检测特定蛋白的表达。建立小鼠异种移植模型观察 linc02231 对 CRC 细胞体内生长的影响。通过高通量测序筛选 linc02231 的靶基因。通过荧光素酶测定分析 STAT2 对 linc02231 的转录活性以及 linc02231/miR-939-5p/hnRNPA1 之间的结合活性。
基于公共数据库和综合生物信息学分析，我们发现 lncRNA linc02231 在 CRC 肿瘤组织中上调，这与我们的临床结果一致。linc02231 促进 CRC 细胞的体外增殖、迁移及其体内致瘤性。此外，linc02231 促进人脐静脉内皮细胞的血管生成能力。机制上，转录因子 STAT2 结合到 linc02231 的启动子区域并激活其转录。linc02231 还与 miR-939-5p 竞争结合致癌靶基因 hnRNPA1，防止其降解。hnRNPA1 阻止血管生成素样蛋白 4（ANGPTL4）信使 RNA 的成熟，导致肿瘤血管生成受损和 CRC 转移增加。
由 STAT2 诱导的 linc02231 的表达通过与 miR-939-5p 结合并同时增加 hnRNPA1 的表达来抑制 ANGPTL4，增强 CRC 的增殖、转移和血管生成。这些发现表明 linc02231 可作为 CRC 的潜在生物标志物和治疗靶点。
