STAT2‐induced linc02231 promotes tumorigenesis and angiogenesis through modulation of hnRNPA1/ANGPTL4 in colorectal cancer

Abstract

Background 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. Methods 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. Results 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. Conclusions 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.

Interplay between JAK/STAT pathway and non-coding RNAs in different cancers

“…Mechanistically, hnRNPA1 prevents the maturation of ANGPTL4 (angiopoietin-like protein 4) in colorectal cancer cells. There was a significant shrinkage in the transplanted tumor tissues after linc02231 knockdown [ 43 ].…”