A novel lncRNA LOC101928222 promotes colorectal cancer angiogenesis by stabilizing HMGCS2 mRNA and increasing cholesterol synthesis

• Published in: Journal of experimental & clinical cancer research 2024-07, Vol.43 (1), p.185-19, Article 185
• Main Authors: Chang, Lisha, Ding, Jie, Pu, Juan, Zhu, Jing, Zhou, Xiang, Luo, Qian, Li, Jie, Qian, Mengsen, Lin, Shuhui, Li, Juan, Wang, Keming
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animals; Biosynthesis; Blood vessels; Cell Line, Tumor; Cholesterol; Cholesterol - metabolism; Cholesterol synthesis; Colorectal cancer; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Development and progression; Ethylenediaminetetraacetic acid; Female; Gene Expression Regulation, Neoplastic; Genes; Genomes; Health aspects; Humans; Hydroxymethylglutaryl-CoA Synthase - genetics; Hydroxymethylglutaryl-CoA Synthase - metabolism; Invoices; LOC101928222; m6A; Male; Messenger RNA; Metabolism; Metabolites; Metastasis; Methyltransferases; Mice; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; Proteins; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Scientific equipment and supplies industry; Tumors
• ISSN: 1756-9966; 0392-9078; 1756-9966
• DOI: 10.1186/s13046-024-03095-8

Metastasis is the leading cause of mortality in patients with colorectal cancer (CRC) and angiogenesis is a crucial factor in tumor invasion and metastasis. Long noncoding RNAs (lncRNAs) play regulatory functions in various biological processes in tumor cells, however, the roles of lncRNAs in CRC-associated angiogenesis remain to be elucidated in CRC, as do the underlying mechanisms. We used bioinformatics to screen differentially expressed lncRNAs from TCGA database. LOC101928222 expression was assessed by qRT-PCR. The impact of LOC101928222 in CRC tumor development was assessed both in vitro and in vivo. The regulatory mechanisms of LOC101928222 in CRC were investigated by cellular fractionation, RNA-sequencing, mass spectrometric, RNA pull-down, RNA immunoprecipitation, RNA stability, and gene-specific m6A assays. LOC101928222 expression was upregulated in CRC and was correlated with a worse outcome. Moreover, LOC101928222 was shown to promote migration, invasion, and angiogenesis in CRC. Mechanistically, LOC101928222 synergized with IGF2BP1 to stabilize HMGCS2 mRNA through an m6A-dependent pathway, leading to increased cholesterol synthesis and, ultimately, the promotion of CRC development. In summary, these findings demonstrate a novel, LOC101928222-based mechanism involved in the regulation of cholesterol synthesis and the metastatic potential of CRC. The LOC101928222-HMGCS2-cholesterol synthesis pathway may be an effective target for diagnosing and managing CRC metastasis.