APC-activated long noncoding RNA inhibits colorectal carcinoma pathogenesis through reduction of exosome production

• Published in: The Journal of clinical investigation Vol. 129; no. 2; pp. 727 - 743
• Main Authors: Wang, Feng-Wei, Cao, Chen-Hui, Han, Kai, Zhao, Yong-Xiang, Cai, Mu-Yan, Xiang, Zhi-Cheng, Zhang, Jia-Xing, Chen, Jie-Wei, Zhong, Li-Ping, Huang, Yong, Zhou, Su-Fang, Jin, Xiao-Han, Guan, Xin-Yuan, Xu, Rui-Hua, Xie, Dan
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.02.2019
• Subjects: Adenomatous polyposis coli; Adenomatous Polyposis Coli Protein - genetics; Adenomatous Polyposis Coli Protein - metabolism; Angiogenesis; Animals; Antisense RNA; Apoptosis; Biomedical research; Cancer metastasis; Cancer patients; Cancer therapies; Carcinoma; Care and treatment; Cell adhesion & migration; Cell cycle; Cell growth; Cell migration; Cell proliferation; Cell Proliferation - genetics; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Development and progression; DNA microarrays; Drug development; Endothelial cells; Endothelium; Exosomes; Exosomes - genetics; Exosomes - metabolism; Exosomes - pathology; Familial polyposis; Gene expression; Gene Expression Regulation, Neoplastic; Gene mutation; Genes; Genetic aspects; Genetic disorders; HCT116 Cells; Health aspects; Humans; Kinases; Lymph nodes; MAP kinase; MAP Kinase Signaling System; Medical prognosis; Messenger RNA; Metastases; Metastasis; Mice; Mice, Nude; mRNA; Mutation; Pathogenesis; Patients; Phosphatase; Phosphorylation; Polyposis coli; Polyps; Proteins; RNA; RNA, Long Noncoding - biosynthesis; RNA, Long Noncoding - genetics; RNA, Neoplasm - biosynthesis; RNA, Neoplasm - genetics; Tumorigenesis; Tumors; Wnt protein; Wnt1 Protein - genetics; Wnt1 Protein - metabolism; Oncology; Cell migration/adhesion; Colorectal cancer; Gastroenterology
• ISSN: 0021-9738; 1558-8238; 1558-8238
• DOI: 10.1172/JCI122478

The adenomatous polyposis coli (APC) gene plays a pivotal role in the pathogenesis of colorectal carcinoma (CRC) but remains a challenge for drug development. Long noncoding RNAs (lncRNAs) are invaluable in identifying cancer pathologies and providing therapeutic options for patients with cancer. Here, we identified a lncRNA (lncRNA-APC1) activated by APC through lncRNA microarray screening and examined its expression in a large cohort of CRC tissues. A decrease in lncRNA-APC1 expression was positively associated with lymph node and/or distant metastasis, a more advanced clinical stage, as well as a poor prognosis for patients with CRC. Additionally, APC could enhance lncRNA-APC1 expression by suppressing the enrichment of PPARα on the lncRNA-APC1 promoter. Furthermore, enforced lncRNA-APC1 expression was sufficient to inhibit CRC cell growth, metastasis, and tumor angiogenesis by suppressing exosome production through the direct binding of Rab5b mRNA and a reduction of its stability. Importantly, exosomes derived from lncRNA-APC1-silenced CRC cells promoted angiogenesis by activating the MAPK pathway in endothelial cells, and, moreover, exosomal Wnt1 largely enhanced CRC cell proliferation and migration through noncanonicial Wnt signaling. Collectively, lncRNA-APC1 is a critical lncRNA regulated by APC in the pathogenesis of CRC. Our findings suggest that an APC-regulated lncRNA-APC1 program is an exploitable therapeutic approach for the treatment of patients with CRC.