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

J Clin Invest. 2019 Feb 1;129(2):727-743. doi: 10.1172/JCI122478. Epub 2019 Jan 14.

Abstract

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.

Keywords: Cell migration/adhesion; Colorectal cancer; Gastroenterology; Oncology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenomatous Polyposis Coli Protein* / genetics
  • Adenomatous Polyposis Coli Protein* / metabolism
  • Animals
  • Cell Proliferation / genetics
  • Colorectal Neoplasms* / genetics
  • Colorectal Neoplasms* / metabolism
  • Colorectal Neoplasms* / pathology
  • Exosomes* / genetics
  • Exosomes* / metabolism
  • Exosomes* / pathology
  • Gene Expression Regulation, Neoplastic
  • HCT116 Cells
  • Humans
  • MAP Kinase Signaling System*
  • Mice
  • Mice, Nude
  • RNA, Long Noncoding* / biosynthesis
  • RNA, Long Noncoding* / genetics
  • RNA, Neoplasm* / biosynthesis
  • RNA, Neoplasm* / genetics
  • Wnt1 Protein / genetics
  • Wnt1 Protein / metabolism

Substances

  • APC protein, human
  • Adenomatous Polyposis Coli Protein
  • RNA, Long Noncoding
  • RNA, Neoplasm
  • WNT1 protein, human
  • Wnt1 Protein