APC-activated long noncoding RNA inhibits colorectal carcinoma pathogenesis through reduction of exosome production
Feng-Wei Wang, … , Rui-Hua Xu, Dan Xie
Feng-Wei Wang, … , Rui-Hua Xu, Dan Xie
Published February 1, 2019; First published December 4, 2018
Citation Information: J Clin Invest. 2019;129(2):727-743. https://doi.org/10.1172/JCI122478.
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Categories: Research Article Gastroenterology Oncology

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

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.

Authors

Feng-Wei Wang, Chen-Hui Cao, Kai Han, Yong-Xiang Zhao, Mu-Yan Cai, Zhi-Cheng Xiang, Jia-Xing Zhang, Jie-Wei Chen, Li-Ping Zhong, Yong Huang, Su-Fang Zhou, Xiao-Han Jin, Xin-Yuan Guan, Rui-Hua Xu, Dan Xie

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Figure 1

Upregulation of lncRNA-APC1 by APC.

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Upregulation of lncRNA-APC1 by APC. Expression of APC in the indicated c...
Expression of APC in the indicated cell lines transfected with control or WT APC vector, as measured by qRT-PCR (A) and Western blotting (B). (C) Number of altered lncRNAs in the indicated cells examined in 2 independently repeated lncRNA microarray tests. (D) qRT-PCR verification of lncRNAs potentially regulated by APC. (E) Expression of lncRNA-APC1 was detected by FISH. Scale bars: 20 μm. (F) Relative expression of lncRNA-APC1 in paired CRC primary tumor tissues and nontumor colonic tissues (n = 30). (G) Kaplan-Meier survival analysis of patients with CRC (n = 110) according to lncRNA-APC1 expression (cutoff value is the median). Experiments in F and G were repeated twice with similar results. Data in A, E, and F represent the mean ± SD of 3 separate experiments. **P < 0.01, ***P < 0.001, and ****P < 0.0001, by independent Student’s t test (A and F) or log-rank test (G). NC, negative control.