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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

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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 7

lncRNA-APC1 inhibits tumor angiogenesis through exosomes.

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lncRNA-APC1 inhibits tumor angiogenesis through exosomes.
(A) Transwell ...
(A) Transwell invasion assay of HUVECs treated with the indicated exosomes (exo). Scale bar: 50 μm. (B) Capillary tube formation assay of HUVECs treated with the indicated exosomes. (C) Transwell invasion assay of HUVECs treated with the indicated exosomes derived from transfected HCT116 cells. Scale bars 100 μm. (D) Capillary tube formation assay of HUVECs treated with the indicated exosomes. Data represent the mean ± SD of 3 independent experiments. **P < 0.01 and ***P < 0.001, by independent Student’s t test.
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