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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 December 4, 2018
Citation Information: J Clin Invest. 2019;129(2):727-743. https://doi.org/10.1172/JCI122478.
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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 5

Suppression of CRC tumor growth by lncRNA-APC1 acts through the inhibition of tumor angiogenesis.

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Suppression of CRC tumor growth by lncRNA-APC1 acts through the inhibiti...
(A) Representative images of H&E-stained sections from xenograft tumors formed in nude mice. Original magnification, ×40 (top); ×400 (bottom). (B) Expression of cell-cycle checkpoint markers as revealed by Western blotting. (C) Flow cytometric analysis of the cell cycle. (D) MVD of the indicated xenograft tumors detected by CD34 staining. Capillary tube formation assay (E) and Transwell invasion assay (F) of HUVECs treated with the indicated exosomes derived from transfected HCT116 cells. Scale bars: 100 μm (D and F). Original magnification, ×40 (E). Data represent the mean ± SD of 3 independent experiments (E and F). ****P < 0.0001, by independent Student’s t test.

Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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