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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.
View: Text | PDF | Corrigendum
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 10

In CRC cells, lncRNA-APC1 interacts with and reduces the stability of Rab5b mRNA.

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In CRC cells, lncRNA-APC1 interacts with and reduces the stability of Ra...
(A) Regions of putative binding between Rab5b mRNA (query) and lncRNA-APC1 (subject). (B) SW480 and DLD-1 cell lysates were incubated with biotin-labeled WT or mutant type (Mut) lncRNA-APC1. After pulldown, mRNA was extracted and measured by qRT-PCR. (C) Model of RIP assay. (D) RIP-derived RNA was examined by qRT-PCR. The levels of the qRT-PCR products were normalized relative to input RNA and IgG control. (E) The stability of Rab5b mRNA and Actb mRNA was measured by qRT-PCR relative to t0 after blocking new RNA synthesis with α-amanitin and normalized to 18S rRNA. Data represent the mean ± SD of 3 independent experiments. **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 1-way ANOVA.

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

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