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

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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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.

Original languageEnglish (US)
Pages (from-to)727-743
Number of pages17
JournalJournal of Clinical Investigation
Volume129
Issue number2
DOIs
StatePublished - Feb 1 2019

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Long Noncoding RNA
Exosomes
Adenomatous Polyposis Coli
Colorectal Neoplasms
APC Genes
Neoplasm Metastasis
Neoplasms
Peroxisome Proliferator-Activated Receptors
Cell Movement

ASJC Scopus subject areas

  • Medicine(all)

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APC-activated long noncoding RNA inhibits colorectal carcinoma pathogenesis through reduction of exosome production. / Wang, Feng Wei; Cao, Chen Hui; Han, Kai; Zhao, Yong Xiang; Cai, Mu Yan; Xiang, Zhi Cheng; Zhang, Jia Xing; Chen, Jie Wei; Zhong, Li Ping; Huang, Yong; Zhou, Su Fang; Jin, Xiao Han; Guan, Xin-Yuan; Xu, Rui-Hua; Xie, Dan.

In: Journal of Clinical Investigation, Vol. 129, No. 2, 01.02.2019, p. 727-743.

Research output: Contribution to journalArticle

Wang, FW, Cao, CH, Han, K, Zhao, YX, Cai, MY, Xiang, ZC, Zhang, JX, Chen, JW, Zhong, LP, Huang, Y, Zhou, SF, Jin, XH, Guan, X-Y, Xu, R-H & Xie, D 2019, 'APC-activated long noncoding RNA inhibits colorectal carcinoma pathogenesis through reduction of exosome production', Journal of Clinical Investigation, vol. 129, no. 2, pp. 727-743. https://doi.org/10.1172/JCI122478
Wang, Feng Wei ; Cao, Chen Hui ; Han, Kai ; Zhao, Yong Xiang ; Cai, Mu Yan ; Xiang, Zhi Cheng ; Zhang, Jia Xing ; Chen, Jie Wei ; Zhong, Li Ping ; Huang, Yong ; Zhou, Su Fang ; Jin, Xiao Han ; Guan, Xin-Yuan ; Xu, Rui-Hua ; Xie, Dan. / APC-activated long noncoding RNA inhibits colorectal carcinoma pathogenesis through reduction of exosome production. In: Journal of Clinical Investigation. 2019 ; Vol. 129, No. 2. pp. 727-743.
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AU - Cao, Chen Hui

AU - Han, Kai

AU - Zhao, Yong Xiang

AU - Cai, Mu Yan

AU - Xiang, Zhi Cheng

AU - Zhang, Jia Xing

AU - Chen, Jie Wei

AU - Zhong, Li Ping

AU - Huang, Yong

AU - Zhou, Su Fang

AU - Jin, Xiao Han

AU - Guan, Xin-Yuan

AU - Xu, Rui-Hua

AU - Xie, Dan

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AB - 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.

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