APC-activated long noncoding RNA inhibits colorectal carcinoma pathogenesis through reduction of exosome production
APC-activated long noncoding RNA inhibits colorectal carcinoma pathogenesis through reduction of exosome production
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APC 激活的长非编码 RNA 通过减少外泌体产生抑制结直肠癌发病机制
DOI：
10.1172/jci122478
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发表时间：
2019-02-01
影响因子：
15.9
通讯作者：
Xie, Dan
中科院分区：
文献类型：
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作者：
Wang, Feng-Wei;Cao, Chen-Hui;Xie, Dan
大肠腺瘤性息肉病(APC)基因在结直肠癌(CRC)的发病机制中起着关键作用，但仍是药物开发的一个挑战。长非编码RNA(LncRNAs)在识别癌症病理和为癌症患者提供治疗选择方面具有非常重要的价值。在这里，我们通过lncRNA微阵列筛选确定了一个由APC激活的lncRNA(lncRNA-APC1)，并检测了它在大量结直肠癌组织中的表达。LncRNA-APC1表达降低与结直肠癌患者的淋巴转移和/或远处转移、临床分期越高以及预后越差呈正相关。此外，APC还可通过抑制PPAR和agr；在lncRNA-APC1启动子上的聚集而增强lncRNA-APC1的表达。此外，增强的lncRNA-APC1表达足以抑制CRC细胞的生长、转移和肿瘤血管生成，因为它通过与Rab5b mRNA的直接结合而抑制外体的产生，并降低其稳定性。重要的是，来自LncRNA-APC1沉默的结直肠癌细胞的外体通过激活内皮细胞中的MAPK通路来促进血管生成，而且，外体WNT1通过非规范的Wnt信号大大促进了结直肠癌细胞的增殖和迁移。总之，lncRNA-APC1是APC调控的一种关键的lncRNA，在结直肠癌的发病机制中起着重要的作用。我们的研究结果表明，APC调节的lncRNA-APC1方案是治疗结直肠癌患者的一种可开发的治疗方法。
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 PPAR&agr; 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.