Long noncoding RNAs (lncRNAs) have been confirmed, which are involved in tumorigenesis and metastasis in colorectal cancer (CRC). FOXC2 antisense RNA 1 (FOXC2-AS1) was reported, facilitating the proliferation and progression in several cancers. However, the role of FOXC2-AS1 in CRC cell migration and metastasis is not unclear. In this study, we observed that lncRNA FOXC2-AS1 was upregulated in CRC tissues, and its high expression indicated the poor survival in CRC patients. Meanwhile, FOXC2-AS1 was higher in CRC tissues with metastasis than that of nonmetastatic tumor tissues. We found that FOXC2-AS1 was predominately expressed in the nucleus of tissues and cells. FOXC2-AS1 knockdown suppressed CRC cell growth, invasion, and metastasis in vitro and in vivo. Moreover, FOXC2-AS1 could positively regulate the neighboring gene FOXC2 and stabilized FOXC2 mRNA by forming a RNA duplex. Meanwhile, ectopic expression of FOXC2 could obviously alleviate the suppressed effects caused by silencing FOXC2-AS1. For the mechanism, FOXC2-AS1 knockdown could reduce intracellular Ca2+ levels, inhibited FA formation and FAK signaling, and these suppressed effects were mitigated by increasing FOXC2 expression. These results demonstrated that FOXC2-AS1 enhances FOXC2 mRNA stability to promote CRC proliferation, migration, and invasion by activation of Ca2+-FAK signaling, which implicates that FOXC2-AS1 may represent a latent effective therapeutic target for CRC progression.

译文

:已证实长非编码RNA(lncRNA),它们参与了结直肠癌(CRC)的肿瘤发生和转移。据报道,FOXC2反义RNA 1(FOXC2-AS1)促进了几种癌症的增殖和进展。然而,FOXC2-AS1在CRC细胞迁移和转移中的作用尚不清楚。在这项研究中,我们观察到lncRNA FOXC2-AS1在CRC组织中被上调,其高表达表明CRC患者的生存期较差。同时,转移的CRC组织中的FOXC2-AS1高于非转移性肿瘤组织中的FOXC2-AS1。我们发现FOXC2-AS1主要在组织和细胞的细胞核中表达。 FOXC2-AS1组合物在体外和体内均抑制CRC细胞的生长,侵袭和转移。此外,FOXC2-AS1可以通过形成RNA双链体来正向调节邻近基因FOXC2,并稳定FOXC2 mRNA。同时,异位表达FOXC2可明显减轻沉默FOXC2-AS1引起的抑制作用。对于该机制,FOXC2-AS1敲低可以降低细胞内Ca2水平,抑制FA形成和FAK信号传导,并且通过增加FOXC2表达来减轻这些抑制作用。这些结果表明FOXC2-AS1通过激活Ca2-FAK信号来增强FOXC2 mRNA的稳定性,从而促进CRC增殖,迁移和侵袭,这暗示FOXC2-AS1可能代表了CRC进展的潜在有效治疗靶点。

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