Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi'an 710069, China.
Int J Mol Sci. 2020 Dec 8;21(24):9359. doi: 10.3390/ijms21249359.
Colorectal cancer (CRC) is one of the most common malignant carcinomas in the world, and metastasis is the main cause of CRC-related death. However, the molecular network involved in CRC metastasis remains poorly understood. Long noncoding RNA (lncRNA) plays a vital role in tumorigenesis and may act as a competing endogenous RNA (ceRNA) to affect the expression of mRNA by suppressing miRNA function. In this study, we identified 628 mRNAs, 144 lncRNAs, and 25 miRNAs that are differentially expressed (DE) in metastatic CRC patients compared with nonmetastatic CRC patients from the Cancer Genome Atlas (TCGA) database. Functional enrichment analyses confirmed that the identified DE mRNAs are extensively involved in CRC tumorigenesis and migration. By bioinformatics analysis, we constructed a metastasis-associated ceRNA network for CRC that includes 28 mRNAs, 12 lncRNAs, and 15 miRNAs. We then performed multivariate Cox regression analysis on the ceRNA-related DE lncRNAs and identified a 3-lncRNA signature (LINC00114, LINC00261, and HOTAIR) with the greatest prognostic value for CRC. Clinical feature analysis and functional enrichment analysis further proved that these three lncRNAs are involved in CRC tumorigenesis. Finally, we used Transwell, Cell Counting Kit (CCK)-8, and colony formation assays to clarify that the inhibition of LINC00114 promotes the migratory, invasive, and proliferative abilities of CRC cells. The results of the luciferase assay suggest that LINC00114 is the direct target of miR-135a, which also verified the ceRNA network. In summary, this study provides a metastasis-associated ceRNA network for CRC and suggests that the 3-lncRNA signature may be a useful candidate for the diagnosis and prognosis of CRC.
结直肠癌(CRC)是世界上最常见的恶性癌之一,转移是 CRC 相关死亡的主要原因。然而,CRC 转移涉及的分子网络仍了解甚少。长链非编码 RNA(lncRNA)在肿瘤发生中起着至关重要的作用,并且可以作为竞争性内源 RNA(ceRNA)通过抑制 miRNA 功能来影响 mRNA 的表达。在这项研究中,我们从癌症基因组图谱(TCGA)数据库中鉴定了 628 个差异表达(DE)的 mRNA、144 个 lncRNA 和 25 个 miRNA,这些基因在转移性 CRC 患者中与非转移性 CRC 患者相比存在差异表达。功能富集分析证实,鉴定出的 DE mRNAs 广泛参与 CRC 肿瘤发生和迁移。通过生物信息学分析,我们构建了一个 CRC 转移相关的 ceRNA 网络,其中包括 28 个 mRNA、12 个 lncRNA 和 15 个 miRNA。然后,我们对 ceRNA 相关的 DE lncRNAs 进行了多变量 Cox 回归分析,确定了一个具有最大预后价值的 3-lncRNA 特征(LINC00114、LINC00261 和 HOTAIR)。临床特征分析和功能富集分析进一步证明了这三个 lncRNA 参与了 CRC 肿瘤发生。最后,我们使用 Transwell、细胞计数试剂盒(CCK)-8 和集落形成实验阐明了抑制 LINC00114 可促进 CRC 细胞的迁移、侵袭和增殖能力。荧光素酶测定结果表明,LINC00114 是 miR-135a 的直接靶标,也验证了 ceRNA 网络。总之,本研究为 CRC 提供了一个转移相关的 ceRNA 网络,并表明 3-lncRNA 特征可能是 CRC 诊断和预后的有用候选物。
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