ECRG4 Represses Cell Proliferation and Invasiveness via NFIC/OGN/NF-κB Signaling Pathway in Bladder Cancer
ECRG4 Represses Cell Proliferation and Invasiveness via NFIC/OGN/NF-κB Signaling Pathway in Bladder Cancer
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DOI：
10.3389/fgene.2020.00846
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发表时间：
2020-08-14
影响因子：
3.7
通讯作者：
Wu, Changli
中科院分区：
文献类型：
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作者：
Liang, Xin;Gao, Jiangang;Wu, Changli
膀胱癌（BCa）是泌尿系统的恶性肿瘤，在全球范围内具有较高的癌症相关死亡率。然而，许多基因在BCa中失调的分子机制仍不清楚。在此，我们发现，食管癌相关基因-4（ECRG 4），这是下调的BCa组织和细胞系，与骨甘氨酸（OGN）呈正相关。进一步的功能实验研究表明ECRG 4和OGN都抑制BCa细胞的增殖、迁移和侵袭。此外，ECRG 4作为肿瘤抑制因子，通过上调核因子1C型（NFIC）促进OGN的表达，所述核因子1C型（NFIC）可结合OGN的启动子区并调节其转录。生物信息学分析显示，NFIC在BCa组织中表达下调，并与ECRG 4或OGN呈正相关。食管癌相关基因-4可正向调节BCa细胞中NFIC的蛋白水平。此外，我们首次证明ECRG 4通过上调BCa细胞中OGN来抑制核因子（NF）-κ B信号通路。总之，这些发现提供了证据，证明ECRG 4和OGN都作为肿瘤抑制因子发挥作用，并且ECRG 4的过表达通过促进BCa细胞中的NFIC/OGN信号传导来抑制NF-κ B信号传导途径。我们的研究结果揭示了ECRG 4介导的BCa中NFIC/OGN/NF-κ B信号通路抑制的分子调控机制，并为BCa提供了潜在的生物标志物或治疗靶点。
Bladder cancer (BCa) is a malignant tumor in the urinary system with high cancer-related mortality worldwide. However, the molecular mechanisms of many genes dysregulated in BCa are still unclear. Herein, we showed that esophageal cancer-related gene-4 (ECRG4), which is downregulated in BCa tissues and cell lines, has a positive correlation with osteoglycin (OGN). Further functional experimental studies suggested that both ECRG4 and OGN inhibit cell proliferation, migration, and invasion in BCa cells. Moreover, ECRG4 acts as a tumor repressor and promotes the expression of OGN via the upregulation of nuclear factor 1 C-type (NFIC), which can bind to the promoter region of OGN and regulate its transcription. Bioinformatics analysis revealed that NFIC is downregulated in BCa tissues and has a positive correlation with ECRG4 or OGN. Esophageal cancer-related gene-4 could positively regulate the protein levels of NFIC in BCa cells. In addition, we demonstrated for the first time that ECRG4 inhibits the nuclear factor (NF)-kappa B signaling pathway via the upregulation of OGN in BCa cells. Overall, these findings provide evidence that both ECRG4 and OGN function as tumor repressors and that overexpression of ECRG4 inhibits the NF-kappa B signaling pathway by promoting NFIC/OGN signaling in BCa cells. Our results reveal the molecular regulatory mechanisms of the ECRG4-mediated repression of the NFIC/OGN/NF-kappa B signaling pathway in BCa and provide potential biomarkers or therapeutic targets for BCa.