Data_Sheet_1_ECRG4 Represses Cell Proliferation and Invasiveness via NFIC/OGN/NF-κB Signaling Pathway in Bladder Cancer.PDF

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)-κB 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-κB 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-κB signaling pathway in BCa and provide potential biomarkers or therapeutic targets for BCa.

膀胱癌（BCa）是全球范围内与癌症相关死亡率较高的泌尿系统恶性肿瘤。然而，众多在BCa中失调的基因的分子机制尚不明确。本研究揭示了食管癌相关基因-4（ECRG4），其在BCa组织和细胞系中表达下调，与骨桥蛋白（OGN）呈正相关。进一步的功能性实验研究表明，ECRG4和OGN均能在BCa细胞中抑制细胞增殖、迁移和侵袭。此外，ECRG4作为肿瘤抑制因子，通过上调核因子1C型（NFIC）的表达，促进OGN的表达，而NFIC能够结合于OGN启动子区域并调控其转录。生物信息学分析显示，NFIC在BCa组织中表达下调，并与ECRG4或OGN呈正相关。ECRG4能够正调控BCa细胞中NFIC的蛋白水平。此外，本研究首次证实ECRG4通过上调OGN在BCa细胞中抑制核因子（NF）-κB信号通路。综上所述，这些发现提供了ECRG4作为肿瘤抑制因子以及OGN在BCa细胞中通过促进NFIC/OGN信号通路抑制NF-κB信号通路的证据。本研究揭示了ECRG4介导的NFIC/OGN/NF-κB信号通路在BCa中的分子调控机制，并为BCa提供了潜在的生物标志物或治疗靶点。