TGF-β1-SOX9 axis-inducible COL10A1 promotes invasion and metastasis in gastric cancer via epithelial-to-mesenchymal transition.
TGF-β1-SOX9 axis-inducible COL10A1 promotes invasion and metastasis in gastric cancer via epithelial-to-mesenchymal transition.
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TGF-β1-SOX9轴诱导的COL10A1通过上皮间质转化促进胃癌侵袭和转移
DOI：
10.1038/s41419-018-0877-2
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发表时间：
2018-08-28
影响因子：
9
通讯作者：
Li G
中科院分区：
文献类型：
--
作者：
Li T;Huang H;Shi G;Zhao L;Li T;Zhang Z;Liu R;Hu Y;Liu H;Yu J;Li G
预测疾病进展的分子生物标志物可能促进侵袭性癌症（如胃癌（GC））的药物开发和治疗策略。高通量mRNA测序（RNA-seq）显示，X型胶原α 1（COL 10A 1）是一种疾病进展相关基因。对103例胃癌患者的分析表明，COL 10A 1 mRNA的高表达与胃癌转移和生存率降低有关。我们利用UCSC基因组网站和JASPAR数据库对COL 10A 1启动子进行分析，发现了潜在的SOX 9结合位点。在这里，我们证明了SOX 9和COL 10A 1在GC中都上调。我们观察到SOX 9和COL 10A 1在GC细胞和组织中的表达模式之间呈正相关。电泳迁移率变动分析（EMSA）、染色质免疫沉淀分析（ChIP）和启动子报告基因分析结果表明，SOX 9能直接与COL 10A 1基因启动子结合并激活其转录。生物学功能实验表明，COL 10A 1对胃癌细胞的迁移和侵袭有调节作用。在裸鼠模型中，敲低COL 10A 1抑制肺和腹腔转移。转化生长因子-β1（TGF-β1）处理可上调Smad 2的磷酸化水平，增加SOX 9和COL 10A 1的表达。COL 10A 1被证实是上皮细胞向间质细胞转化（EMT）的潜在诱导剂。SOX 9是COL 10A 1介导的EMT、细胞迁移、侵袭和转移所必需的。SOX 9和COL 10A 1的共表达与肿瘤进展相关，并强烈预测GC患者的总生存期。总之，这项研究阐明了COL 10A 1和TGF-β1-SOX 9轴之间的机制联系。这些发现表明COL 10A 1可能在GC进展中起关键作用，并可作为GC患者的潜在生物标志物和治疗靶点。
Molecular biomarkers that predict disease progression might promote drug development and therapeutic strategies in aggressive cancers, such as gastric cancer (GC). High-throughput mRNA sequencing (RNA-seq) revealed that collagen type X alpha 1 (COL10A1) is a disease progression-associated gene. Analysis of 103 GC patients showed that high COL10A1 mRNA expression was associated with GC metastasis and reduced survival. We analyzed the COL10A1 promoter using the UCSC genome website and JASPAR database, and we found potential SOX9 binding site. Here, we demonstrated that SOX9 and COL10A1 were both up-regulated in GC. We observed a positive correlation between the expression patterns of SOX9 and COL10A1 in GC cells and tissues. The results of electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP) assay and promoter reporter indicated that SOX9 could directly bind to the COL10A1 gene promoter and activate its transcription. Biological function experiments showed that COL10A1 regulated the migration and invasion of GC cells. Knockdown COL10A1 inhibited lung and abdominal cavity metastasis in a nude mouse model. Moreover, transforming growth factor-β1 (TGF-β1) treatment up-regulated the phosphorylation of Smad2 and increased SOX9 and COL10A1 expression. COL10A1 was confirmed to be a potential inducer of epithelial-to-mesenchymal transition (EMT). SOX9 was essential for COL10A1-mediated EMT, and cell migration, invasion and metastasis. Co-expression of SOX9 and COL10A1 was associated with tumor progression and was strongly predictive of overall survival in GC patients. In summary, this study elucidated the mechanistic link between COL10A1 and the TGF-β1-SOX9 axis. These findings indicated that COL10A1 might play a crucial role in GC progression and serve as a potential biomarker and therapeutic target in GC patients.
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