Wnt/β-Catenin Signaling Axis Is Required for TFEB-Mediated Gastric Cancer Metastasis and Epithelial-Mesenchymal Transition
Wnt/β-Catenin Signaling Axis Is Required for TFEB-Mediated Gastric Cancer Metastasis and Epithelial-Mesenchymal Transition
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Wnt/β-连环蛋白信号轴是 TFEB 介导的胃癌转移和上皮间质转化所必需的
DOI：
10.1158/1541-7786.mcr-20-0180
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发表时间：
2020-11-01
影响因子：
5.2
通讯作者：
Wang, Lan
中科院分区：
文献类型：
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作者：
Li, Shuxuan;Liu, Fenglin;Wang, Lan
胃癌仍然是癌症相关死亡的第三大原因，肿瘤转移是胃癌患者预后不良的主要危险因素。转录因子EB （Transcription factor EB， TFEB）是MiT家族成员，已发现在许多组织中驱动肿瘤发生，但很少有研究关注其在胃癌中的促转移作用和机制。我们发现，与邻近正常胃上皮组织相比，胃癌组织中TFEB表达上调。胃癌组织芯片免疫组化分析显示，胃癌TFEB与肿瘤浸润深度、淋巴结或远处转移、肿瘤肿瘤-淋巴结转移分期及总生存期相关。TFEB过表达的胃癌细胞表现出细胞迁移或侵袭以及上皮-间质转化（EMT）的增加。此外，基因相关分析和基因集富集分析富集了TFEB高表达组Wnt/ β -catenin信号通路成员，TOP/FOPflash实验验证了TFEB对β -catenin转录活性的影响。此外，我们发现TFEB可以触发β -catenin在细胞核内的聚集并激活其转录，促进Wnt/ β -catenin靶基因和emt相关标志物的表达，而Wnt/ β -catenin抑制剂XAV-939可以逆转这一过程。总的来说，TFEB通过激活Wnt/ β -catenin信号通路增强胃癌转移潜力，可能成为胃癌转移的一个有希望的治疗靶点。
Gastric cancer remains the third leading cause of cancer-related death, and tumor metastasis is the main risk factor for poor prognosis of patients with gastric cancer. Transcription factor EB (TFEB) is a MiT family member and has been found to drive tumorigenesis in a number of tissues, whereas few studies were focused on investigating its prometastasis role and mechanism in gastric cancer. Here, we found TFEB was upregulated in gastric cancer tissues compared with adjacent normal gastric epithelial tissues. IHC analysis from gastric cancer tissue microarray revealed that TFEB in gastric cancer was correlated with depth of tumor invasion, lymph node or distant metastasis, tumor tumor-nodemetastasis stage, and overall survival. Gastric cancer cells with TFEB overexpression presented an increased cell migration or invasion, and epithelial-mesenchymal transition (EMT). Furthermore, gene correlation analysis and gene set enrichment analysis enriched Wnt/beta-catenin signaling pathway members in TFEB high-expression group, and the TOP/FOPflash assay verified the effect of TFEB on beta-catenin transcription activity. Besides, we found that TFEB could trigger the aggregation of beta-catenin in nucleus and activate its transcription, as well as facilitate the expression of Wnt/beta-catenin target genes and EMT-related markers, which could be reversed by the Wnt/beta-catenin inhibitor XAV-939. Collectively, TFEB enhances gastric cancer metastatic potential by activating Wnt/ beta-catenin signaling pathway and may become a promising therapeutic target for gastric cancer metastasis.