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ZEB1 promotes invasion and metastasis of endometrial cancer by interacting with HDGF and inducing its transcription.

ABSTRACT: Zinc finger E-box binding homeobox 1 (ZEB1), as a typical transcription inhibitory factor of E-cadherin, plays a major role in stimulating the invasion and metastasis of tumors via modulating the epithelial-mesenchymal transition (EMT) signal. However, its function and modulatory mechanisms in endometrial carcinoma (EC) remain unclear. In this study, silencing ZEB1 significantly reduced EC cell migration, invasion, and metastasis, as well as enhanced the sensitivity of EC cells to cisplatin (cDDP) in vitro and in vivo. Mechanism analysis indicated that ZEB1 interacts with hepatoma-derived growth factor (HDGF) and co-localizes in the nucleus. In addition, ZEB1 as a transcription factor binds to the promoter of HDGF to stimulate HDGF transcription. Furthermore, suppression of HDGF in ZEB1-overexpressed EC cells not only reduced the expression of ?-catenin, TCF4, and ZEB1, but also repressed ?-catenin translocation from the cytoplasm into the nucleus and further downregulated the combination with TCF4. Interestingly, the ?-catenin/TCF4 signaling feedback stimulates ZEB1 transcription and therefore constitutes a positive feedback loop. In clinical samples, ZEB1 positively correlates with HDGF expression, and co-expression of ZEB1 and HDGF promotes the pathogenesis of EC. In summary, our study demonstrated that the positive feedback loop of ZEB1/HDGF/?-catenin/TCF4 plays an unfavorable role in the metastasis of endometrial carcinoma.

SUBMITTER: Xiao YY

PROVIDER: S-EPMC6895452 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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ZEB1 promotes invasion and metastasis of endometrial cancer by interacting with HDGF and inducing its transcription.

Xiao Yan-Yi YY Lin Li L Li Yong-Hao YH Jiang Hui-Ping HP Zhu Li-Tong LT Deng Yuan-Run YR Lin Dan D Chen Wei W Zeng Cheng-Ying CY Wang Li-Jing LJ Chen Shao-Cheng SC Jiang Qing-Ping QP Liu Chun-Hua CH Fang Wei-Yi WY Guo Sui-Qun SQ

American journal of cancer research 20191101 11

Zinc finger E-box binding homeobox 1 (ZEB1), as a typical transcription inhibitory factor of E-cadherin, plays a major role in stimulating the invasion and metastasis of tumors via modulating the epithelial-mesenchymal transition (EMT) signal. However, its function and modulatory mechanisms in endometrial carcinoma (EC) remain unclear. In this study, silencing ZEB1 significantly reduced EC cell migration, invasion, and metastasis, as well as enhanced the sensitivity of EC cells to cisplatin (cDD ...[more]

PMID: 31815037

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Project description:BackgroundTumour-derived exosomes have recently been shown to participate in the formation and progression of different cancer processes, including tumour microenvironment remodelling, angiogenesis, invasion, metastasis, and drug resistance. However, the function and mechanism of exosome-encapsulated nucleic acids and proteins in bladder cancer remain unclear. This study aimed to investigate the effects of tumour-derived exosomes on the tumorigenesis and development of bladder cancer.MethodsIn this study, gene expression profiles and clinical information were collected from The Cancer Genome Atlas (TCGA) database and two independent Gene Expression Omnibus (GEO) datasets. The nucleic acids and proteins encapsulated in bladder cancer-derived exosomes were obtained from the ExoCarta database. Based on these databases, the expression patterns of exosomal mRNAs and proteins and the matched clinicopathological characteristics were analysed. Furthermore, we carried out a series of experiments to verify the relevant findings.ResultsA total of 7280 differentially expressed mRNAs were found in TCGA data, of which 52 mRNAs were shown to be encapsulated in bladder cancer-derived exosomes. Survival analysis based on the UALCAN database showed that among the top 10 upregulated and the top 10 downregulated exosomal genes, only the expression of KRT6B had a statistically significant effect on the survival of bladder cancer patients. Additionally, clinical correlation analysis showed that the elevated level of KRT6B was highly associated with bladder cancer stage, grade, and metastasis status. GSEA revealed that KRT6B was involved not only in epithelial-mesenchymal transition-related pathways but also in the immune response in bladder cancer. Ultimately, our experimental results were also consistent with the bioinformatic analysis.ConclusionKRT6B, which can be detected in bladder cancer-derived exosomes, plays an important role in the epithelial-mesenchymal transition and immune responses in bladder cancer. Further research will enable its potentially prognostic marker and therapeutic target for bladder cancer.

Dataset Information

ZEB1 promotes invasion and metastasis of endometrial cancer by interacting with HDGF and inducing its transcription.

Publications

ZEB1 promotes invasion and metastasis of endometrial cancer by interacting with HDGF and inducing its transcription.

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