TXNDC12 promotes EMT and metastasis of hepatocellular carcinoma cells via activation of β-catenin

Yuan, Kefei; Xie, Kunlin; Lan, Tian; Xu, Lin; Chen, Xiangzheng; Li, Xuefeng; Liao, Mingheng; Li, Jiaxin; Huang, Jiwei; Zeng, Yong; Wu, Hong

doi:10.1038/s41418-019-0421-7

Cited by 83 publications

(62 citation statements)

References 36 publications

(45 reference statements)

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“…A series of transcriptional factors could drive EMT process and thereby tumor-initiation, metastasis, response to chemotherapy and immune evasion (26,27). Our previous work has demonstrated Zeb1 as a vital activator in thioredoxin domain-containing protein 12-mediated EMT process of HCC (28). In the present work, we demonstrated that EMT process was dispensable for NCSTN-regulated HCC cell growth and metastasis, and Zeb1 was the key activator involved.…”

Section: Discussionsupporting

confidence: 55%

NCSTN promotes hepatocellular carcinoma cell growth and metastasis via β-catenin activation in a Notch1/AKT dependent manner

Lan

et al. 2020

Preprint

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Background Hepatocellular carcinoma is the third top cause of cancer-related mortalities worldwide. The prognosis of HCC patients remains poor due to rapid progression and high incidence of tumor recurrence. Nicastrin (NCSTN), a core subunit of γ-Secretase, has been reported to play a vital role in tumor progression. However, no study till now has revealed its role in HCC. Methods The expression of NCSTN was evaluated by immunohistochemical staining, Western blot, and quantitative real-time PCR. Cell counting kit-8, colony formation and cell cycle assays were used for evaluating cell growth in vitro. Transwell and wound-healing assays were used for evaluating cell migration and invasion capacity. Immunofluorescence, subcellular protein fractionation and co-immunoprecipitation were used for location analysis of β-catenin. The in vivo functions of NCSTN were illustrated by xenograft tumor models. Results NCSTN was dramatically overexpressed in HCC compared to normal liver tissues. Elevated NCSTN expression level was significantly correlated to worse overall and recurrence-free survival of HCC patients. Enhanced NCSTN expression promoted HCC cell growth, migration and invasion in vitro and in vivo. Mechanistic investigations showed that NCSTN induced epithelial-mesenchymal transition (EMT) process via upregulation of Zeb1. Subsequently, we revealed that NCSTN facilitated nuclear translocation of β-catenin, a positive transcriptional regulator of Zeb1. Using Notch and AKT inhibitors, we revealed that NCSTN promoted β-catenin activation through Notch1 and AKT signaling pathway. NCSTN increased AKT and GSK-3β phosphorylation by cleavage of Notch1, which decreased GSK-3β/β-catenin complex. The inactivation of GSK-3β inhibited the β-catenin degradation and promoted nuclear translocation of β-catenin to initiate transcription of Zeb1, resulting in malignant phenotype. Conclusions Our results demonstrated that NCSTN promoted HCC cell growth and metastasis via β-catenin-mediated upregulation of Zeb1 in a Notch1/AKT dependent manner, suggesting that NCSTN might serve as a potential prognostic marker and therapeutic target for HCC.

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Section: Discussionsupporting

confidence: 55%

NCSTN promotes hepatocellular carcinoma cell growth and metastasis via β-catenin activation in a Notch1/AKT dependent manner

Lan

et al. 2020

Preprint

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“…Upregulated expression of LINC00978 is a marker of poor prognosis in HCC (Xu X. et al, 2019). In addition, elevated expression of TXNDC12 has been correlated with elevated expression of nuclear β-catenin and with OS and disease-free survival (Yuan et al, 2019). These studies indicated that next-generation sequencing could be performed to distinguish the biomarkers of HCC.…”

Section: Introductionmentioning

confidence: 93%

Identification of Crucial Genes Associated With Immune Cell Infiltration in Hepatocellular Carcinoma by Weighted Gene Co-expression Network Analysis

Wang

Liu

et al. 2020

Front. Genet.

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“…Epithelial to mesenchymal transition (EMT), a process that epithelial cells lose their polarized organization and acquire migratory and invasive capabilities, is considered to contribute to cancer metastasis ( 11 , 12 ). Therapeutics targeted to EMT pathway show a great potential for preventing tumor dissemination or sweeping off metastatic cancer cells in patients in advanced stage ( 13 , 14 ).…”

Section: Introductionmentioning

confidence: 99%

TDO2 Promotes the EMT of Hepatocellular Carcinoma Through Kyn-AhR Pathway

Wang

et al. 2021

Front. Oncol.

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Tryptophan 2,3-dioxygenase (TDO2), an enzyme involved in tryptophan (Trp) metabolism has been linked with some malignant traits of various cancers. Kyn, the main product of Trp metabolism pathway catalyzed by TDO2 and indoleamine 2,3-dioxygenase (IDO) in tumor cells, was also demonstrated to activate aryl hydrocarbon receptor (AhR), which may regulate cancer growth and invasion in some malignancies. However, whether TDO2 participates in the metastasis and invasion of HCC has not been explored before. The underlying mechanism played by TDO2 in this process still requires further investigation. Here, we demonstrated that overexpression of TDO2 correlates with advanced stage or malignant traits in HCC patients. Knockdown or inhibition of TDO2 suppressed the migration and invasion of HCC cells in vitro and in vivo. Epithelial to mesenchymal transition (EMT) is an essential program happened in the initial phase of cancer metastasis. We found that in HCC cells, TDO2 promoted the EMT process evidenced by altered levels of biomarkers for EMT. Mechanically, TDO2 regulated the Kyn production in HCC cell via activated aryl hydrocarbon receptor (AhR). Together, these results indicate that TDO2 promotes the EMT of hepatocellular carcinoma through activating Kyn-AhR pathway, thereby participating in the metastasis and invasion of HCC.

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TXNDC12 promotes EMT and metastasis of hepatocellular carcinoma cells via activation of β-catenin

Cited by 83 publications

References 36 publications

NCSTN promotes hepatocellular carcinoma cell growth and metastasis via β-catenin activation in a Notch1/AKT dependent manner

NCSTN promotes hepatocellular carcinoma cell growth and metastasis via β-catenin activation in a Notch1/AKT dependent manner

Identification of Crucial Genes Associated With Immune Cell Infiltration in Hepatocellular Carcinoma by Weighted Gene Co-expression Network Analysis

TDO2 Promotes the EMT of Hepatocellular Carcinoma Through Kyn-AhR Pathway

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