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

ABSTRACT: Metastasis is one of the main contributors to the poor prognosis of hepatocellular carcinoma (HCC). However, the underlying mechanism of HCC metastasis remains largely unknown. Here, we showed that TXNDC12, a thioredoxin-like protein, was upregulated in highly metastatic HCC cell lines as well as in portal vein tumor thrombus and lung metastasis tissues of HCC patients. We found that the enforced expression of TXNDC12 promoted metastasis both in vitro and in vivo. Subsequent mechanistic investigations revealed that TXNDC12 promoted metastasis through upregulation of the ZEB1-mediated epithelial-mesenchymal transition (EMT) process. We subsequently showed that TXNDC12 overexpression stimulated the nuclear translocation and activation of ?-catenin, a positive transcriptional regulator of ZEB1. Accordingly, we found that TXNDC12 interacted with ?-catenin and that the thioredoxin-like domain of TXNDC12 was essential for the interaction between TXNDC12 and ?-catenin as well as for TXNDC12-mediated ?-catenin activation. Moreover, high levels of TXNDC12 in clinical HCC tissues correlated with elevated nuclear ?-catenin levels and predicted worse overall and disease-free survival. In summary, our study demonstrated that TXNDC12 could activate ?-catenin via protein-protein interaction and promote ZEB1-mediated EMT and HCC metastasis.

SUBMITTER: Yuan K

PROVIDER: S-EPMC7206186 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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

Yuan Kefei K Xie Kunlin K Lan Tian T Xu Lin L Chen Xiangzheng X Li Xuefeng X Liao Mingheng M Li Jiaxin J Huang Jiwei J Zeng Yong Y Wu Hong H

Cell death and differentiation 20190930 4

Metastasis is one of the main contributors to the poor prognosis of hepatocellular carcinoma (HCC). However, the underlying mechanism of HCC metastasis remains largely unknown. Here, we showed that TXNDC12, a thioredoxin-like protein, was upregulated in highly metastatic HCC cell lines as well as in portal vein tumor thrombus and lung metastasis tissues of HCC patients. We found that the enforced expression of TXNDC12 promoted metastasis both in vitro and in vivo. Subsequent mechanistic investig ...[more]

PMID: 31570854

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Project description:BackgroundHepatocellular 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.MethodsThe 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.ResultsNCSTN 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.ConclusionsOur 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.

Project description:Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death worldwide. Chronic liver inflammation due to hepatitis virus infection and other major effectors is a major risk factor of HCC. Indoleamine 2,3-dioxygenase 1 (IDO1), a heme enzyme highly expressed upon stimulation with proinflammatory cytokines such as interferon-γ (IFN-γ), is activated to modulate the tumor microenvironment and potentially crucial in the development of certain cancer types. Earlier studies have majorly reported an immunomodulatory function of IDO1. However, the specific role of IDO1 in cancer cells, particularly HCC, remains to be clarified. Analysis of The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA LIHC) dataset in the current study revealed a significant correlation between IDO1 expression and HCC. We further established inducible IDO1-expressing cell models by coupling lentivirus-mediated knockdown and IFN-γ induction of IDO1 in normal and HCC cells. In functional assays, proliferation and motility-related functions of HCC cells were compromised upon suppression of IDO1, which may partially be rescued by its enzymatic product, kynurenine (KYN), while normal hepatocytes were not affected. Aryl hydrocarbon receptor (AhR), a reported endogenous KYN receptor, is suggested to participate in tumorigenesis. In mechanistic studies, IDO1 activation promoted both AhR and β-catenin activity and nuclear translocation. Immunofluorescence staining and co-immunoprecipitation assays further disclosed interactions between AhR and β-catenin. In addition, we identified a Src-PTEN-PI3K/Akt-GSK-3β axis involved in β-catenin stabilization and activation following IDO1-mediated AhR activation. IDO1-induced AhR and β-catenin modulated the expression of proliferation- and EMT-related genes to facilitate growth and metastasis of HCC cells. Our collective findings provide a mechanistic basis for the design of more efficacious IDO1-targeted therapy for HCC.

Project description:BackgroundHepatocellular carcinoma (HCC) is the second lethal malignancy among all cancers. Many molecular alterations have been found in HCC. However, the interactions and modulatory mechanisms among these molecules in HCC are still unclear.MethodsCTB-193M12.5 expression in tissues and cells were detected by quantitative polymerase chain reaction (qPCR). In vitro experiments were conducted to evaluate the function of CTB-193M12.5 in cell proliferation, apoptosis, migration and invasion. The interaction between CTB-193M12.5 and nuclear receptor binding SET domain-containing protein 1 (NSD1) was assessed by RNA-protein pull-down and RNA immunoprecipitation assays. The roles of CTB-193M12.5 on WNT10B and Wnt/β-catenin signaling was detected by chromatin immunoprecipitation assay, qPCR, Western blot, and dual luciferase reporter assay.ResultsWe identified a novel prognosis-related long noncoding RNA (lncRNA) CTB-193M12.5 in HCC. CTB-193M12.5 was upregulated in HCC and its high expression was correlated with alpha fetoprotein, large tumor size, aggressive clinical characteristics, and poor survival. Functional experiments showed that CTB-193M12.5 enhanced HCC cellular proliferation, suppressed HCC cellular apoptosis, and promoted HCC cellular migration and invasion. CTB-193M12.5 knockdown exerted opposite effects in HCC. Mechanistic investigation demonstrated that CTB-193M12.5 was mainly distributed in nucleus. Histone methyltransferase NSD1 was identified as a CTB-193M12.5 interactor. CTB-193M12.5 bound and recruited NSD1 to the promoter of WNT10B, leading to an increase in di-methylation of histone H3 at lysine 36 (H3K36me2) and the reduction of tri-methylation of histone H3 at lysine 27 (H3K27me3) at WNT10B promoter. Therefore, CTB-193M12.5 epigenetically activated WNT10B transcription. Through upregulating WNT10B, CTB-193M12.5 further activated Wnt/β-catenin signaling. Functional rescue experiments demonstrated that overexpression of WNT10B reversed the tumor suppressive roles of CTB-193M12.5 knockdown, while Wnt/β-catenin signaling inhibitor ICG-001 abolished the oncogenic roles of CTB-193M12.5 overexpression.ConclusionCTB-193M12.5 was a highly expressed and poor prognosis-related lncRNA in HCC. CTB-193M12.5 functioned as an oncogenic lncRNA through promoting NSD1-mediated WNT10B/Wnt/β-catenin signaling activation.

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

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

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