Dataset Information

Knockdown of MUC16 (CA125) Enhances the Migration and Invasion of Hepatocellular Carcinoma Cells.

ABSTRACT: As an important global medical problem, hepatocellular carcinoma (HCC) has been recognized as the most frequent primary liver cancer and a leading cause of death among patients with cirrhosis. Surveillance of HCC using serum markers aims to reduce the disease-related mortality of HCC. MUC16 (mucin 16, also known as carbohydrate antigen 125, CA125) has been predicted as a tumor biomarker for many cancer types. Based on the high frequency mutation rate in a database from the Cancer Genome Atlas (TCGA), we investigated the effects of MUC16 knockdown and the regulatory profile of MUC16 in HepG2 and Huh7 cell lines. Knockdown of MUC16 was conducted via siRNA transfection, and the proliferation of cells was not affected by CCK8 assay results. Moreover, decreasing the expression of MUC16 enhanced the migration and invasion of cells, as shown by wound healing and transwell assays. Furthermore, RNA-seq was used to investigate the effect of MUC16 knockdown on the gene expression profile of HepG2 and Huh7 cells. Our study demonstrated the significant role of MUC16 in the inhibition of the migration and invasion of HepG2 and Huh7 cells.

SUBMITTER: Huang Y

PROVIDER: S-EPMC8208084 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Knockdown of MUC16 (CA125) Enhances the Migration and Invasion of Hepatocellular Carcinoma Cells.

Huang Yao Y Huang Xiaoyu X Zeng Jianxing J Lin Jun J

Frontiers in oncology 20210602

As an important global medical problem, hepatocellular carcinoma (HCC) has been recognized as the most frequent primary liver cancer and a leading cause of death among patients with cirrhosis. Surveillance of HCC using serum markers aims to reduce the disease-related mortality of HCC. MUC16 (mucin 16, also known as carbohydrate antigen 125, CA125) has been predicted as a tumor biomarker for many cancer types. Based on the high frequency mutation rate in a database from the Cancer Genome Atlas (T ...[more]

PMID: 34150633

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Project description:BackgroundNADH: ubiquinone oxidoreductase subunit C1(NDUFC1) encodes a subunit of the Complex I, which may support the structural stability of Complex I and assist in its biogenesis. The expression and functional roles of NDUFC1 in hepatocellular carcinoma (HCC) remain unknown.ResultWe knocked down the expression of NDUFC1 in HCC cell lines to explore the effects of NDUFC1 downregulation on HCC in vitro. MTT assay determined that downregulation of NDUFC1 significantly inhibited cell proliferation. Flow cytometry with (propidium iodide) PI staining indicated silencing of NDUFC1 arrested cell cycle of BEL-7404 cells at G2 phase and SK-HEP-1 cells at S/G2 phase. Annexin V-PI double staining and flow cytometric analysis showed that the downregulation of NDUFC1 significantly increased the population of apoptotic cells. Wound-healing assay and transwell assay indicated that the downregulation of NDUFC1 suppressed the migration and invasion of HCC cells. According to the detection of complex1 activity, we found that the activity of NDUFC1 silenced group decreased, whereas the content of ROS increased. Furthermore, combined with bioinformatics analysis of senescence-related genes, we found that the silence of NDUFC1 in HCC could induce senescence and inhibit autophagy. In addition, NDUFC1 could correlate positively with cancer-related pathways, among which the p53 pathways and the PI3K/Akt/mTOR pathways. Finally, NDUFC1 is high expression in HCC specimens. High NDUFC1 expression was associated with poor prognosis and was an independent risk factor for reduced overall survival (OS).ConclusionsOur study indicated, for the first time, that NDUFC1 is an independent risk factor for the poor prognosis of HCC patients. NDUFC1 may promote tumor progression by inhibiting mitochondrial Complex I and up-regulating ROS through multiple cancer-related and senescence-related pathways of HCC, including p53 pathways and PI3K/Akt/mTOR pathways. We suppose that NDUFC1 might be a potential target for the mitochondrial metabolism therapy of HCC.

Project description:The CA125 antigen is found in the serum of many patients with serous ovarian cancer and has been widely used as a disease marker. CA125 has been shown to be an independent factor for clinical outcome in this disease. In The Cancer Genome Atlas ovarian cancer project, MUC16 expression levels are frequently increased, and the highest levels of MUC16 expression are linked to a significantly worse survival. To examine the biologic effect of the proximal portion of MUC16/CA125, NIH/3T3 (3T3) fibroblast cell lines were stably transfected with the carboxy elements of MUC16. As few as 114 amino acids from the carboxy-terminal portion of MUC16 were sufficient to increase soft agar growth, promote matrigel invasion, and increase the rate of tumor growth in athymic nude mice. Transformation with carboxy elements of MUC16 was associated with activation of the AKT and ERK pathways. MUC16 transformation was associated with up-regulation of a number of metastases and invasion gene transcripts, including IL-1β, MMP2, and MMP9. All observed oncogenic changes were exclusively dependent on the extracellular "ectodomain" of MUC16. The biologic impact of MUC16 was also explored through the creation of a transgenic mouse model expressing 354 amino acids of the carboxy-terminal portion of MUC16 (MUC16c354). Under a CMV, early enhancer plus chicken β actin promoter (CAG) MUC16c354 was well expressed in many organs, including the brain, colon, heart, kidney, liver, lung, ovary, and spleen. MUC16c354 transgenic animals appear to be viable, fertile, and have a normal lifespan. However, when crossed with p53-deficient mice, the MUC16c354:p53+/- progeny displayed a higher frequency of spontaneous tumor development compared to p53+/- mice alone. We conclude that the carboxy-terminal portion of the MUC16/CA125 protein is oncogenic in NIH/3T3 cells, increases invasive tumor properties, activates the AKT and ERK pathways, and contributes to the biologic properties of ovarian cancer.

Dataset Information

Knockdown of MUC16 (CA125) Enhances the Migration and Invasion of Hepatocellular Carcinoma Cells.

Publications

Knockdown of MUC16 (CA125) Enhances the Migration and Invasion of Hepatocellular Carcinoma Cells.

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