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CRIF1 overexpression facilitates tumor growth and metastasis through inducing ROS/NF?B pathway in hepatocellular carcinoma.

ABSTRACT: CR6-interacting factor 1 (Crif1) is a mitochondrial protein which is required for the assembly of oxidative phosphorylation (OXPHOS) complexes. Our bioinformatics analysis based on Cancer Genome Atlas (TCGA) database revealed an aberrant overexpression of CRIF1 in hepatocellular carcinoma (HCC). However, the clinical significance and biological functions of CRIF1 are still unclear in this malignancy. Here, we report that CRIF1 is frequently overexpressed in HCC cells mainly due to the downregulation of miR-497-5p, which is associated with poor prognosis of patients with HCC. CRIF1-promoted HCC growth and metastasis by suppressing cell apoptosis and inducing cell cycle progression and epithelial to mesenchymal transition (EMT). Mechanistically, increased mitochondrial ROS production and consequently activation of the NF?B signaling pathway was found to be involved in the promotion of growth and metastasis by CRIF1 in HCC cells. In summary, CRIF1 plays an oncogenic role in HCC progression through activating ROS/NFKB pathway, implying CRIF1 as a potential prognostic factor and therapeutic target in HCC.

SUBMITTER: Chang H

PROVIDER: S-EPMC7205899 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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CRIF1 overexpression facilitates tumor growth and metastasis through inducing ROS/NFκB pathway in hepatocellular carcinoma.

Chang Hulin H Li Juntang J Qu Kai K Wan Yong Y Liu Sinan S Zheng Wei W Zhang Zhiyong Z Liu Chang C

Cell death & disease 20200507 5

CR6-interacting factor 1 (Crif1) is a mitochondrial protein which is required for the assembly of oxidative phosphorylation (OXPHOS) complexes. Our bioinformatics analysis based on Cancer Genome Atlas (TCGA) database revealed an aberrant overexpression of CRIF1 in hepatocellular carcinoma (HCC). However, the clinical significance and biological functions of CRIF1 are still unclear in this malignancy. Here, we report that CRIF1 is frequently overexpressed in HCC cells mainly due to the downregula ...[more]

PMID: 32382077

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Project description:BackgroundBladder carcinoma is one of the most common urological cancers. ITPR3, as a ubiquitous endoplasmic reticulum calcium channel protein, was reported to be involved in the development and progression of various types of cancer. However, the potential roles and molecular mechanism of ITPR3 in bladder cancer are still unclear. Herein, we elucidated a novel role of ITPR3 in regulating the proliferation, metastasis, and stemness of bladder cancer cells.MethodsThe expression of ITPR3 in bladder cancer was analyzed using public databases and bladder cancer tissue microarrays. To demonstrate the role of ITPR3 in regulating the NF-ĸB/CD44 pathway and the progression of bladder cancer, a series of molecular biology and biochemistry methods was performed on clinical tissues, along with in vivo and in vitro experiments. The methods used included western blot assay, quantitative RT-PCR assay, immunofluorescence assay, immunohistochemistry (IHC) assays, wound healing assay, Transwell assay, colony formation assay, tumorsphere formation assay, cell flow cytometry analysis, EdU assay, MTT assay, cell transfection, bisulfite sequencing PCR (BSP), a xenograft tumor model and a tail vein cancer metastasis model.ResultsHigher ITPR3 expression was found in bladder cancer tissues and bladder cancer cells compared with the corresponding normal peritumor tissues and SV-HUC-1 cells, which was attributed to demethylation in the ITPR3 promoter region. ITPR3 promoted the proliferation of bladder cancer by accelerating cell cycle transformation and promoted local invasion and distant metastasis by inducing epithelial-to-mesenchymal transition (EMT). Meanwhile, ITPR3 maintained the cancer stemness phenotype by regulating CD44 expression. NF-κB, which is upstream of CD44, also played a critical role in this process.ConclusionsOur study clarifies that ITPR3 serves as an oncogene in bladder cancer cells and represents a novel candidate for bladder cancer diagnosis and treatment.

Project description:BackgroundMitochondrial dysfunction and metabolic reprogramming can lead to the development and progression of hepatocellular carcinoma (HCC). Ferredoxin 1 (FDX1) is a small mitochondrial protein and recent studies have shown that FDX1 plays an important role in tumor cuproptosis, but its role in HCC is still elusive. In this study, we aim to investigate the expression and novel functions of FDX1 in HCC.MethodsFDX1 expression was first analyzed in publicly available datasets and verified by immunohistochemistry, qRT-PCR and Western blot. In vitro and in vivo experiments were applied to explore the functions of FDX1. Non-targeted metabolomics and RNA-sequencing were used to determine molecular mechanism. mRFP-GFP-LC3 lentivirus transfection, Mito-Tracker Red and Lyso-Tracker Green staining, transmission electron microscopy, flow cytometry, JC-1 staining, etc. were used to analyze mitophagy or ROS levels. Hydrodynamic tail vein injection (HTVi) and patient-derived organoid (PDO) models were used to analyze effect of FDX1 overexpression.ResultsFDX1 expression is significantly downregulated in HCC tissues. FDX1 downregulation promotes HCC cell proliferation, invasion in vitro and growth, metastasis in vivo. In addition, FDX1 affects metabolism of HCC cells and is associated with autophagy. We then confirmed that FDX1 deficiency increases ROS levels, activates mitophagy and the PI3K/AKT signaling pathway in HCC cells. Interestingly, scavenging ROS attenuates the tumor-promoting role and mitophagy of FDX1 downregulation. The results of HTVi and PDO models both find that FDX1 elevation significantly inhibits HCC progression. Moreover, low FDX1 expression is associated with shorter survival and is an independent risk factor for prognosis in HCC patients.ConclusionsOur research had investigated novel functions of FDX1 in HCC. Downregulation of FDX1 contributes to metabolic reprogramming and leads to ROS-mediated activation of mitophagy and the PI3K/AKT signaling pathway. FDX1 is a potential prognostic biomarker and increasing FDX1 expression may be a potential therapeutic approach to inhibit HCC progression.

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CRIF1 overexpression facilitates tumor growth and metastasis through inducing ROS/NF?B pathway in hepatocellular carcinoma.

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CRIF1 overexpression facilitates tumor growth and metastasis through inducing ROS/NFκB pathway in hepatocellular carcinoma.

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