Novel copper complex CTB regulates methionine cycle induced TERT hypomethylation to promote HCC cells senescence via mitochondrial SLC25A26

Jin, Chen; Li, Yujia; Su, Ying; Guo, Zijian; Wang, Xiaoyong; Wang, Shijun; Zhang, Feng; Zhang, Zili; Zheng, Shizhong

doi:10.1038/s41419-020-03048-x

Cited by 20 publications

(27 citation statements)

References 46 publications

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“…Previous studies have provided a possible relationship between metal ion homeostasis and vascular invasion in HCC, which may be mediated by p53 51 – 53 . Disturbance in Cu and Zn homeostasis has been reported as a significant factor associated with tumor proliferation, angiogenesis and invasion in HCC, and furthermore, cellular response to Cu and Zn is probably involved in mitochondrial accumulation and stability of p53, so as to influence proliferation and apoptosis of hepatoma cells 54 – 56 .…”

Section: Discussionmentioning

confidence: 99%

High expression of PARD3 predicts poor prognosis in hepatocellular carcinoma

Huang

Yang

et al. 2021

Sci Rep

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Hepatocellular carcinoma (HCC) is one of the most commonly cancers with poor prognosis and drug response. Identifying accurate therapeutic targets would facilitate precision treatment and prolong survival for HCC. In this study, we analyzed liver hepatocellular carcinoma (LIHC) RNA sequencing (RNA-seq) data from The Cancer Genome Atlas (TCGA), and identified PARD3 as one of the most significantly differentially expressed genes (DEGs). Then, we investigated the relationship between PARD3 and outcomes of HCC, and assessed predictive capacity. Moreover, we performed functional enrichment and immune infiltration analysis to evaluate functional networks related to PARD3 in HCC and explore its role in tumor immunity. PARD3 expression levels in 371 HCC tissues were dramatically higher than those in 50 paired adjacent liver tissues (p < 0.001). High PARD3 expression was associated with poor clinicopathologic feathers, such as advanced pathologic stage (p = 0.002), vascular invasion (p = 0.012) and TP53 mutation (p = 0.009). Elevated PARD3 expression also correlated with lower overall survival (OS, HR = 2.08, 95% CI = 1.45–2.98, p < 0.001) and disease-specific survival (DSS, HR = 2.00, 95% CI = 1.27–3.16, p = 0.003). 242 up-regulated and 71 down-regulated genes showed significant association with PARD3 expression, which were involved in genomic instability, response to metal ions, and metabolisms. PARD3 is involved in diverse immune infiltration levels in HCC, especially negatively related to dendritic cells (DCs), cytotoxic cells, and plasmacytoid dendritic cells (pDCs). Altogether, PARD3 could be a potential prognostic biomarker and therapeutic target of HCC.

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Section: Discussionmentioning

confidence: 99%

High expression of PARD3 predicts poor prognosis in hepatocellular carcinoma

Huang

Yang

et al. 2021

Sci Rep

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“…CTB administration in HepG2 cells inhibits aerobic glycolysis and promotes DRP1 recruiting and the opening of mitochondrial pores, thus contributing to the activation of fission and mitophagy [ 244 ]. Furthermore, CTB affects TERT methylation and expression, leading to the inhibition of both cell senescence and the growth of implanted tumors in mice [ 245 ]. Parvalbumin, a mitochondrial Ca 2+ -buffering protein, dramatically lowered ROS production and invasiveness, and suppressed EMT in HCC cells by modulating the Ca 2+ flow into mitochondria and rescuing the NAD + /SIRT3/SOD2 axis [ 246 , 247 ].…”

Section: Targeting Mitochondria In Nafld–hcc: New Challenges For a Bright Futurementioning

confidence: 99%

Remodeling of Mitochondrial Plasticity: The Key Switch from NAFLD/NASH to HCC

Longo

Paolini

Meroni

et al. 2021

IJMS

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Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and the third-leading cause of cancer-related mortality. Currently, the global burden of nonalcoholic fatty liver disease (NAFLD) has dramatically overcome both viral and alcohol hepatitis, thus becoming the main cause of HCC incidence. NAFLD pathogenesis is severely influenced by lifestyle and genetic predisposition. Mitochondria are highly dynamic organelles that may adapt in response to environment, genetics and epigenetics in the liver (“mitochondrial plasticity”). Mounting evidence highlights that mitochondrial dysfunction due to loss of mitochondrial flexibility may arise before overt NAFLD, and from the early stages of liver injury. Mitochondrial failure promotes not only hepatocellular damage, but also release signals (mito-DAMPs), which trigger inflammation and fibrosis, generating an adverse microenvironment in which several hepatocytes select anti-apoptotic programs and mutations that may allow survival and proliferation. Furthermore, one of the key events in malignant hepatocytes is represented by the remodeling of glucidic–lipidic metabolism combined with the reprogramming of mitochondrial functions, optimized to deal with energy demand. In sum, this review will discuss how mitochondrial defects may be translated into causative explanations of NAFLD-driven HCC, emphasizing future directions for research and for the development of potential preventive or curative strategies.

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“…A hypoxia-linked gene signature for prognosis prediction and evaluating the immune microenvironment in patients with hepatocellular carcinoma stages coupled with the rapid progress of the disease, most of the individuals with HCC are diagnosed at an advanced stage and are unable to undergo surgical resection (5)(6)(7). To enhance the survival of individuals with HCC, it is necessary to find reliable tumor markers for early diagnosis and molecular targets for effective treatment.…”

Section: Original Articlementioning

confidence: 99%

“…As curative therapeutic HCC options consisting of surgical resection, ablation treatments along with liver transplantation are effective for early-stage HCC, the timely diagnosis coupled with early intervention have remarkable impacts on the prognosis of individuals with HCC ( 4 ). Because of the lack of symptoms in the early HCC stages coupled with the rapid progress of the disease, most of the individuals with HCC are diagnosed at an advanced stage and are unable to undergo surgical resection ( 5 - 7 ). To enhance the survival of individuals with HCC, it is necessary to find reliable tumor markers for early diagnosis and molecular targets for effective treatment.…”

Section: Introductionmentioning

confidence: 99%

A hypoxia-linked gene signature for prognosis prediction and evaluating the immune microenvironment in patients with hepatocellular carcinoma

Wang¹,

Yu²,

Zhang³

et al. 2021

Transl Cancer Res TCR

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Background: Previous research indicates that hypoxia critically affects the initiation and progression of hepatocellular carcinoma (HCC). Nevertheless, the molecular mechanisms responsible for HCC development are poorly understood. Herein, we purposed to build a prognostic model using hypoxia-linked genes to predict patient prognosis and investigate the relationship of hypoxia with immune status in the tumor microenvironment (TME). Methods:The training cohort included transcriptome along with clinical data abstracted from The Cancer Genome Atlas (TCGA). The validation cohort was abstracted from Gene Expression Omnibus (GEO).Univariate along with multivariate Cox regression were adopted to create the prediction model. We divided all patients into low-and high-risk groups using median risk scores. The estimation power of the prediction model was determined with bioinformatic tools.Results: Six hypoxia-linked genes, HMOX1, TKTL1, TPI1, ENO2, LDHA, and SLC2A1, were employed to create an estimation model. Kaplan-Meier, ROC curve, and risk plot analyses demonstrated that the estimation potential of the risk model was satisfactory. Univariate along with multivariate regression data illustrated that the risk model could independently predict the overall survival (OS). A nomogram integrating the risk signature and clinicopathological characteristics showed a good potential to estimate HCC prognosis. Gene set enrichment analysis (GSEA) revealed that genes associated with cell proliferation and metabolism cascades were abundant in high-risk group. Furthermore, the signature showed a strong ability to distinguish the two groups in terms of immune status.Conclusions: A prediction model for predicting HCC prognosis using six hypoxia-linked genes was designed in this study, facilitating the diagnosis and treatment of HCC.

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Novel copper complex CTB regulates methionine cycle induced TERT hypomethylation to promote HCC cells senescence via mitochondrial SLC25A26

Cited by 20 publications

References 46 publications

High expression of PARD3 predicts poor prognosis in hepatocellular carcinoma

High expression of PARD3 predicts poor prognosis in hepatocellular carcinoma

Remodeling of Mitochondrial Plasticity: The Key Switch from NAFLD/NASH to HCC

A hypoxia-linked gene signature for prognosis prediction and evaluating the immune microenvironment in patients with hepatocellular carcinoma

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