DNA and RNA sequencing identified a novel oncogene VPS35 in liver hepatocellular carcinoma

Zhang, Guiji; Tang, Xia; Liang, Li; Zhang, Wanfeng; Li, Dewei; Li, Xiaoyuan; Zhao, Dachun; Zheng, Yaqiu; Chen, Yanhong; Hao, Bingtao; Wang, Kai; Tang, Ni; Ding, Keyue

doi:10.1038/s41388-020-1215-6

Cited by 33 publications

(32 citation statements)

References 54 publications

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“…Our study con rmed that overexpression of VPS35, regulated by KLF7, promoted the tumor growth in vitro and in vivo, and contributed to cell invasion, cell cycle and blocked cell apoptosis. These results were consistent with a recent published study, that demonstrated that VPS35 promoted the proliferation of hepatoma cell via the PI3K/AKT pathway [13].…”

Section: Discussionsupporting

confidence: 94%

“…Mutation of VPS35 has emerged as a novel cause of autosomal dominant Parkinson's disease (PD), identi ed by exome sequencing [12]. Recently, it has been demonstrated that VPS35 participates in hepatocellular carcinoma tumor growth by activating PI3K/AKT signaling pathway [13]. Moreover, somatic copy number variations (CNV) spanning VPS35 was identi ed in several tumors [14].…”

Section: Introductionmentioning

confidence: 99%

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KLF7/VPS35 Axis Contributes to Hepatocellular Carcinoma Progression through CCDC85C-activated β Catenin Pathway

Guo

Chai

Jia

et al. 2020

Preprint

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Objective: Dysregulation of KLF7 participates in the development of various cancers, but it is unclear whether there is a link between HCC and aberrant expression of KLF7. The aim of this study was to investigate the role of KLF7 in proliferation and migration of hepatocellular carcinoma (HCC) cells. Methods: CCK8, colony growth, transwell, cell cycle analysis and apoptosis detection were performed to explore the effect of KLF7, VPS35 and Ccdc85c on cell function in vitro. Xenografted tumor growth was used to assess in vivo role of KLF7. Chip-qPCR and luciferase reporter assays were applied to check whether KLF7 regulated VPS35 at transcriptional manner. Co-IP assay was performed to detect the interaction between VPS35 and Ccdc85c. Human HCC tissues were collected to study the clinical significance VPS35 and β-catenin. Results: Firstly, KLF7 overexpression contributed to cell proliferation and invasion of HCC cells in vitro and in vivo. KLF7 transcriptional activation of VPS35 was necessary for HCC tumor growth and metastasis. Further, co-IP studies revealed that VPS35 could interact with Ccdc85c in HCC cells. Rescue assay confirmed that overexpression of VPS35 and knockdown of Ccdc85c abolished the VPS35-medicated promotion effect on cell proliferation and invasion. Finally, KLF7/VPS35 axis regulated Ccdc85c, which involved in activation of β-catenin signaling pathway, confirmed using β-catenin inhibitor, GK974. Functional studies suggested that downregulation of Ccdc85c partly reversed the capacity of cell proliferation and invasion in HCC cells, which was regulated by VPS35 upregulation. Conclusion: We demonstrated that KLF7/VPS35 axis promoted HCC cell progression by activating Ccdc85c-medicated β-catenin pathway. Targeting this signal axis might be a potential treatment strategy for HCC.

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Section: Discussionsupporting

confidence: 94%

Section: Introductionmentioning

confidence: 99%

KLF7/VPS35 Axis Contributes to Hepatocellular Carcinoma Progression through CCDC85C-activated β Catenin Pathway

Guo

Chai

Jia

et al. 2020

Preprint

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“…Among the eight autophagy-related prognostic genes we identified, VPS35 has been proposed as a potential new oncogene of HCC, as it promotes the liver tumor cell proliferation via PI3K/AKT signaling (28). A previous study indicated that VPS26A might be associated with cancer prognosis (29).…”

Section: Discussionmentioning

confidence: 97%

Identification of an autophagy-related gene signature predicting overall survival for hepatocellular carcinoma

Guo

Lü

et al. 2021

Bioscience Reports

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The poor prognosis of hepatocellular carcinoma (HCC) calls for the development of accurate prognostic models. The growing number of studies indicating a correlation between autophagy activity and HCC indicates there is a commitment to finding solutions for the prognosis of HCC from the perspective of autophagy. We used a cohort in The Cancer Genome Atlas (TCGA) to evaluate the expression of autophagy-related genes in 371 HCC samples using univariate Cox and lasso Cox regression analysis, and the prognostic features were identified. A prognostic model was established by combining the expression of selected genes with the multivariate Cox regression coefficient of each gene. Eight autophagy-related genes were selected as prognostic features of HCC. We established the HCC prognostic risk model in TCGA dataset using these identified prognostic genes. The model’s stability was confirmed in two independent verification sets (GSE14520 and GSE36376). The model had a good predictive power for the overall survival (OS) of HCC (Hazard Ratio=2.32, 95% Confidence Interval=1.76–3.05, p<0.001). Moreover, the risk score computed by the model did not depend on other clinical parameters. Finally, the applicability of the model was demonstrated through a nomogram (C-index=0.701). In this study, we established an autophagy-related risk model having a high prediction accuracy for OS in HCC. Our findings will contribute to the definition of prognosis and establishment of personalized therapy for HCC patients.

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“…Phosphatidylinositol-3-kinase (PI3K)/AKT signaling promotes the proliferation of hepatoma cell and EMT in HCC, which contributes to HCC growth, migration and invasion. 3,133,134 They transmit cell surface receptor signals and affect a variety of tissue-dependent cellular functions. The PI3K/AKT/mTOR signaling pathway not only directly mediates aerobic glycolysis but also regulates HIF-1α.…”

Section: Signaling Pathways Involved In Hcc Glucometabolic Reprogrammingmentioning

confidence: 99%

“…2 The main risk factors for HCC are hepatitis B virus (HBV), hepatitis C virus (HCV), cirrhosis, aflatoxin-contaminated foodstuffs, alcohol abuse, obesity, and type 2 diabetes. 1,[3][4][5] Decades ago, Otto Warburg observed that cancer cells rely on glycolysis for the generation of energy even in a normoxic environment, which was known as the "Warburg effect" or "aerobic glycolysis". 6,7 Aerobic glycolysis not only provides energy but also provides intermediates (nucleotides, amino acids, lipids and NADPH) for biosynthesis, 8,9 which explains why aerobic glycolysis occurs prior to oxidative phosphorylation (OXPHOS) in proliferation cells such as tumor cells.…”

Section: Introductionmentioning

confidence: 99%

<p>Glucometabolic Reprogramming in the Hepatocellular Carcinoma Microenvironment: Cause and Effect</p>

Tian

Zhu

et al. 2020

CMAR

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Hepatocellular carcinoma (HCC) is a tumor that exhibits glucometabolic reprogramming, with a high incidence and poor prognosis. Usually, HCC is not discovered until an advanced stage. Sorafenib is almost the only drug that is effective at treating advanced HCC, and promising metabolism-related therapeutic targets of HCC are urgently needed. The "Warburg effect" illustrates that tumor cells tend to choose aerobic glycolysis over oxidative phosphorylation (OXPHOS), which is closely related to the features of the tumor microenvironment (TME). The HCC microenvironment consists of hypoxia, acidosis and immune suppression, and contributes to tumor glycolysis. In turn, the glycolysis of the tumor aggravates hypoxia, acidosis and immune suppression, and leads to tumor proliferation, angiogenesis, epithelial-mesenchymal transition (EMT), invasion and metastasis. In 2017, a mechanism underlying the effects of gluconeogenesis on inhibiting glycolysis and blockading HCC progression was proposed. Treating HCC by increasing gluconeogenesis has attracted increasing attention from scientists, but few articles have summarized it. In this review, we discuss the mechanisms associated with the TME, glycolysis and gluconeogenesis and the current treatments for HCC. We believe that a treatment combination of sorafenib with TME improvement and/or anti-Warburg therapies will set the trend of advanced HCC therapy in the future.

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DNA and RNA sequencing identified a novel oncogene VPS35 in liver hepatocellular carcinoma

Cited by 33 publications

References 54 publications

KLF7/VPS35 Axis Contributes to Hepatocellular Carcinoma Progression through CCDC85C-activated β Catenin Pathway

KLF7/VPS35 Axis Contributes to Hepatocellular Carcinoma Progression through CCDC85C-activated β Catenin Pathway

Identification of an autophagy-related gene signature predicting overall survival for hepatocellular carcinoma

<p>Glucometabolic Reprogramming in the Hepatocellular Carcinoma Microenvironment: Cause and Effect</p>

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