LDHA promotes tumor metastasis by facilitating epithelial-mesenchymal transition in renal cell carcinoma

Zhao, Juping; Huang, Xin; Xu, Zifeng; Dai, Jun; He, Hongchao; Zhu, Yu; Wang, Haofei

doi:10.3892/mmr.2017.7637

Cited by 65 publications

(42 citation statements)

References 30 publications

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“…Several lines of evidence suggest that EMT promotes tumour metastasis in various cancers, including RCC [32][33][34][35][36][37]. Previous molecular analysis indicated that the high expression of AGK can induce the expression of HIF1a and promote EMT in cervical squamous carcinoma cells [11].…”

Section: Discussionmentioning

confidence: 99%

Acylglycerol kinase promotes tumour growth and metastasis via activating the PI3K/AKT/GSK3β signalling pathway in renal cell carcinoma

Zhu

Zhong

et al. 2020

J Hematol Oncol

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Background: Clinically, the median survival in patients with metastatic renal cell carcinoma (RCC) was only 6-12 months and a 5-year survival rate of less than 20%. Therefore, an in-depth study of the molecular mechanisms involved in RCC is of great significance for improving the survival of patients with advanced RCC. Acylglycerol kinase (AGK) is a newly discovered lipid kinase that has been reported to be a potent oncogene that may be involved in the regulation of malignant progression in a variety of tumours. However, the expression and biological characteristics of the AGK gene in RCC remain unclear. Methods: AGK expression was quantified by quantitative real-time PCR, Western blotting and immunohistochemistry in RCC cell lines and paired patient tissues. Kaplan-Meier method and Cox proportional hazards models were used to evaluate the prognostic value of AGK in human RCC tissue samples. Chi-squared test was performed to analyse the correlation between AGK expression and the clinicopathological features. Stable overexpression and knockdown of AGK in RCC cells was constructed with lentivirus. The oncogenic effects of AGK in human RCC progression were investigated using assays of colony formation, anchorage-independent growth, EdU assay, cell cycle analysis, wound-healing, trans-well analysis and xenograft tumour model. GSEA and KEGG analysis were conducted to detect the potential pathway of AGK involved in RCC. These results were further confirmed using the luciferase reporter assays, immunofluorescence and in vivo experiments. Results: AGK expression is significantly elevated in RCC and closely related to the malignant development and poor prognosis in RCC patients. By in vitro and in vivo experiments, AGK was shown to enhance the proliferation of RCC cells by promoting the transition from the G1 phase to the S phase in the cell cycle and to enhance the migration and invasion by promoting epithelial-mesenchymal transition. By activating the PI3K/AKT/GSK3β signalling pathway in RCC, AGK can increase nuclear accumulation of β-catenin, which further upregulated TCF/LEF transcription factor activity. Conclusions: AGK promotes the progression of RCC via activating the PI3K/AKT/GSK3β signalling pathway and might be a potential target for the further research of RCC.

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Section: Discussionmentioning

confidence: 99%

Acylglycerol kinase promotes tumour growth and metastasis via activating the PI3K/AKT/GSK3β signalling pathway in renal cell carcinoma

Zhu

Zhong

et al. 2020

J Hematol Oncol

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“…Notably, as seen in Figure 3A , OPN mRNA levels significantly correlated with LDHA, which has been associated with the response to chemotherapy and tumor invasion. 19 , 20 Additionally, the knockdown of OPN using siOPN-1/siOPN-2 decreased LDHA protein levels ( Figure 3B ) and lactate production ( Figure 3C ) in NSCLC cell lines compared with cells treated with siNC. Finally, to verify lactate contributes to OPN caused CDDP resistance in NSCLC cells, the lactate treatment (5 mM, 24 hours) was found to increase NSCLC cells CDDP (5 µg/mL, 24 hours) resistance and partial rescue OPN-deficiency led CDDP sensitivity ( Figure 3D ).…”

Section: Resultsmentioning

confidence: 92%

Osteopontin promotes cancer cell drug resistance, invasion, and lactate production and is associated with poor outcome of patients with advanced non-small-cell lung cancer

Ouyang¹,

Huang²,

Jin³

et al. 2018

OTT

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BackgroundOsteopontin (OPN), a member of the small integrin binding ligand N-linked glycoprotein family, has been analyzed in numerous types of human malignancy.PurposeThe present study detected the expression levels of OPN and evaluated its role in tumor progression in patients with non-small cell lung cancer (NSCLC).Patients and methodsOPN expression levels were detected using immunohistochemistry in 101 NSCLC tumors. The mRNA and protein levels have significant difference between advanced NSCLC and stage I/II NSCLC. The drug resistance, invasive ability and lactate production of NSCLC cancer cell lines (A549 and SK-MES-1) were detected in cancer cells with the disturbance of OPN.ResultsImmunostaining indicated that OPN was primarily expressed in the cytoplasm of NSCLC cells. Moreover, OPN correlates with NSCLC clinical traits. The results demonstrated that OPN expression levels significantly correlated with cancer differentiation, distant metastasis and the efficacy of platinum-based treatment. Notably, the results identified OPN expression levels as a potential factor for predicting the response of cells to first-line platinum-based chemotherapy using multivariate analysis, as well as predicting cancer differentiation and distant metastasis. Additionally, the abrogation of OPN levels reduced lactate production in NSCLC cells and occurred along side with the downregulation of lactate dehydrogenase A (LDHA).ConclusionThe results of the current study suggest that OPN may be able to predict poor prognosis and cisplatin resistance in patients.

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“…According to the results of GO and KEGG enrichment analysis, key module genes were primarily enriched in cell adhesion and ECM function regulation. Recent studies reported that LDHA can promote the progression of renal cell carcinoma and bladder cancer by promoting EMT (29,30). Moreover, lactate, the ultimate metabolite of aerobic glycolysis, led to an acidic tumor microenvironment that facilitated the degradation of ECM and the production of actin filaments (31).…”

Section: Discussionmentioning

confidence: 99%

LDHA Promotes Oral Squamous Cell Carcinoma Progression Through Facilitating Glycolysis and Epithelial–Mesenchymal Transition

Cai

Zhang

et al. 2019

Front. Oncol.

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Aerobic glycolysis is the main pathway for energy metabolism in cancer cells. It provides energy and biosynthetic substances for tumor progression and metastasis by increasing lactate production. Lactate dehydrogenase A (LDHA) promotes glycolysis process by catalyzing the conversion of pyruvate to lactate. Despite LDHA exhibiting carcinogenesis in various cancers, its role in oral squamous cell carcinoma (OSCC) remains unclear. This study demonstrated that LDHA was over-expressed in both OSCC tissues and cell lines, and was significantly associated with lower overall survival rates in patients with OSCC. Using weighted gene correlation network analysis and gene set enrichment analysis for the gene expression data of patients with OSCC (obtained from The Cancer Genome Atlas database), a close association was identified between epithelial-mesenchymal transition (EMT) and LDHA in promoting OSCC progression. The knockdown of LDHA suppressed EMT, cell proliferation, and migration and invasion of OSCC cells in vitro. Moreover, the silencing of LDHA inhibited tumor growth in vivo. Oxamate, as a competitive LDHA inhibitor, was also suppressed diverse malignant biocharacteristics of OSCC cells. Our findings reveal that LDHA acts as an oncogene to promote malignant progression of OSCC by facilitating glycolysis and EMT, and LDHA may be a potential anticancer therapeutic target.

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LDHA promotes tumor metastasis by facilitating epithelial-mesenchymal transition in renal cell carcinoma

Cited by 65 publications

References 30 publications

Acylglycerol kinase promotes tumour growth and metastasis via activating the PI3K/AKT/GSK3β signalling pathway in renal cell carcinoma

Acylglycerol kinase promotes tumour growth and metastasis via activating the PI3K/AKT/GSK3β signalling pathway in renal cell carcinoma

Osteopontin promotes cancer cell drug resistance, invasion, and lactate production and is associated with poor outcome of patients with advanced non-small-cell lung cancer

LDHA Promotes Oral Squamous Cell Carcinoma Progression Through Facilitating Glycolysis and Epithelial–Mesenchymal Transition

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