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

ABSTRACT: 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.

SUBMITTER: Cai H

PROVIDER: S-EPMC6930919 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundEsophageal squamous cell carcinoma (ESCC) is one of the most prevalent cancers worldwide. Due to its high morbidity and mortality rates, it is urgent to find a molecular target that contributes to esophageal carcinogenesis and progression. In this research, we aimed to investigate the functions of Latent transforming growth factor β binding protein 1(LTBP1) in ESCC progression and elucidate the underlying mechanisms.MethodsThe tandem mass tag-based quantitative proteomic approach was applied to screen the differentially expressed proteins (DEPs) between 3 cases of ESCC tumor samples and paired normal tissues. Then the DEPs were validated in human ESCC tissues using western blot assays and GEPIA database respectively. The expression level of LTBP1 was detected in 152 cases of ESCC tissues and paired normal tissues. Loss-of-function assays were performed to detect the function of LTBP1 in vivo and in vitro. Immunofluorescence and Western blot assays were used to detect the expression of apoptosis, epithelial-mesenchymal transition (EMT) and cancer-associated fibroblasts (CAFs) markers.ResultsA total of 39 proteins were screened to be up-regulated (ratio > 2.0) in all three ESCC tissues. The results of immunohistochemistry assays indicated that the expression level of LTBP1 was higher in ESCC tissues than that in paired normal tissues (p < 0.001). Overexpression of LTBP1 was positively associated with lymphatic metastasis in ESCC (p = 0.002). Down-regulation of LTBP1 inhibited the invasion and migration as well as metastatic abilities in vitro and in vivo. It was also observed the down-regulation of LTBP1 not only decreased the mesenchymal phenotypes but also inhibited TGFβ-induced EMT in ESCC cells. We further found that down-regulation of LTBP1 enhanced ESCC cells' sensitivity to 5-FU treatment. Inhibition of LTBP1 expression could also attenuate induction of CAFs transformation and restrain fibroblast express fibronectin (FN1) in ESCC cells.ConclusionOverexpression of LTBP1 was associated with lymph node metastasis in ESCC. Our results indicated that LTBP1 not only increased the malignant behaviors of ESCC cells but also induced EMT and CAFs transformation. Our studies suggested an oncogenic role of LTBP1 in ESCC progression and it may serve as a potential therapeutic target for ESCC patients.

Project description:BackgroundAdenosine deaminases acting on RNA (ADARs) are involved in adenosine-to-inosine (A-to-I) editing and implicated in tumorigenesis and prognosis. Emerging evidence has indicated that ADAR1, an ADAR family member, participates in the regulation of various cancers; however, its biological function in oral squamous cell carcinoma (OSCC) remains unclear. This study aimed to determine the role of ADAR1 in OSCC progression.MethodsADAR1 expression in both normal tissues and carcinoma tissues and in OSCC cell lines was examined by real-time PCR and western blotting. Gain-of-function and loss-of-function approaches were used to examine the effect of ADAR1 on the migration, invasion, epithelial-mesenchymal transition (EMT) and stemness of OSCC. Furthermore, the relationship between ADAR1 and Dicer was determined by co-immunoprecipitation, and the expression of OSCC-associated oncogenic miRNAs was evaluated by real-time PCR. For in vivo experiments, a xenograft model where OSCC cells stably expressing ADAR1 were implanted was used to investigate the effect of ADAR1 on tumor growth and progression, and the expression of ADAR1, PCNA, SOX2 and POU5F1 was further detected by immunohistochemistry. The impact of ADAR1 expression on the survival status of OSCC patients was determined by survival analysis.ResultsADAR1 was overexpressed in OSCC and significantly associated with poor patient survival. There was a positive correlation between ADAR1 and the migration, invasion, EMT and stemness of OSCC. Mechanistically, ADAR1 was physically associated with Dicer, and six OSCC-associated oncogenic miRNAs were increased in OSCC cells with ADAR1 overexpression. In the mouse xenograft model of OSCC, ADAR1 overexpression promoted tumor growth and progression. Moreover, ADAR1 was highly expressed in OSCC patients with low survival rates.ConclusionsOur findings demonstrated that ADAR1 may play a significant role in OSCC progression via combining with Dicer to regulate oncogenic miRNA maturation and further affect cell migration and invasion.

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

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