LDH-A promotes malignant behavior via activation of epithelial-to-mesenchymal transition in lung adenocarcinoma

Hou, Xiaoming; Yuan, Shengtao; Zhao, Da; Liu, Xiaojun; Wu, Xinan

doi:10.1042/bsr20181476

Cited by 74 publications

(49 citation statements)

References 25 publications

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“…Hence, altered expression of LDHC could be involved in maintaining an alternative energy source by contributing to the metabolic switch in cancer cells. In addition, increased LDHA and decreased LDHB expressions facilitate tumor formation and progression through remodeling of the tumor microenvironment, increasing proliferation, and inducing epithelial-to-mesenchymal transition, cell migration and invasion, and angiogenesis [10][11][12][13][14][15][16][17][18][19][20]. In line with this, two studies to date demonstrate that enhanced expression of LDHC induces epithelial-to-mesenchymal transition, matrix metalloproteinase-9 (MMP9) expression and promotes cancer cell migration and invasion [7,21].…”

Section: Introductionmentioning

confidence: 81%

Identification of two HLA-A*0201 immunogenic epitopes of lactate dehydrogenase C (LDHC): potential novel targets for cancer immunotherapy

Thomas

Shaath

Belič

et al. 2020

Cancer Immunol Immunother

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Lactate dehydrogenase C (LDHC) is an archetypical cancer testis antigen with limited expression in adult tissues and reexpression in tumors. This restricted expression pattern together with the important role of LDHC in cancer metabolism renders LDHC a potential target for immunotherapy. This study is the first to investigate the immunogenicity of LDHC using T cells from healthy individuals. LDHC-specific T cell responses were induced by in vitro stimulation with synthetic peptides, or by priming with autologous peptide-pulsed dendritic cells. We evaluated T cell activation by IFN-γ ELISpot and determined cytolytic activity of HLA-A*0201-restricted T cells in breast cancer cell co-cultures. In vitro T cell stimulation induced IFN-γ secretion in response to numerous LDHC-derived peptides. Analysis of HLA-A*0201 responses revealed a significant T cell activation after stimulation with peptide pools 2 (PP2) and 8 (PP8). The PP2-and PP8-specific T cells displayed cytolytic activity against breast cancer cells with endogenous LDHC expression within a HLA-A*0201 context. We identified peptides LDHC 41−55 and LDHC 288−303 from PP2 and PP8 to elicit a functional cellular immune response. More specifically, we found an increase in IFN-γ secretion by CD8 + T cells and cancer-cell-killing of HLA-A*0201/LDHC positive breast cancer cells by LDHC 41−55-and LDHC 288−303-induced T cells, albeit with a possible antigen recognition threshold. The majority of induced T cells displayed an effector memory phenotype. To conclude, our findings support the rationale to assess LDHC as a targetable cancer testis antigen for immunotherapy, and in particular the HLA-A*0201 restricted LDHC 41-55 and LDHC 288-303 peptides within LDHC.

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Section: Introductionmentioning

confidence: 81%

Identification of two HLA-A*0201 immunogenic epitopes of lactate dehydrogenase C (LDHC): potential novel targets for cancer immunotherapy

Thomas

Shaath

Belič

et al. 2020

Cancer Immunol Immunother

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“…LDHA (lactate dehydrogenase A), as a crucial enzyme of energy metabolism, is elevated in various cancers compared with inormal tissues. Previous studies showed that LDHA could promote tumor cells proliferation, invasion, migration, tumor progression, and metastasis, and might be a potential therapeutic target [25][26][27][28][29]. MELTF, also known as MAP97, MTf (Melanotransferrin), or MTF1 (metal regulatory transcription factor 1), as an iron (Fe) binding transferrin homolog, is mainly expressed in melanoma and is low expression in noncancerous tissues.…”

Section: Discussionmentioning

confidence: 99%

Identification of a four-gene panel predicting overall survival for lung adenocarcinoma

Chunyu

Qizhong

Danni

et al. 2020

Preprint

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Background: Lung cancer is the most frequently diagnosed carcinoma and the leading cause of cancer-related mortality. Although molecular targeted therapy and immunotherapy have made great progress, the overall survival (OS) is still poor due to a lack of accurate and available prognostic biomarkers. Therefore, in this study we aimed to establish a multiple-gene panel predicting OS for lung adenocarcinoma. Methods: We obtained the mRNA expression and clinical data of lung adenocarcinoma (LUAD) from TCGA database for further integrated bioinformatic analysis. Lasso regression and Cox regression were performed to establish a prognosis model based on a multi-gene panel. Nomogram was built based on the model. The receiver operating characteristic (ROC) curve and the Kaplan–Meier curve were used to assess the predicted capacity of the model. The prognosis value of the multi-gene panel was further validated in TCGA-LUAD patients with EGFR, KRAS and TP53 mutation and a dataset from GEO. Gene set enrichment analysis (GSEA) was performed to explore potential biological mechanisms of a novel prognostic gene signature. Results: A four-gene panel (including DKK1, GNG7, LDHA, MELTF) was established as a prognostic indicator for OS of LUAD. The ROC curve revealed good predicted performance in both test cohort (AUC = 0.740) and validation cohort (AUC = 0.752). Each patient was calculated a risk score according to the model based on the four-gene panel. The results showed that the risk score was an independent prognostic factor, and the high-risk group had a worse OS compared with the low-risk group. The nomogram based on this model shows better prediction performance. The four-gene panel was still good predictors for OS in LUAD patients with TP53 and KRAS mutations. The four genes may be significantly related to the metabolism of genetic material, especially in the regulation of cell cycle pathway. Conclusion: Our study proposed a novel four-gene panel to predict the OS of LUAD, which may contribute to predicting prognosis accurately and making the clinical decisions of individual therapy for LUAD patients.

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“…LDHA (lactate dehydrogenase A), as a crucial enzyme of energy metabolism, is elevated in various cancers compared with normal tissues. Previous studies showed that LDHA could promote tumor cells proliferation, invasion, migration, tumor progression, and metastasis, and might be a potential therapeutic target [25][26][27][28][29]. MELTF, also known as MAP97, MTf (Melanotransferrin), or MTF1 (metal regulatory transcription factor 1), as an iron (Fe) binding transferrin homolog, is mainly expressed in melanoma and is low expression in noncancerous tissues.…”

Section: Discussionmentioning

confidence: 99%

Identification of a four-gene panel predicting overall survival for lung adenocarcinoma

Chunyu

Qizhong

Danni

et al. 2020

Preprint

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Abstract Background: Lung cancer is the most frequently diagnosed carcinoma and the leading cause of cancer-related mortality. Although molecular targeted therapy and immunotherapy have made great progress, the overall survival (OS) is still poor due to a lack of accurate and available prognostic biomarkers. Therefore, in this study we aimed to establish a multiple-gene panel predicting OS for lung adenocarcinoma.Methods: We obtained the mRNA expression and clinical data of lung adenocarcinoma (LUAD) from TCGA database for further integrated bioinformatic analysis. Lasso regression and Cox regression were performed to establish a prognosis model based on a multi-gene panel. Nomogram was built based on the model. The receiver operating characteristic (ROC) curve and the Kaplan–Meier curve were used to assess the predicted capacity of the model. The prognosis value of the multi-gene panel was further validated in TCGA-LUAD patients with EGFR, KRAS and TP53 mutation and a dataset from GEO. Gene set enrichment analysis (GSEA) was performed to explore potential biological mechanisms of a novel prognostic gene signature.Results: A four-gene panel (including DKK1, GNG7, LDHA, MELTF) was established as a prognostic indicator for OS of LUAD. The ROC curve revealed good predicted performance in both test cohort (AUC = 0.740) and validation cohort (AUC = 0.752). Each patient was calculated a risk score according to the model based on the four-gene panel. The results showed that the risk score was an independent prognostic factor, and the high-risk group had a worse OS compared with the low-risk group. The nomogram based on this model shows better prediction performance. The four-gene panel was still good predictors for OS in LUAD patients with EGFR, KRAS and TP53 mutations. The four genes may be significantly related to the metabolism of genetic material, especially in the regulation of cell cycle pathway.Conclusion: Our study proposed a novel four-gene panel to predict the OS of LUAD, which may contribute to predicting prognosis accurately and making the clinical decisions of individual therapy for LUAD patients.

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LDH-A promotes malignant behavior via activation of epithelial-to-mesenchymal transition in lung adenocarcinoma

Cited by 74 publications

References 25 publications

Identification of two HLA-A*0201 immunogenic epitopes of lactate dehydrogenase C (LDHC): potential novel targets for cancer immunotherapy

Identification of two HLA-A*0201 immunogenic epitopes of lactate dehydrogenase C (LDHC): potential novel targets for cancer immunotherapy

Identification of a four-gene panel predicting overall survival for lung adenocarcinoma

Identification of a four-gene panel predicting overall survival for lung adenocarcinoma

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