Expression and Clinical Significance of Lactate Dehydrogenase A in Colon Adenocarcinoma

Wang, Yutong; Nie, Hui; Liao, Zhiming; He, Xiaoyun; Xu, Zhijie; Zhou, Jianhua; Ou, Chunlin

doi:10.3389/fonc.2021.700795

Cited by 8 publications

(8 citation statements)

References 52 publications

(55 reference statements)

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“…The quality of life of patients is usually very low, and the prognosis of most patients is poor. The occurrence and development of COAD are the results of a variety of mixed factors in vivo and in vitro , which involve a series of molecules and signal pathways ( Wang et al, 2021 ). Although substantive diagnosis and treatment strategies such as surgery, neoadjuvant therapy, and targeted therapy are constantly being developed, the recurrence rate of postoperative COAD is still high, and the 5-year survival rate of patients with advanced COAD is still very low (The 5-year survival rate after distant metastasis is less than 15%) ( Patel et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Immune ULBP1 is Elevated in Colon Adenocarcinoma and Predicts Prognosis

et al. 2022

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Background: Colon adenocarcinoma (COAD) is still the main cause of cancer deaths worldwide. Although immunotherapy has made progress in recent years, there is still a need to improve diagnosis, prognosis, and treatment tools. UL-16 binding protein 1 (ULBP1) is a ligand that activates the receptor natural killer cell group 2 receptor D (NKG2D) and plays an important immunomodulatory role. We aimed to investigate the clinical significance of ULBP1 in COAD.Methods: We obtained the relevant data from The Cancer Genome Atlas (TCGA). A total of 438 patients with COAD were included in this study, with a mean age of 67.1 ± 13.03 years old, of which 234 (53.42%) were male. The diagnostic value of COAD tumor tissues and adjacent tissues was analyzed by ROC curve. Univariate and multivariate survival analysis investigated the prognostic value of ULBP1 gene, and Gene Set Enrichment Analysis (GSEA) curve was performed to analyze the biological process and enriched enrichment pathway of ULBP1 in COAD. Combination survival analysis investigated the combined prognostic effect of prognostic genes.Results:ULBP1 gene had a high diagnostic value in COAD [AUC (TCGA) = 0.959; AUC (Guangxi) = 0.898]. Up-regulated ULBP1 gene of patients with COAD predicted a worse prognosis compared to those patients with down-regulated ULBP1 gene (Adjusted HR = 1.544, 95% CI = 1.020–2.337, p = 0.040). The GSEA showed that ULBP1 was involved in the apoptotic pathway and biological process of T cell mediated cytotoxicity, regulation of natural killer cell activation, and T cell mediated immunity of COAD. The combination survival analysis showed that the combination of high expression of ULBP1, AARS1, and DDIT3 would increase the 2.2-fold death risk of COAD when compared with those of low expression genes.Conclusion: The immune-related ULBP1 gene had diagnostic and prognostic value in COAD. The combination of ULBP1, AARS1, and DDIT3 genes could improve the prognostic prediction performance in COAD.

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Section: Introductionmentioning

confidence: 99%

Immune ULBP1 is Elevated in Colon Adenocarcinoma and Predicts Prognosis

et al. 2022

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“…The analyses of LDHA and PDK1 in situ protein expression also showed association with poor survival and therapy resistance in many malignancies (colon, breast, uterine, pancreas, lung, renal, gastric cancers, CNS malignancies, etc.). Considering the increasing serum lactate level of end-stage cachexia patients, these observations are not surprising [196][197][198][199][200][201].…”

Section: Tissue Heterogeneity Of Certain Metabolic Enzymes and Their ...mentioning

confidence: 81%

The role of metabolic ecosystem in cancer progression — metabolic plasticity and mTOR hyperactivity in tumor tissues

Sebestyén

Dankó

Sztankovics

et al. 2021

Cancer Metastasis Rev

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Despite advancements in cancer management, tumor relapse and metastasis are associated with poor outcomes in many cancers. Over the past decade, oncogene-driven carcinogenesis, dysregulated cellular signaling networks, dynamic changes in the tissue microenvironment, epithelial-mesenchymal transitions, protein expression within regulatory pathways, and their part in tumor progression are described in several studies. However, the complexity of metabolic enzyme expression is considerably under evaluated. Alterations in cellular metabolism determine the individual phenotype and behavior of cells, which is a well-recognized hallmark of cancer progression, especially in the adaptation mechanisms underlying therapy resistance. In metabolic symbiosis, cells compete, communicate, and even feed each other, supervised by tumor cells. Metabolic reprogramming forms a unique fingerprint for each tumor tissue, depending on the cellular content and genetic, epigenetic, and microenvironmental alterations of the developing cancer. Based on its sensing and effector functions, the mechanistic target of rapamycin (mTOR) kinase is considered the master regulator of metabolic adaptation. Moreover, mTOR kinase hyperactivity is associated with poor prognosis in various tumor types. In situ metabolic phenotyping in recent studies highlights the importance of metabolic plasticity, mTOR hyperactivity, and their role in tumor progression. In this review, we update recent developments in metabolic phenotyping of the cancer ecosystem, metabolic symbiosis, and plasticity which could provide new research directions in tumor biology. In addition, we suggest pathomorphological and analytical studies relating to metabolic alterations, mTOR activity, and their associations which are necessary to improve understanding of tumor heterogeneity and expand the therapeutic management of cancer.

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“…In this process, LDHA is a key player responsible for the production of ATP and the regeneration of oxidized NAD, factors necessary for the processes of synthesis that enable cancer cell proliferation and invasion [27]. There are a number of studies indicating that LDHA expression is elevated in a wide variety of cancers, including colorectal cancer, breast cancer, pancreatic cancer, and oral squamous cell carcinoma, and that its level is closely correlated with tumor progression [28][29][30][31]. We, in our work using the Gene Expression database of Normal and Tumor tissues 2 (GENT2), which is a rich collection of gene expression patterns in various normal and tumor tissues compiled from public gene expression datasets, found that also in esophageal cancers LDHA expression is significantly higher, compared to normal controls, which is in line with previous reports [32].…”

Section: Discussionmentioning

confidence: 99%

Effect of LDHA Inhibition on TNF-α-Induced Cell Migration in Esophageal Cancers

Forkasiewicz

Stach

Wierzbicki

et al. 2022

IJMS

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Cell migration is an essential part of the complex and multistep process that is the development of cancer, a disease that is the second most common cause of death in humans. An important factor promoting the migration of cancer cells is TNF-α, a pro-inflammatory cytokine that, among its many biological functions, also plays a major role in mediating the expression of MMP9, one of the key regulators of cancer cell migration. It is also known that TNF-α is able to induce the Warburg effect in some cells by increasing glucose uptake and enhancing the expression and activity of lactate dehydrogenase subunit A (LDHA). Therefore, the aim of the present study was to investigate the interrelationship between the TNF-α-induced promigratory activity of cancer cells and their glucose metabolism status, using esophageal cancer cells as an example. By inhibiting LDHA activity with sodium oxamate (SO, also known as aminooxoacetic acid sodium salt or oxamic acid sodium salt) or siRNA-mediated gene silencing, we found using wound healing assay and gelatin zymography that LDHA downregulation impairs TNF-α-dependent tumor cell migration and significantly reduces TNF-α-induced MMP9 expression. These effects were associated with disturbances in the activation of the ERK1/2 signaling pathway, as we observed by Western blotting. We also reveal that in esophageal cancer cells, SO effectively reduces the production of lactic acid, which, as we have shown, synergizes the stimulating effect of TNF-α on MMP9 expression. In conclusion, our findings identified LDHA as a regulator of TNF-α-induced cell migration in esophageal cancer cells by the ERK1/2 signaling pathway, suggesting that LDHA inhibitors that limit the migration of cancer cells caused by the inflammatory process may be considered as an adjunct to standard therapy in esophageal cancer patients.

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Expression and Clinical Significance of Lactate Dehydrogenase A in Colon Adenocarcinoma

Cited by 8 publications

References 52 publications

Immune ULBP1 is Elevated in Colon Adenocarcinoma and Predicts Prognosis

Immune ULBP1 is Elevated in Colon Adenocarcinoma and Predicts Prognosis

The role of metabolic ecosystem in cancer progression — metabolic plasticity and mTOR hyperactivity in tumor tissues

Effect of LDHA Inhibition on TNF-α-Induced Cell Migration in Esophageal Cancers

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