Increased Lactate in Gastric Cancer Tumor-Infiltrating Lymphocytes Is Related to Impaired T Cell Function Due to miR-34a Deregulated Lactate Dehydrogenase A

Wang, Ping; Senyan, Hu; Li, Gu; Chen, Yan; Lü, Long

doi:10.1159/000493110

Cited by 41 publications

(27 citation statements)

References 25 publications

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“…MicroRNA (miRNA), a kind of small non‐coding RNA, could inhibit translation or promote degradation of targets via combining to the specific region of 3′‐untranslated region (3′‐UTR) in targeted mRNA . Until now, several miRNAs like miR‐34a, miR‐34c, miR‐369‐3p, miR‐374a, miR‐30a‐5p, miR‐142‐3p, miR‐30d‐5p, miR‐323a‐3p, miR‑199a‑3p, miR‐449a, and miR‐4524a/b have been found to target the mRNA of LDHA . In a recent study on colorectal cancer, miR‐34a, miR‐34c, miR‐369‐3p, miR‐374a, and miR‐4524a/b were established to directly inhibit LDHA .…”

Section: Regulation Modes Of Ldhamentioning

confidence: 99%

Lactate dehydrogenase A: A key player in carcinogenesis and potential target in cancer therapy

et al. 2018

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Elevated glycolysis remains a universal and primary character of cancer metabolism, which deeply depends on dysregulated metabolic enzymes. Lactate dehydrogenase A (LDHA) facilitates glycolytic process by converting pyruvate to lactate. Numerous researches demonstrate LDHA has an aberrantly high expression in multiple cancers, which is associated with malignant progression. In this review, we summarized LDHA function in cancer research. First, we gave an introduction of structure, location, and basic function of LDHA. Following, we discussed the transcription and activation mode of LDHA. Further, we focused on the function of LDHA in cancer bio‐characteristics. Later, we discussed the clinical practice of LDHA in cancer prevention and treatment. What we discussed gives a precise insight into LDHA especially in cancer research, which will contribute to exploring cancer pathogenesis and its handling measures.

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Section: Regulation Modes Of Ldhamentioning

confidence: 99%

Lactate dehydrogenase A: A key player in carcinogenesis and potential target in cancer therapy

et al. 2018

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“…miR-34a suppresses glycolysis and cell proliferation in breast cancer through directly targeting LDHA (Xiao et al, 2016). miR-34a may also impact the function of tumor infiltrated lymphocytes (TILs) through regulating LDHA expression (Ping et al, 2018). Hypoxia-driven downregulation of miR-34a in gastric cancer led to increased LDHA expression and lactate levels in TILs and impaired function of Th1 cells and CTLs (Ping et al, 2018).…”

Section: Mir-34a Regulation Of Cancer Metabolismmentioning

confidence: 99%

MicroRNA-34a: Potent Tumor Suppressor, Cancer Stem Cell Inhibitor, and Potential Anticancer Therapeutic

Wang

Liu

et al. 2021

Front. Cell Dev. Biol.

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Overwhelming evidence indicates that virtually all treatment-naive tumors contain a subpopulation of cancer cells that possess some stem cell traits and properties and are operationally defined as cancer cell stem cells (CSCs). CSCs manifest inherent heterogeneity in that they may exist in an epithelial and proliferative state or a mesenchymal non-proliferative and invasive state. Spontaneous tumor progression, therapeutic treatments, and (epi)genetic mutations may also induce plasticity in non-CSCs and reprogram them into stem-like cancer cells. Intrinsic cancer cell heterogeneity and induced cancer cell plasticity, constantly and dynamically, generate a pool of CSC subpopulations with varying levels of epigenomic stability and stemness. Despite the dynamic and transient nature of CSCs, they play fundamental roles in mediating therapy resistance and tumor relapse. It is now clear that the stemness of CSCs is coordinately regulated by genetic factors and epigenetic mechanisms. Here, in this perspective, we first provide a brief updated overview of CSCs. We then focus on microRNA-34a (miR-34a), a tumor-suppressive microRNA (miRNA) devoid in many CSCs and advanced tumors. Being a member of the miR-34 family, miR-34a was identified as a p53 target in 2007. It is a bona fide tumor suppressor, and its expression is dysregulated and downregulated in various human cancers. By targeting stemness factors such as NOTCH, MYC, BCL-2, and CD44, miR-34a epigenetically and negatively regulates the functional properties of CSCs. We shall briefly discuss potential reasons behind the failure of the first-in-class clinical trial of MRX34, a liposomal miR-34a mimic. Finally, we offer several clinical settings where miR-34a can potentially be deployed to therapeutically target CSCs and advanced, therapy-resistant, and p53-mutant tumors in order to overcome therapy resistance and curb tumor relapse.

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“…Lactate dehydrogenase A (LDH-A) expression has influence on the tumor microenvironment through HIF signaling, and the immune response is modulated via expression levels of hexokinase 1 and 2 (HK 1 and 2) and VEGF secretion (106). The increased lactate is responsible for impaired T cell function via hypoxia-reduced microRNA 34a (miR-34a) expression in gastric cancer-associated tumorinfiltrating lymphocytes, too (107).…”

Section: Reprogrammed Metabolism As a Cause Of Cancer Developmentmentioning

confidence: 99%

Shedding New Light on Cancer Metabolism: A Metabolic Tightrope Between Life and Death

2020

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Since the earliest findings of Otto Warburg, who discovered the first metabolic differences between lactate production of cancer cells and non-malignant tissues in the 1920s, much time has passed. He explained the increased lactate levels with dysfunctional mitochondria and aerobic glycolysis despite adequate oxygenation. Meanwhile, we came to know that mitochondria remain instead functional in cancer cells; hence, metabolic drift, rather than being linked to dysfunctional mitochondria, was found to be an active act of direct response of cancer cells to cell proliferation and survival signals. This metabolic drift begins with the use of sugars and the full oxidative phosphorylation via the mitochondrial respiratory chain to form CO 2 , and it then leads to the formation of lactic acid via partial oxidation. In addition to oncogene-driven metabolic reprogramming, the oncometabolites themselves alter cell signaling and are responsible for differentiation and metastasis of cancer cells. The aberrant metabolism is now considered a major characteristic of cancer within the past 15 years. However, the proliferating anabolic growth of a tumor and its spread to distal sites of the body is not explainable by altered glucose metabolism alone. Since a tumor consists of malignant cells and its tumor microenvironment, it was important for us to understand the bilateral interactions between the primary tumor and its microenvironment and the processes underlying its successful metastasis. We here describe the main metabolic pathways and their implications in tumor progression and metastasis. We also portray that metabolic flexibility determines the fate of the cancer cell and ultimately the patient. This flexibility must be taken into account when deciding on a therapy, since singular cancer therapies only shift the metabolism to a different alternative path and create resistance to the medication used. As with Otto Warburg in his days, we primarily focused on the metabolism of mitochondria when dealing with this scientific question.

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Increased Lactate in Gastric Cancer Tumor-Infiltrating Lymphocytes Is Related to Impaired T Cell Function Due to miR-34a Deregulated Lactate Dehydrogenase A

Cited by 41 publications

References 25 publications

Lactate dehydrogenase A: A key player in carcinogenesis and potential target in cancer therapy

Lactate dehydrogenase A: A key player in carcinogenesis and potential target in cancer therapy

MicroRNA-34a: Potent Tumor Suppressor, Cancer Stem Cell Inhibitor, and Potential Anticancer Therapeutic

Shedding New Light on Cancer Metabolism: A Metabolic Tightrope Between Life and Death

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