ABSTRACT
Abstract Oral potentially malignant disorders (OPMD) are associated with an increased risk of oral squamous cell carcinoma (OSCC). OSCC has an aggressive profile and is the most prevalent among different head and neck malignancies. Most OSCC patients are diagnosed with advanced stage tumors and have a poor prognosis. Cancer cells are able to reprogram their metabolism, even in the presence of oxygen, enhancing the conversion of glucose to lactate via the glycolytic pathway, a phenomenon mainly regulated by hypoxia-inducible factor (HIF) signaling. Thus, several glycometabolism-related biomarkers are upregulated. Objectives This study aimed to evaluate the immunoexpression of the HIF targets GLUT1, GLUT3, HK2, PFKL, PKM2, pPDH, LDHA, MCT4, and CAIX in OPMD and OSCC samples, in order to identify potential correlations between biomarkers' immunoexpression, clinicopathological features, and prognostic parameters. Methodology OSCC and OPMD samples from 21 and 34 patients (respectively) were retrospectively collected and stained for the different biomarkers by immunohistochemistry. Results CAIX and MCT4 expressions were significantly higher in OSCC samples when compared with OPMD samples, while the rest were also expressed by OPMD. GLUT3 and PKM2 alone, and the concomitant expression of more than four glycometabolism-related biomarkers were significantly correlated with the presence of dysplasia in OPMD. When considering OSCC cases, a trend toward increased expression of biomarkers and poor clinicopathological features was observed, and the differences regarding HK2, PFKL, LDHA and MCT4 expression were significant. Moreover, HK2 and CAIX were correlated with low survival rates. GLUT1 and GLUT3 were significantly associated with poor outcome when their expression was observed in the hypoxic region of malignant lesions. Conclusion OPMD and OSCC cells overexpress glycolysis-related proteins, which is associated with aggressive features and poor patient outcome. Further research is needed to deeply understand the glycolic phenotype in the process of oral carcinogenesis.
ABSTRACT
Monocarboxylate transporters (MCTs) are members of the solute carrier 16 (SLC16) family of proteins. They mediate the proton-linked transport of monocarboxylates, including lactate, across the plasma membrane. In recent years, studies have shown the association of MCT dysregulation with tumor progression in various types of solid tumors. MCTs were shown to participate in maintaining the hyper-glycolytic and acid-resistant phenotypes and the intracellular and extracellular pH levels of tumor cells by mediating lactate transport. In addition, lactate transport mediated by MCTs was shown to promote tumor angiogenesis and induce tumor immune tolerance. Therefore, in this article, we have reviewed research on lactate transport mediated by MCTs in tumors.
ABSTRACT
The growth of tumour cells is closely related to cancer-associated fibroblasts (CAFs)present within their microenvironment. CAFs, the most abundant cells in tumour stroma, secretegrowth factors that play pivotal roles in tumour cell proliferation, metabolism, angiogenesis andmetastasis. Tumour cells adapt to rapid environmental changes from normoxia to hypoxia throughmetabolic interplay with CAFs. In this mini review, we discuss the role of lactate dehydrogenases(LDHs) and monocarboxylate transporters (MCTs) on the metabolic interplay between tumourcells and CAFs under hypoxia compared to normoxia. The LDHs catalyse the interchange oflactate and pyruvate, whereas MCTs facilitate the influx and efflux of monocarboxylates, especiallylactate and pyruvate. To sum up, tumour cells switch their metabolic state between glycolysis andoxidative phosphorylation through metabolic interplay with CAFs, which exhibit the Warburgeffect under hypoxia and reverse Warburg effect under normoxia.
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Some horse breeds are highly selected for athletic activities. The athletic potential of each animal can be measured by its performance in sports. High athletic performance depends on the animal capacity to produce energy through aerobic and anaerobic metabolic pathways, among other factors. Transmembrane proteins called monocarboxylate transporters, mainly the isoform 1 (MCT1) and its ancillary protein CD147, can help the organism to adapt to physiological stress caused by physical exercise, transporting lactate and H+ ions. Horse breeds are selected for different purposes so we might expect differences in the amount of those proteins and in the genotypic frequencies for genes that play a significant role in the performance of the animals. The study of MCT1 and CD147 gene polymorphisms, which can affect the formation of the proteins and transport of lactate and H+, can provide enough information to be used for selection of athletic horses increasingly resistant to intense exercise. Two other candidate genes, the PDK4 and DMRT3, have been associated with athletic potential and indicated as possible markers for performance in horses. The oxidation of fatty acids is highly effective in generating ATP and is controlled by the expression of PDK4 (pyruvate dehydrogenase kinase, isozyme 4) in skeletal muscle during and after exercise. The doublesex and mab-3 related transcription factor 3 (DMRT3) gene encodes an important transcription factor in the setting of spinal cord circuits controlling movement in vertebrates and may be associated with gait performance in horses. This review describes how the monocarboxylate transporters work during physical exercise in athletic horses and the influence of polymorphisms in candidate genes for athletic performance in horses.(AU)
Algumas raças de equinos são altamente selecionadas para atividades desportivas. O potencial atlético de cada animal pode ser medido pelo seu desempenho nas competições equestres. Um alto potencial atlético depende, entre outros fatores, da capacidade do animal de produzir energia através dos metabolismos aeróbio e anaeróbio. As proteínas transmembrana chamadas transportadores de monoxarboxilato, principalmente a isoforma 1 (MCT1) e sua proteína auxiliar CD147, podem ajudam o organismo a se adaptar ao estresse fisiológico causado pelo exercício físico, transportando íons lactato e H+. Algumas raças de equinos são selecionadas para diferentes objetivos, portanto é provável que existam diferenças nas quantidades de transportadores monocarboxilatos e na frequência genotípica dos seus respectivos genes. O estudo de polimorfismos nos genes das proteínas MCT1 e CD147, afetando a sua formação e o transporte dos íons lactato e H+, podem fornecer informações suficientes para a seleção de equinos com capacidade de serem altamente treinados e resistentes a intensos exercícios. Dois outros genes candidatos que têm sido relacionados com potencial atlético e utilizados como possíveis marcadores para desempenho em equinos são o PDK4 e o DMRT3. A oxidação de ácidos graxos é altamente efetiva para produção de ATP e é controlada pela expressão do gene PDK4 (pyruvate dehydrogenase kinase, isozyme 4) no musculo esquelético durante e após do exercício físico. O gene DMRT3 (doublesex and mab-3 related transcription factor 3) codifica um importante fator de transcrição no controle dos movimentos em vertebrados e pode ser associado com a marcha em algumas raças de equinos. Esta revisão descreve como agem os transportadores de monocarboxilatos durante o exercício físico em equinos atletas e qual a influência de alguns polimorfismos em genes candidatos para o desempenho atlético em equinos.(AU)
Subject(s)
Animals , Genetic Association Studies , Horses/genetics , Horses/physiology , Lactates/analysis , Muscle Fatigue , Polymorphism, Genetic , Stress, PhysiologicalABSTRACT
Purpose To explore the expression of monocarboxylate transporters 4 (MCT4) and its clinicopathologic significance in cer-vical squamous cell carcinoma. Methods The expression level of MCT4 in 72 cervical squamous cell carcinoma tissues and 48 cervi-cal normal tissues were detected by immunohistochemistry assay, and its relationship with clinical pathological features was analyzed. Results The positive rate of MCT4 was 81. 9% (59/72) in cervical squamous cell carcinoma tissues and 35. 4% (17/48) in normal cervical tissues. The positive rate of MCT4 in cervical squamous cell carcinoma was significantly higher than that in cervical normal tis-sues (χ2 =26. 848, P<0. 001). In addition, the expression of MCT4 protein was correlated with clinical stage (χ2 =5. 389, P=0. 020) and lymph node metastasis (χ2 =4. 706, P=0. 030). However, it did not correlated with age (χ2 =1. 238, P=0. 266), tumor differentiation (χ2 =0. 530, P=0. 467) or infiltration degree (χ2 =1. 300, P=0. 254) in patients with cervical squamous cell carcinoma. Conclusion The expression of MCT4 is up-regulated in cervical squamous cell carcinoma and correlate with clinical stage and lymph node metastasis of cervical squamous cell carcinoma. MCT4 may be a biomarker for evaluating the biological behavior of cer-vical squamous cell carcinoma.
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Objective To study the expression of monocarboxylate transporter l(MCTl), CD147, and CD44 mRNA in non-small cell lung cancer(NSCLC), and its role in the development, progression and prognosis of NSCLC. Methods Fifty-six NSCLC specimens and the adjacent tissues (more than 5 cm from the tumors), 20 specimens of benign pulmonary diseases and 7 specimens of normal pulmonary tissues were included in the present study. The expression of MCT1, CD147, and CD44 mRNA was examined by real-time quantitative RT-PCR in the above specimens. The relationship of their expression with the clinical and pathological features of NSCLC patients was analyzed. Results (l)The expression rates of MCT1, CD147, and CD44 mRNA in NSCLC specimens were significantly higher than those in the adjacent tissues, normal pulmonary tissues, and benign pulmonary disease tissues (all P<0. 05). (2) The expression of MCT1, CD147, and CD44 in NSCLC tissue was significantly correlated with each other(P<0. 05). (3) The expression of MCT1, CD147, and CD44 mRNA in NSCLC tissue was not correlated with age, gender, smoking, site and dimension of lesion, or pTNM stage, and was correlated with the histological types (all P<0. 05) and lymph node metastasis of NSCLC(all P<0. 05). In addition, we also found that MCT1 and CD44 expression was correlated with the differentiation degree of NSCLC(all P<0. 05). Conclusion The expression of MCT1, CD147, and CD44 mRNA is up-regulated in the NSCLC specimens. MCT1, CD147 and CD44 may participate in the development and progression of NSCLC, and they may also act as markers for diagnosis and prognosis of NSCLC.