How does hypoxia inducible factor-1α participate in enhancing the glycolysis activity in cervical cancer?

Cheng, Yanxiang; Chen, Gantao; Li, Hong; Zhou, Limei; Hu, Min; Li, Bingshu; Huang, Jinling; Xia, Liangbin; Li, Cuilan

doi:10.1016/j.anndiagpath.2012.12.002

Cited by 30 publications

(18 citation statements)

References 16 publications

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“…The clinicopathological significance of the metabolic markers analysed in the present study has been previously evaluated by us and others [ 33 – 36 , 52 – 55 ]. Although we were not able to found any associations with the clinicopathological data of SCC in our previous studies with MCTs and CD147 [ 33 , 34 ], other studies have found association of CD147, GLUT1 and CAIX expression with lymph-node metastasis [ 35 , 52 , 54 ], while CAIX was also associated with advanced tumour stage, greater invasion depth, undifferentiated tumour grade [ 52 ], as well as distant metastasis in early-stage cervical cancer [ 53 ]. Also, absence of GLUT1 was shown to significantly increase the likelihood of metastasis-free survival in locally advanced cervical carcinoma but not of disease-free or recurrence-free survival [ 55 ].…”

Section: Discussioncontrasting

confidence: 72%

“…GLUT1 expression, although with significantly different frequencies of expression among the lesions, did not follow a gradual increase towards malignancy. Previous results from others have described a progressive increase of GLUT1 from normal cervical tissue, to precursor lesions and SCC [ 35 , 36 ]. CAIX showed a gradual expression frequency in cervical lesions, according to lesion grade.…”

Section: Discussionmentioning

confidence: 98%

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Lactate transporters and vascular factors in HPV-induced squamous cell carcinoma of the uterine cervix

et al. 2014

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BackgroundTumour microenvironment is a fundamental aspect of tumour behaviour, modulating important events as cancer cell migration and invasion, as well as angiogenesis and metastisation. Among other microenvironment features, hypoxia and acidity play important roles in this modulation. As the metabolic reprogramming of cancer cells induces extracellular acidity, which in turn induces angiogenesis, and hypoxia induces both the metabolic reprogramming and angiogenesis, the present study aims to evaluate the immunohistochemical expression of a variety of metabolic and vascular markers as common targets of the hypoxic microenvironment in a series of cervical squamous cells carcinoma, as well as using an in vitro 3D culture model.MethodsImmunohistochemical expression of MCT1, MCT4, CD147, GLUT1 and CAIX was assessed in a series of 28 chronic cervicitis, 34 LSIL, 29 HSIL, 38 cases of squamous cells carcinoma (SCC), as well as in in vitro 3D culture of keratinocytes expressing HPV genes. Furthermore, VEGF family members’ expression was assessed in the SCC cases. The expression profiles were associated with patients’ clinicopathological parameters.ResultsWe found an increase of MCT4 expression along progression to malignancy in cervical samples. Also, MCT4 was associated with CD147 and CAIX expression. VEGF-A expression was more frequently found in cases without MCT1 expression. Both MCT4 and CD147 were more frequently expressed in younger patients at diagnosis while no associations were found between VEGF family and clinicopathological parameters. Finally, we show evidence for the upregulation of MCT4, as well as CD147 and CAIX, after HPV transfection.ConclusionsThe results herein presented point at MCT4 as a promising therapeutic target in squamous cells carcinoma of the uterine cervix. Importantly, we show a possible association between lactate transport and angiogenesis, which should be further explored.

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Section: Discussioncontrasting

confidence: 72%

Section: Discussionmentioning

confidence: 98%

Lactate transporters and vascular factors in HPV-induced squamous cell carcinoma of the uterine cervix

et al. 2014

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“…In fact, we found GLUT1, alone or in combination with MCT1, but not MCT4, to be associated with presence of distant metastasis. Although GLUT1 has been previously associated with lymphnode metastasis in cervical cancer [ 44 ], to the best of our knowledge, this is the first report associating GLUT1 with distant metastasis in cervical cancer. This finding contradicts another study in locally advanced cervical carcinoma, where absence of GLUT1 was shown to significantly increase the likelihood of metastasis-free survival [ 45 ].…”

Section: Discussionmentioning

confidence: 94%

Reprogramming energy metabolism and inducing angiogenesis: co-expression of monocarboxylate transporters with VEGF family members in cervical adenocarcinomas

et al. 2015

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BackgroundDeregulation of cellular energetic metabolism was recently pointed out as a hallmark of cancer cells. This deregulation involves a metabolic reprogramming that leads to a high production of lactate. Lactate efflux, besides contributing for the glycolytic flux, also acts in the extracellular matrix, contributing for cancer malignancy, by, among other effects, induction of angiogenesis. However, studies on the interplay between cancer metabolism and angiogenesis are scarce. Therefore, the aim of the present study was to evaluate the metabolic and vascular molecular profiles of cervical adenocarcinomas, their co-expression, and their relation to the clinical and pathological behavior.MethodsThe immunohistochemical expression of metabolism-related proteins (MCT1, MCT4, CD147, GLUT1 and CAIX) as well as VEGF family members (VEGF-A, VEGF-C, VEGF-D, VEGFR-1, VEGFR-2 and VEGFR-3) was assessed in a series of 232 cervical adenocarcinomas. The co-expression among proteins was assessed and the expression profiles were associated with patients’ clinicopathological parameters.ResultsAmong the metabolism-related proteins, MCT4 and CAIX were the most frequently expressed in cervical adenocarcinomas while CD147 was the less frequently expressed protein. Overall, VEGF family members showed a strong and extended expression with VEGF-C and VEGFR-2 as the most frequently expressed and VEGFR-1 as the less expressed member. Co-expression of MCT isoforms with VEGF family members was demonstrated. Finally, MCT4 was associated with parametrial invasion and HPV18 infection, CD147 and GLUT1 with distant metastasis, CAIX with tumor size and HPV18 infection, and VEGFR-1 with local and lymphnode metastasis.ConclusionsThe results herein presented provide additional evidence for a crosstalk between deregulating cellular energetics and inducing angiogenesis. Also, the metabolic remodeling and angiogenic switch are relevant to cancer progression and aggressiveness in adenocarcinomas.

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“…Furthermore, HIF-1α has been demonstrated to directly mediate glycolysis (33,34). Therefore, an aim of the present study was to determine the involvement of miR-138 and HIF-1α in glycolysis in MM cells.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-138 suppresses proliferation, invasion and glycolysis in malignant melanoma cells by targeting HIF-1α

Yao

Cao

Wang

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. MicroRNAs (miRs) may induce mRNA degradation or inhibit protein translation by directly binding to the 3'-untranslational region of target mRNAs. It has been reported that miR-138 is downregulated in malignant melanoma (MM) cells. However, the role of miR-138 in MM cell proliferation, invasion and energy metabolism remains unknown. These were investigated using reverse transcription-quantitative polymerase chain reaction was used to evaluate the expression of miR-138 and the mRNA expression of hypoxia-inducible factor-1α (HIF-1α), as HIF-1α serves a crucial role in glycolysis, which is important for tumor growth. In addition, western blot analysis was used to detected the protein expression of HIF-1α, while MTT and Transwell assays evaluated cell proliferation and invasion, respectively. Furthermore, glucose consumption and lactic acid production were assessed. These tests were conducted using the normal human melanocyte cell line HM and the MM cell line WM451, which was transfected variously with scramble miR mimics, miR-138 mimics, miR-138 inhibitor, non-specific small interfering (si)RNA, HIF-1α siRNA, or co-transfected with miR-138 mimics and pc-DNA3.1(+)-HIF-1α plasmid. The results showed that miR-138 was significantly downregulated in MM WM451 cells compared to a normal melanocyte cell line HM. Overexpression of miR-138 significantly inhibited the proliferation and invasion of WM451 cells. These effects were similar to those induced by the siRNA-mediated knockdown of HIF-1α, a direct target of miR-138. Further investigation found that miR-138 negatively regulated the protein expression of HIF-1α in WM451 cells. Moreover, upregulation of miR-138 notably inhibited the glycolysis level, as demonstrated by reduced glucose consumption and lactic acid production,

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How does hypoxia inducible factor-1α participate in enhancing the glycolysis activity in cervical cancer?

Cited by 30 publications

References 16 publications

Lactate transporters and vascular factors in HPV-induced squamous cell carcinoma of the uterine cervix

Lactate transporters and vascular factors in HPV-induced squamous cell carcinoma of the uterine cervix

Reprogramming energy metabolism and inducing angiogenesis: co-expression of monocarboxylate transporters with VEGF family members in cervical adenocarcinomas

MicroRNA-138 suppresses proliferation, invasion and glycolysis in malignant melanoma cells by targeting HIF-1α

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