Leptin promotes epithelial-mesenchymal transition of breast cancer via the upregulation of pyruvate kinase M2

Wei, Lan; Li, Kuangfa; Pang, Xiaowu; Guo, Bianqin; Min, Su; Huang, Yi; Wang, Nian; Ji, Feihu; Zhong, Changli; Yang, Junhong; Zhang, Zhiqian; Jiang, Yulin; Liu, Yifeng; Chen, Tingmei

doi:10.1186/s13046-016-0446-4

Cited by 88 publications

(65 citation statements)

References 42 publications

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“…D). Our data also showed that KIFC1 activates PI3K/Akt signaling, thus up‐regulating PKM2, which is consistent with previous studies . We found marked changes in PKM2 expression as well as PI3K/Akt signaling activation in HCC cell lines with varied KIFC1 expression under normoxia.…”

Section: Resultssupporting

confidence: 92%

Circular RNA MAT2B Promotes Glycolysis and Malignancy of Hepatocellular Carcinoma Through the miR‐338‐3p/PKM2 Axis Under Hypoxic Stress

et al. 2019

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Glucose metabolism reprogramming, which is a well‐established characteristic of multiple cancers, demands a higher rate of glycolysis to meet the increasing demands for macromolecular synthesis and to maintain rapid proliferation in a hypoxic environment. However, the mechanism underlying this switch remains to be elucidated. In this study, we investigated the function of circular RNA MAT2B (circMAT2B) in hepatocellular carcinoma (HCC) glucose metabolism reprogramming and malignancy. CircMAT2B was identified by bioinformatics analysis of Gene Expression Omnibus data sets. CircMAT2B expression was up‐regulated in HCC tissues and cell lines. HCC patients with high circMAT2B expression had shortened overall survival. We analyzed the positive correlation between glycolysis and circMAT2B expression in HCC using a maximum standardized uptake value determined by preoperative positron emission tomography/computed tomography scanning combined with high‐performance liquid chromatography assessment of the metabolites of glycolysis and the citric acid cycle. The effect of circMAT2B on glycolysis was validated in vitro and in vivo under hypoxic (1% O2) conditions. Functional assays were performed in HCC cells, HCC organoids, and nude mice to explore the tumor‐promoting roles of circMAT2B in HCC. Biotin‐coupled probe pull‐down assays, biotin‐coupled microRNA capture, luciferase reporter assays, fluorescence in situ hybridization, and RNA immunoprecipitation assays were performed to confirm the interaction among different RNAs. Mechanistically, we demonstrated that circMAT2B up‐regulated expression levels of the microRNA (miR)‐338‐3p target gene PKM2, which encodes a key enzyme in the process of glycolysis, through “sponging” miR‐338‐3p; thus, glycolysis and HCC progression are promoted through this mechanism. Conclusion: CircMAT2B promoted HCC progression by enhanced glycolysis by activating the circMAT2B/miR‐338‐3p/PKM2 axis under hypoxia, which may provide a therapeutic target for HCC.

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Section: Resultssupporting

confidence: 92%

Circular RNA MAT2B Promotes Glycolysis and Malignancy of Hepatocellular Carcinoma Through the miR‐338‐3p/PKM2 Axis Under Hypoxic Stress

et al. 2019

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“…The EMT program activation is regulated by specific TFs such as Twist and -catenin, which are associated with cell invasion and metastasis [13,14]. In this study, we showed that leptininduced Twist expression is an early event that may contribute to the initial establishment of EMT, which is in agreement with studies performed in the breast cancer cell lines MCF7 and SK-BR-3, where leptin also induced the expression of this TF [9,10]. Here, we demonstrated that Twist expression and localization is regulated in a Src-and FAK-dependent manner.…”

Section: Discussionsupporting

confidence: 90%

“…Twist and -catenin are TFs that play an important role during EMT, tumor progression, chemoresistance, and cancer stem cell (CSC) maintenance [59][60][61]. Importantly, leptin induces the expression of Twist and β-catenin in breast cancer cells [9,10]. Therefore, we evaluated whether leptin induces the expression of these two TFs in a cellular model of nontumor mammary epithelium.…”

Section: Leptin Regulates the Expression And Subcellular Localizationmentioning

confidence: 99%

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Leptin promotes expression of EMT-related transcription factors and invasion in a Src and FAK-dependent pathway in MCF10A mammary epithelial cells

Olea-Flores

Zuñiga-Eulogio

Tacuba-Saavedra

et al. 2019

Preprint

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Leptin is one of the main adipokines secreted in breast tissue, and has been associated with epithelial-mesenchymal transition (EMT) and tumor progression in breast cancer. Leptin promotes EMT, cell migration and invasion in epithelial breast cells, leading to tumor progression. However, the molecular mechanism that underlies these events is not fully understood; however, the activation of different signaling pathways appears to be essential. In this sense, the effect of leptin on the activation of kinases like Src and FAK, which regulate signaling pathways that activate the EMT program, has not been completely described. Therefore, we investigated the involvement of these kinases using an in vitro model for leptin-induced EMT process in the non-tumorigenic MCF10A cell line. To this end, MCF10A cells were stimulated with leptin, and Src and FAK activation was assessed. Specific events occurring during EMT were also evaluated in the presence or absence of the kinases's chemical inhibitors PP2 and PF-573228. For instance, we tested the expression and subcellular localization of the EMT--catenin, by western blot and immunofluorescence. We also evaluated the secretion and activation of matrix metalloproteases (MMP-2 and MMP-9) by gelatin zymography. Invasiveness properties of leptin-stimulated cells were determined by invadopodia formation assays, and by the transwell chamber method. Our results showed that leptin promotes EMT through Src and FAK activation, which leads to the secretion and activation of MMP-2 and MMP-9, invadopodia formation and cell invasion in MCF10A cells. In conclusion, our data suggest that -catenin, the secretion of MMP-2, MMP-9, the invadopodia formation and invasion in MCF10A cells in a Src and FAK-dependent manner.

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“…Lu et al reported that L1, L5, and VLDL could promote breast cancer progression and metastasis through Akt‐induced EMT . Leptin was reported to promote the breast cancer cells EMT by activating the PI3K/AKT signaling pathway . miR‐564 could directly target the AKT2 and inhibit the PI3K/AKT pathway, and further inhibit the EMT process, proliferation, and invasion of breast cancer .…”

Section: Discussionmentioning

confidence: 99%

Manganese‐12 acetate suppresses the migration, invasion, and epithelial–mesenchymal transition by inhibiting Wnt/β‐catenin and PI3K/AKT signaling pathways in breast cancer cells

Xing

et al. 2018

Thoracic Cancer

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BackgroundBreast cancer is the leading cause of cancer‐related death in the world, and it is of great value to reveal the molecular mechanisms of breast cancer progression and develop new therapeutic targets.MethodsTranswell assay is used to analyze the migration and invasion of breast cancer cells. Real‐time PCR and western blotting assay are applied to detect the expression levels of epithelial–mesenchymal transition markers and the key members of Wnt/β‐catenin and PI3K/AKT signaling pathways.ResultsManganese‐12 acetate (Mn12Ac) significantly inhibited the migration and invasion of MCF7 and MDA‐MB‐231 breast cancer cells. Western blotting assay further showed that Mn12Ac significantly upregulated E‐cadherin, and downregulated N‐cadherin and vimentin. We further found that Mn12Ac reduced the mRNA expressions of epithelial–mesenchymal transition‐associated transcription factors snail, slug, twist1, and ZEB1 using real‐time PCR assay. Importantly, we further found that Mn12Ac significantly reduced the Wnt1 and β‐catenin protein expressions, and suppressed the phosphorylation of PI3K and AKT in MCF7 and MDA‐MB‐231 breast cancer cells. Very interestingly, we also showed that Mn12Ac decreased the mRNA and protein expressions of programmed cell death ligand 1.ConclusionTaken together, our results suggested that Mn12Ac inhibited the migration, invasion, and epithelial–mesenchymal transition by regulating Wnt/β‐catenin and PI3K/AKT signaling pathways in breast cancer.

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Leptin promotes epithelial-mesenchymal transition of breast cancer via the upregulation of pyruvate kinase M2

Cited by 88 publications

References 42 publications

Circular RNA MAT2B Promotes Glycolysis and Malignancy of Hepatocellular Carcinoma Through the miR‐338‐3p/PKM2 Axis Under Hypoxic Stress

Circular RNA MAT2B Promotes Glycolysis and Malignancy of Hepatocellular Carcinoma Through the miR‐338‐3p/PKM2 Axis Under Hypoxic Stress

Leptin promotes expression of EMT-related transcription factors and invasion in a Src and FAK-dependent pathway in MCF10A mammary epithelial cells

Manganese‐12 acetate suppresses the migration, invasion, and epithelial–mesenchymal transition by inhibiting Wnt/β‐catenin and PI3K/AKT signaling pathways in breast cancer cells

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