TGF-β1 stimulates migration of type II endometrial cancer cells by down-regulating PTEN via activation of SMAD and ERK1/2 signaling pathways

Xiong, Siyuan; Cheng, Jung‐Chien; Klausen, Christian; Zhao, Jingjie; Leung, Peter C.K.

doi:10.18632/oncotarget.11311

Cited by 35 publications

(39 citation statements)

References 39 publications

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“… 34 Moreover, a report shows that transforming growth factor β1 (TGF-β1) stimulates migration of type II endometrial cancer cells by downregulating PTEN via activation of SMAD and ERK1/2 signaling pathways. 35 In addition, MeCP2 facilitates gastric cancer cell proliferation through activation of the MEK1/2-ERK1/2 signaling pathway by upregulating GIT1. 36 …”

Section: Discussionmentioning

confidence: 99%

miR372 Promotes Progression of Liver Cancer Cells by Upregulating erbB-2 through Enhancement of YB-1

Lin

Meng

et al. 2018

Molecular Therapy - Nucleic Acids

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MicroRNAs are known to be involved in carcinogenesis. Recently, microRNA-372 (miR372) has been proven to play a substantial role in several human cancers, but its functions in liver cancer remain unclear. Herein, our results demonstrate that miR372 accelerates growth of liver cancer cells in vitro and in vivo. Mechanistically, miR372 enhances expression of Y-box-binding protein 1 (YB-1) by targeting for phosphatase and tensin homolog (PTEN) directly and consequently promotes phosphorylation of YB-1 via HULC looping dependent on ERK1/2 and PTEN. In particular, HULC knockdown or PTEN overexpression abrogated this miR372 action. Moreover, miR372 inhibits the degradation of β-catenin dependent on phosphorylation of YB-1 and then enhances the expression and activity of pyruvate kinase M2 isoform (PKM2) by β-catenin-LEF/TCF4 pathway. Furthermore, the loading of LEF/TCF4 on PKM2 promoter region was significantly increased in miR372 overexpressing Hep3B, and thus, glycolytic proton efflux rate (glycoPER) was significantly increased in rLV-miR372 group compared to the rLV group. Moreover, β-catenin knockdown abrogates this function of miR372. Ultimately, miR372 promotes the expression of erbB-2 through PKM2-pH3T11-acetylation on histone H3 lysine 9 (H3K9Ac) pathway. Of significance, both YB-1 knockdown and erbB-2 knockdown abrogate oncogenic action of miR372. Our observations suggest that miR372 promotes liver cancer cell cycle progress by activating cyclin-dependent kinase 2 (CDK2)-cyclin E-P21/Cip1 complex through miR372-YB-1-β-catenin-LEF/TCF4-PKM2-erbB-2 axis. This study elucidates a novel mechanism for miR372 in liver cancer cells and suggests that miR372 can be used as a novel therapeutic target of liver cancer.

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Section: Discussionmentioning

confidence: 99%

miR372 Promotes Progression of Liver Cancer Cells by Upregulating erbB-2 through Enhancement of YB-1

Lin

Meng

et al. 2018

Molecular Therapy - Nucleic Acids

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“…In type II endometrial cancer patients, increased plasma TGF-β1 expression is associated with advanced-stage disease [ 46 ]. TGF-β1 stimulation promotes a migratory phenotype in endometrial tumor cells while downregulating both PTEN mRNA and protein expression [ 47 ]. Disruption of the canonical TGF-β1→SMAD2/3/4 axis attenuated TGF-β1-mediated PTEN down-regulation as did inhibition of TGF-β1-MEK-ERK1/2 signaling in type II endometrial cancer cells [ 47 ].…”

Section: Reciprocal Relationship Between Pten and Tgf-β Signalingmentioning

confidence: 99%

“…TGF-β1 stimulation promotes a migratory phenotype in endometrial tumor cells while downregulating both PTEN mRNA and protein expression [ 47 ]. Disruption of the canonical TGF-β1→SMAD2/3/4 axis attenuated TGF-β1-mediated PTEN down-regulation as did inhibition of TGF-β1-MEK-ERK1/2 signaling in type II endometrial cancer cells [ 47 ]. Ectopic overexpression of PTEN, moreover, abolishes TGF-β1-induced motility in vitro, suggesting that PTEN is a negative regulator of the TGF-β1-stimulated pro-migration pathway.…”

Section: Reciprocal Relationship Between Pten and Tgf-β Signalingmentioning

confidence: 99%

“…It is increasingly evident that loss or aberrant expression/function of certain TGF-β1 pathway repressors (e.g., PTEN) during cancer progression impact genetic programs driven by unexpected consequences on control of the TGF-β1-SMAD2/3/4 signaling network [ 38 , 47 ]. Prostate-specific PTEN loss, for example, not only activates SMAD2/3 but promotes increased protein accumulation of SMAD2/3 and SMAD4 as well which are critical for establishing prostate cell senescence and fibrotic changes in the tumor microenvironment [ 38 ].…”

Section: Pathological Significance Perspectives and Conclusionmentioning

confidence: 99%

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Deregulation of Negative Controls on TGF-β1 Signaling in Tumor Progression

Tang

Gifford

Samarakoon

et al. 2018

Cancers

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The multi-functional cytokine transforming growth factor-β1 (TGF-β1) has growth inhibitory and anti-inflammatory roles during homeostasis and the early stages of cancer. Aberrant TGF-β activation in the late-stages of tumorigenesis, however, promotes development of aggressive growth characteristics and metastatic spread. Given the critical importance of this growth factor in fibrotic and neoplastic disorders, the TGF-β1 network is subject to extensive, multi-level negative controls that impact receptor function, mothers against decapentaplegic homolog 2/3 (SMAD2/3) activation, intracellular signal bifurcation into canonical and non-canonical pathways and target gene promotor engagement. Such negative regulators include phosphatase and tensin homologue (PTEN), protein phosphatase magnesium 1A (PPM1A), Klotho, bone morphogenic protein 7 (BMP7), SMAD7, Sloan-Kettering Institute proto-oncogene/ Ski related novel gene (Ski/SnoN), and bone morphogenetic protein and activin membrane-bound Inhibitor (BAMBI). The progression of certain cancers is accompanied by loss of expression, overexpression, mislocalization, mutation or deletion of several endogenous repressors of the TGF-β1 cascade, further modulating signal duration/intensity and phenotypic reprogramming. This review addresses how their aberrant regulation contributes to cellular plasticity, tumor progression/metastasis and reversal of cell cycle arrest and discusses the unexplored therapeutic value of restoring the expression and/or function of these factors as a novel approach to cancer treatment.

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“…In parallel, reduced Smad2 phosphorylation combined with less Smad2/3 translocation have been reported in NLRP3-deficient B6lpr mice ( 44 ). Furthermore, reduced Smad2/3 phosphorylation results in decreased binding with Smad4 and impaired translocation of the Smad2/3/4 complex into the nucleus ( 45 , 46 ). The Smad complex has been confirmed as a direct binding site-targeted PTEN genetic promoter, which subsequently regulates PTEN transcription ( 45 , 46 ).…”

Section: Discussionmentioning

confidence: 99%

NLRP3 in human glioma is correlated with increased WHO grade, and regulates cellular proliferation, apoptosis and metastasis via epithelial-mesenchymal transition and the PTEN/AKT signaling pathway

et al. 2018

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Glioma is the most prevalent and fatal primary tumor of the central nervous system in adults, while the development of effective therapeutic strategies in clinical practice remain a challenge. Nucleotide-binding domain leucine-rich family pyrin-containing 3 (NLRP3) has been reported to be associated with tumorigenesis and progression; however, its expression and function in human glioma remain unclear. The present study was designed to explore the biological role and potential mechanism of NLRP3 in human glioma. The results demonstrated that overexpression of NLRP3, apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC), caspase-1 and interleukin (IL)-1β protein in human glioma tissues were significantly correlated with higher World Health Organization grades. The in vitro biological experiments demonstrated that NLRP3 downregulation significantly inhibited the proliferation, migration and invasion, and promoted the apoptosis of SHG44 and A172 glioma cell lines. Furthermore, western blot assays revealed that the downregulation of NLRP3 significantly reduced the expression of ASC, caspase-1 and IL-1β protein. Furthermore, NLRP3 knockdown caused the inhibition of epithelial-mesenchymal transition (EMT), and inhibited the phosphorylation of AKT serine/threonine kinase (AKT) and phosphorylation of phosphatase and tensin homolog (PTEN). Consistently, the upregulation of NLRP3 significantly increased the expression of ASC, caspase-1, IL-1β and phosphorylated-PTEN, promoted proliferation, migration, invasion and EMT, inhibited apoptosis, and activated the AKT signaling pathway. The data of the present study indicate that NLRP3 affects human glioma progression and metastasis through multiple pathways, including EMT and PTEN/AKT signaling pathway regulation, enhanced inflammasome activation, and undefined inflammasome-independent mechanisms. Understanding the biological effects of NLRP3 in human glioma and the underlying mechanisms may offer novel insights for the development of glioma clinical therapeutic strategies.

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TGF-β1 stimulates migration of type II endometrial cancer cells by down-regulating PTEN via activation of SMAD and ERK1/2 signaling pathways

Cited by 35 publications

References 39 publications

miR372 Promotes Progression of Liver Cancer Cells by Upregulating erbB-2 through Enhancement of YB-1

miR372 Promotes Progression of Liver Cancer Cells by Upregulating erbB-2 through Enhancement of YB-1

Deregulation of Negative Controls on TGF-β1 Signaling in Tumor Progression

NLRP3 in human glioma is correlated with increased WHO grade, and regulates cellular proliferation, apoptosis and metastasis via epithelial-mesenchymal transition and the PTEN/AKT signaling pathway

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