Podoplanin-mediated TGF-β-induced epithelial-mesenchymal transition and its correlation with bHLH transcription factor DEC in TE-11 cells

Wu, Yunyan; Liu, Qiang; Xu, Yan; Kato, Yukio; Tanaka, Makiko; Inokuchi, Sadaki; Yoshizawa, Tadashi; Morohashi, Satoko; Kijima, Hiroshi

doi:10.3892/ijo.2016.3445

Cited by 15 publications

(25 citation statements)

References 33 publications

(37 reference statements)

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“…Depending on the cell type, podoplanin expression affects cellular EMT status and invasion activity. In such cells, TGF-β induces EMT/invasion possibly through an increase in podoplanin expression 48 .…”

Section: Discussionmentioning

confidence: 99%

A critical role of platelet TGF-β release in podoplanin-mediated tumour invasion and metastasis

Takemoto

Okitaka

Takagi

et al. 2017

Sci Rep

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The tumour microenvironment is critical for various characteristics of tumour malignancies. Platelets, as part of the tumour microenvironment, are associated with metastasis formation via increasing the rate of tumour embolus formation in microvasculature. However, the mechanisms underlying the ability of tumour cells to acquire invasiveness and extravasate into target organs at the site of embolization remain unclear. In this study, we reported that platelet aggregation-inducing factor podoplanin expressed on tumour cell surfaces were found to not only promote the formation of tumour-platelet aggregates via interaction with platelets, but also induced the epithelial-mesenchymal transition (EMT) of tumour cells by enhancing transforming growth factor-β (TGF-β) release from platelets. In vitro and in vivo analyses revealed that podoplanin-mediated EMT resulted in increased invasiveness and extravasation of tumour cells. Treatment of mice with a TGF-β-neutralizing antibody statistically suppressed podoplanin-mediated distant metastasis in vivo, suggesting that podoplanin promoted haematogenous metastasis in part by releasing TGF-β from platelets that was essential for EMT of tumour cells. Therefore, our findings suggested that blocking the TGF-β signalling pathway might be a promising strategy for suppressing podoplanin-mediated haematogenous metastasis in vivo.

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Section: Discussionmentioning

confidence: 99%

A critical role of platelet TGF-β release in podoplanin-mediated tumour invasion and metastasis

Takemoto

Okitaka

Takagi

et al. 2017

Sci Rep

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“…BHLHE40 was identified as a target of TGF-β regulated Smad transcription in colorectal cancer, although it's expression was independent of the growth inhibitory effects of TGF-β in these cells [24]. Significantly, TGF-β upregulated BHLHE40 but downregulated BHLHE41 [123] in a teratocarcinoma cell line, where it promoted chondrogenic differentiation [12], and in pancreatic cancer PANC-1 cells, where it regulated the subcellular localization of Smad3 phosphorylation and suppressed the expression of snail, claudin-4 and N-cadherin [81]. In these examples, therefore, BHLHE40 was involved in tumor suppression downstream of TGF-β.…”

Section: Bhlhe40 Is a Downstream Effector Of Tgf-β/ Smad In Both Tumomentioning

confidence: 99%

Non-circadian aspects of BHLHE40 cellular function in cancer

2020

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While many genes specifically act as oncogenes or tumor suppressors, others are tumor promoters or suppressors in a context-dependent manner. Here we will review the basic-helix-loop-helix (BHLH) protein BHLHE40, (also known as BHLHB2, STRA13, DEC1, or SHARP2) which is overexpressed in gastric, breast, and brain tumors; and downregulated in colorectal, esophageal, pancreatic and lung cancer. As a transcription factor, BHLHE40 is expressed in the nucleus, where it binds to target gene promoters containing the E-box hexanucleotide sequence, but can also be expressed in the cytoplasm, where it stabilizes cyclin E, preventing cyclin E-mediated DNA replication and cell cycle progression. In different organs BHLHE40 regulates different targets; hence may have different impacts on tumorigenesis. BHLHE40 promotes PI3K/Akt/ mTOR activation in breast cancer, activating tumor progression, but suppresses STAT1 expression in clear cell carcinoma, triggering tumor suppression. Target specificity likely depends on cooperation with other transcription factors. BHLHE40 is activated in lung and esophageal carcinoma by the tumor suppressor p53 inducing senescence and suppressing tumor growth, but is also activated under hypoxic conditions by HIF-1α in gastric cancer and hepatocellular carcinomas, stimulating tumor progression. Thus, BHLHE40 is a multi-functional protein that mediates the promotion or suppression of cancer in a context dependent manner.

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“…Our previous study reported that TGF-β induced the expression of DEC1, while it reduced that of DEC2 in human esophageal squamous cell carcinoma TE-11 cells ( 23 ). In the present study, we firstly examined the expression of DEC1 and DEC2 in PC-3 cells in response to various concentrations of TGF-β by western blotting and RT-PCR.…”

Section: Resultsmentioning

confidence: 97%

Correlation between DEC1/DEC2 and epithelial‑mesenchymal transition in human prostate cancer PC‑3 cells

Liu

Seino

et al. 2018

Mol Med Report

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Differentiated embryonic chondrocyte (DEC) genes have been reported to be involved in the regulation of mammalian circadian rhythms, differentiation, apoptosis, the response to hypoxia and epithelial-mesenchymal transition (EMT). Activation of transforming growth factor (TGF)-β signaling is known to promote EMT for the development of metastatic castration-resistant prostate cancer (PCa). However, the role of DEC genes in the TGF-β-induced EMT of PCa remains unclear. In the present study it was demonstrated that TGF-β increased the transcriptional/translational levels of DEC1 but decreased those of DEC2 in PC-3 cells. Moreover, TGF-β evoked the phosphorylation of Smad2, followed by the activation of mesenchymal markers, such as N-cadherin and vimentin, in addition to the suppression of epithelial markers, such as E-cadherin. The knockdown of DEC1 restrained TGF-β-induced cell morphology changes as well as cell motility, which was compatible with the upregulation of E-cadherin and downregulation of pSmad2, N-cadherin, and vimentin. However, DEC2 knockdown endorsed PC-3 cells with a more metastatic phenotype. EMT-related markers in DEC2 siRNA-transfected cells exhibited a reverse expression pattern when compared with that in DEC1 siRNA-transfected cells. Taken together, these results provide evidence that DEC1 and DEC2 have opposite effects on TGF-β-induced EMT in human prostate cancer PC-3 cells.

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Podoplanin-mediated TGF-β-induced epithelial-mesenchymal transition and its correlation with bHLH transcription factor DEC in TE-11 cells

Cited by 15 publications

References 33 publications

A critical role of platelet TGF-β release in podoplanin-mediated tumour invasion and metastasis

A critical role of platelet TGF-β release in podoplanin-mediated tumour invasion and metastasis

Non-circadian aspects of BHLHE40 cellular function in cancer

Correlation between DEC1/DEC2 and epithelial‑mesenchymal transition in human prostate cancer PC‑3 cells

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