TGF-β signaling and epithelial-mesenchymal transition in cancer progression
Department of Cell and Tissue Biology, Programs in Cell Biology and Developmental and Stem Cell Biology, University of California - San Francisco, San Francisco, California, USA. Current opinion in oncology
(Impact Factor: 4.47).
11/2012; 25(1). DOI: 10.1097/CCO.0b013e32835b6371
Purpose of review:
TGF-β acts as a potent driver of cancer progression through the induction of epithelial-mesenchymal transition (EMT), in which epithelial cells acquire mesenchymal phenotype, leading to enhanced motility and invasion. Recent reports highlight the fundamental roles of TGF-β-induced EMT in multiple aspects of cancer progression. In this review, we focus on the novel insights into the roles of TGF-β-induced EMT in cancer progression and the underlying mechanisms that enable TGF-β to activate this epithelial plasticity response at transcription, translation, and posttranslational levels.
Smad-mediated transcription regulation is known to activate TGF-β-induced EMT. More recently, novel mechanisms of epigenetic control, alternative splicing, miRNAs, translation control, and posttranslational modifications have been shown to play key roles in the control of EMT. In addition to initiating carcinoma cell invasion, TGF-β-induced EMT can guide cancer cells to de-differentiate and gain cancer stem-cell-like properties. EMT also allows the generation of stromal cells that support and instruct cancer progression.
The differentiation plasticity of epithelial cells that mediates TGF-β-induced EMT and reversion from mesenchymal to epithelial phenotype are increasingly seen as integral aspects of cancer progression that contribute to survival and dissemination of cancer cells. Further mechanistic insights under physiological conditions may lead to new therapeutic or prognostic strategies in cancer treatment.
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- "IF: 0.926 put forward . Whereafter, tumor stem cells have been isolated from acute myeloid leukemia, breast cancers and brain tumors (such as astrocytic tumors) . Therefore, this study studied on the heat shock protein (HSP) HSP90 and SIR3, both induced epithelial cell mesenchymal transdifferentiation and enhanced tumor stem cell characteristics, so as to promote the occurrence and development of liver cancer, and provide a theoretical reference value for the subsequent treatment of liver cancer. "
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ABSTRACT: To vexplore expression of HSP90, SIRT3 in liver cancer tissue and its effect on liver cancer cell invasion ability.
Moderate expression of HSP90 in SMMC-7721, HepG2, LO2 and Hep-3B cell lines were screened, which was validated by RT-PCR. Over-expression of HSP90 cell line and lentivirus packaging HSP90-RNAi were established, which was validated by RT-PCR and western blot. The level of epithelial-mesenchymal transition (EMT) related gene was detected by western blot. The percentage of cancer stem cells was assayed by flow cytometry.
RT-PCR demonstrated the highest expression of HSP90 mRNA in SMMC-7721 cells, the lowest expression of HSP90 mRNA in Hep3B and LO2 and the moderate expression of HSP90 mRNA in Hep-G2. Therefore, HepG2 was selected as a follow-up experiment cell lines. Compared with the blank control group, expression of HSP90 in HSP overexpression group was increased obviously, and expression of HSP90 in HSP90 shRNA group was significantly decreased, which indicated successful establishment of HSP overexpression and shRNA group. The apoptotic cell in hsp-siRNA group was higher than the blank control group, while the HSP overexpression group showed opposite results. Western blot results showed transfection HSP promoted cells EMT transformation, up-regulated the level of E-cadherin, and down-regulated the level of Vimentin; meanwhile, shRNA group showed opposite results.
Carcinoma HepG2 cell transfected high expression of HSP can promote the transformation of EMT, improve the expression of Vimentin, reduce the expression of E-cadherin, and inhibit apoptosis of cancer stem cells, which improve the invasive ability of cancer of the liver cells. While hsp-siRNA group presents opposite results. In summary, the expression of HSP is closely related to the occurrence, development and invasion of cancer of the liver tissue.
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Available from: Jenny Parvani
- "The loss of ERα expression or function elicits EMT programs in MECs  , as does activation of the TGF-β signaling system   . As such, we monitored the extent to which Deptor expression is downregulated in NMuMG cells stimulated to undergo EMT programs by TGF-β or by overexpression of either PyMT, Twist, or β3 integrin   . "
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ABSTRACT: Transforming growth factor-β (TGF-β) functions to suppress tumorigenesis in normal mammary tissues and early-stage breast cancers and, paradoxically, acts to promote the metastasis and chemoresistance in late-stage breast cancers, particularly triple-negative breast cancers (TNBCs). Precisely how TGF-β acquires oncogenic characteristics in late-stage breast cancers remains unknown, as does the role of the endogenous mammalian target of rapamycin (mTOR) inhibitor, Dep domain-containing mTOR-interacting protein (Deptor), in coupling TGF-β to TNBC development and metastatic progression. Here we demonstrate that Deptor expression was downregulated in basal-like/TNBCs relative to their luminal counterparts. Additionally, Deptor expression was 1) inversely correlated with the metastatic ability of human (MCF10A) and mouse (4T1) TNBC progression series and 2) robustly repressed by several inducers of epithelial-mesenchymal transition programs. Functional disruption of Deptor expression in 4T07 cells significantly inhibited their proliferation and organoid growth in vitro, as well as prevented their colonization and tumor formation in the lungs of mice. In stark contrast, elevated Deptor expression was significantly associated with poorer overall survival of patients harboring estrogen receptor α-negative breast cancers. Accordingly, enforced Deptor expression in MDA-MB-231 cells dramatically enhanced their 1) organoid growth in vitro, 2) pulmonary outgrowth in mice, and 3) resistance to chemotherapies, an event dependent on the coupling of Deptor to survivin expression. Collectively, our findings highlight the dichotomous functions of Deptor in modulating the proliferation and survival of TNBCs during metastasis; they also implicate Deptor and its stimulation of survivin as essential components of TNBC resistance to chemotherapies and apoptotic stimuli.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
Available from: Payaningal R Somanath
- "Thus, EMT is a pre-requisite for the advanced stage cancer cells to gain the invasive characteristics. Whereas TGFβ1 activity is well known to be associated with EMT  , the mediators of TGFβ1- induced EMT are still to be identified. P21 activated kinases (Paks) are the major downstream effectors of small GTPases Rac and cdc42, which are involved in the actin-based cytoskeletal remodeling  . "
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ABSTRACT: Transforming growth factor beta (TGFβ) is believed to play a dual role in prostate cancer. Molecular mechanism by which TGFβ1 suppresses early prostate tumor growth and induces epithelial-to-mesenchymal transition (EMT) in advanced stages is not known. We determined if P21-activated kinase1 (Pak1), which mediates cytoskeletal remodeling is necessary for the TGFβ1 induced prostate cancer EMT. Effects of TGFβ1 on control prostate cancer PC3 and DU145 cells and those with IPA 3 and siRNA mediated Pak1 inhibition were tested for prostate tumor xenograft in vivo and EMT in vitro. TGFβ1 inhibited PC3 tumor xenograft growth via activation of P38-MAPK and caspase-3, 9. Long-term stimulation with TGFβ1 induced PC3 and DU145 cell scattering and increased expression of EMT markers such as Snail and N-cadherin through tumor necrosis factor receptor-associated factor-6 (TRAF6)-mediated activation of Rac1/Pak1 pathway. Selective inhibition of Pak1 using IPA 3 or knockdown using siRNA both significantly inhibited TGFβ1-induced prostate cancer cell EMT and expression of mesenchymal markers. Our study demonstrated that TGFβ1 induces apoptosis and EMT in prostate cancer cells via activation of P38-MAPK and Rac1/Pak1 respectively. Our results reveal the potential therapeutic benefits of targeting TGFβ1-Pak1 pathway for advanced-stage prostate cancer.
Copyright © 2015. Published by Elsevier B.V.
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