-
[show abstract]
[hide abstract]
ABSTRACT: The epithelial-mesenchymal transition (EMT) has been implicated in various patho- physiological processes, including cancer cell migration and distal metastasis. Reactive oxygen species (ROS) and insulin receptor substrate-1 (IRS-1) are important in cancer progression and the regulation of EMT. To explore the biological significance and regulatory mechanism of EMT, we determined the expression, the biological function, and the signaling pathway of prostate transmembrane protein, androgen induced-1 (TMEPAI), during the induction of EMT and cell migration. TGF-β1 significantly upregulated the expression of TMEPAI during EMT in human lung adenocarcinoma. Depletion of TMEPAI abolished TGF-β1-induced downregulation of ferritin heavy chain (FHC) and the subsequent generation of ROS, thus suppressing TGF-β1-induced EMT and cell migration. In addition, increased ROS production and overexpression of TMEPAI downregulated the level of IRS-1. Both the addition of H2O2 and IRS-1 siRNA rescued the ability of TGF-β1 to induce EMT in TMEPAI-depleted cells. Remarkably, the levels of TMEPAI in lung tumor tissues are very high, whereas its expression in normal lung epithelium is very low. Moreover, TMEPAI expression was positively correlated with the cell mesenchymal phenotype and migration potential. Our work reveals that TMEPAI contributes to TGF-β1-induced EMT through ROS production and IRS-1 downregulation in lung cancer cells.
Carcinogenesis 04/2013; · 5.70 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Histone deacetylase (HDAC) inhibitors are candidates of anti-cancer drugs as they can effectively kill cancer cells while have little or no toxicity to non-cancer cells, but the molecular mechanism underlying this process remains unclear. We previously reported that HDAC inhibitors could protect normal mouse hepatocytes from apoptosis induced by transforming growth factor-β1 (TGF-β1) with the requirement of extracellular signal-regulated kinase 1/2 (ERK1/2). In this study, we investigate the roles of trichostatin A (TSA), a typical HDAC inhibitor, on three non-cancer cell lines AML-12, MDCK and 3T3-L1, and four cancer cell lines Hep-3B, HeLa, A549 and MCF-7. TSA is a fermentation product of Streptomyces originally used as an antifungal agent. Our results showed that TSA blocked not only the TGF-β1-induced apoptosis but also serum starvation-induced apoptosis in all the non-cancer cells, whereas it could induce strong apoptosis in all the cancer cells. Further investigation revealed that TSA can induce the activation of ERK1/2 in the three non-cancer cells but not in the cancer cells. In summary, these findings indicated that TSA protect non-cancer cells from apoptosis via activating ERK1/2, providing a useful insight into the better application of HDAC inhibitors in cancer therapy.
Toxicon 03/2011; 57(6):932-7. · 2.51 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Epithelial-mesenchymal transition (EMT) has been implicated in embryonic development, fibrosis, and tumor metastasis. Histone deacetylases (HDACs) also play important roles in the control of various physiological and pathological events. However, whether HDACs are involved in the control of EMT in liver cells remains unidentified. Three structurally unrelated HDAC inhibitors completely suppress transforming growth factor-beta1 (TGF-beta1)-induced EMT in AML-12 murine hepatocytes and primary mouse hepatocytes. Expression of a dominant-negative mutant of HDAC1 but not HDAC2 or downregulation of HDAC1 but not HDAC2 by RNAi suppressed TGF-beta1-induced EMT. In addition, both HDAC inhibitor TSA and HDAC1 RNAi blocked cell migration. Overexpression of HDAC1 in invasive hepatocellular carcinoma (HCC) samples was detected. Further study showed that the mRNA levels of ZO-1 and E-cadherin were downregulated during TGF-beta1-induced EMT, and HDAC1 can downregulate the promoter activities of ZO-1 and E-cadherin. Conclusions: our results demonstrate that HDAC1 is required for TGF-beta1-induced EMT and cell migration in hepatocytes. Its high expression levels in majority of invasive HCC samples suggest that, by promoting EMT, HDAC1 can be related with the invasiveness of HCC. The data also suggest that the repression of transcription of ZO-1 and E-cadherin by HDAC1 may be involved in TGF-beta1-induced EMT.
The international journal of biochemistry & cell biology 09/2010; 42(9):1489-97. · 4.89 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We investigated the regulatory effect of insulin receptor substrate-1 (IRS-1) on transforming growth factor-beta1 (TGF-beta1)-induced epithelial-mesenchymal transition (EMT). TGF-beta1-induced EMT and cell migration in A549 cells are associated with a decrease in IRS-1 tyrosine phosphorylation and protein levels. Tissue microarray analysis of human lung carcinoma shows a correlation between IRS-1 protein levels and E-cadherin protein levels. High IRS-1 levels coexist with high E-cadherin levels, whereas low IRS-1 levels coexist with low E-cadherin levels, implying a possibility that IRS-1 protein levels may be linked with EMT. Surprisingly, overexpression of IRS-1 in A549 cells completely blocked TGF-beta1-induced EMT and cell migration, inhibited TGF-beta1-mediated expression of snail and slug genes, and abolished TGF-beta1-mediated repression of E-cadherin promoter activity. In contrast, IRS-1 knockdown by RNAi increased the expression of snail and slug genes and induced EMT. Inhibition of protein tyrosine phosphatase with sodium vanadate, which greatly increased the levels of tyrosine-phosphorylated IRS-1, suppressed TGF-beta1-induced actin remodeling and cell morphologic changes. These results show for the first time that TGF-beta1 induces EMT through mechanisms involving the modulation of IRS-1 signaling, and that IRS-1 functions as a critical EMT suppressor that suppresses TGF-beta1-induced EMT via inhibition of snail and slug expression.
Cancer Research 10/2009; 69(18):7180-7. · 7.86 Impact Factor
-
Ke-Hua Zhang,
Hong-Yu Tian,
Xia Gao,
Wei-Wei Lei, Ying Hu,
Dong-Mei Wang,
Xin-Chao Pan,
Mei-Lan Yu,
Gen-Jun Xu,
Fu-Kun Zhao,
Jian-Guo Song
[show abstract]
[hide abstract]
ABSTRACT: The epithelial-mesenchymal transition (EMT) plays a critical role in tumor progression. To obtain a broad view of the molecules involved in EMT, we carried out a comparative proteomic analysis of transforming growth factor-beta1 (TGF-beta1)-induced EMT in AML-12 murine hepatocytes. A total of 36 proteins with significant alterations in abundance were identified. Among these proteins, ferritin heavy chain (FHC), a cellular iron storage protein, was characterized as a novel modulator in TGF-beta1-induced EMT. In response to TGF-beta1, there was a dramatic decrease in the FHC levels, which caused iron release from FHC and, therefore, increased the intracellular labile iron pool (LIP). Abolishing the increase in LIP blocked TGF-beta1-induced EMT. In addition, increased LIP levels promoted the production of reactive oxygen species (ROS), which in turn activated p38 mitogen-activated protein kinase. The elimination of ROS inhibited EMT, whereas H2O2 treatment rescued TGF-beta1-induced EMT in cells in which the LIP increase was abrogated. Overexpression of exogenous FHC attenuated the increases in LIP and ROS production, leading to a suppression of EMT. We also showed that TGF-beta1-mediated down-regulation of FHC occurs via 3' untranslated region-dependent repression of the translation of FHC mRNA. Moreover, we found that FHC down-regulation is an event that occurs between the early and highly invasive advanced stages in esophageal adenocarcinoma and that depletion of LIP or ROS suppresses the migration of tumor cells. Our data show that cellular iron homeostasis regulated by FHC plays a critical role in TGF-beta1-induced EMT.
Cancer Research 07/2009; 69(13):5340-8. · 7.86 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: STAT3 (signal transducer and activator of transcription 3) is an important transcription factor involved in many biological events, including apoptosis, tumorigenesis, angiogenesis and epithelial-to-mesenchymal transition. However, no direct evidence for a role of STAT3 in 3T3-L1 adipocyte differentiation has been reported.
In the present study, we found that rapid activation of STAT3, lasting for more than 48 h, was elicited upon induction of adipogenesis. Both the STAT3-selective inhibitor stattic and the JAK2 (Janus kinase 2)/STAT3-selective inhibitors AG490 and Gö6976 inhibited STAT3 activation, leading to the suppression of adipocyte differentiation. Adipocyte differentiation was also suppressed by STAT3 siRNA (small interfering RNA) or dominant-negative STAT3. Interestingly, the PPARgamma (peroxisome-proliferator-activated receptor gamma) agonist TAZ (troglitazone) abolished the STAT3-inhibitor- and RNAi (RNA interference)-mediated suppression of adipogenesis. However, TAZ treatment had no effect on the stattic- and AG490-mediated down-regulation of STAT3 activation, suggesting that STAT3 regulates adipocyte differentiation through signalling that occurs upstream of PPARgamma.
These data indicate that STAT3 functions as a critical factor for adipogenesis via a mechanism involving the PPARgamma activation pathway.
Biology of the Cell 07/2009; 102(1):1-12. · 3.60 Impact Factor
