TGFB1

Gene Summary

Gene:TGFB1; transforming growth factor beta 1
Aliases: CED, LAP, DPD1, TGFB, TGFbeta
Location:19q13.2
Summary:This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate a latency-associated peptide (LAP) and a mature peptide, and is found in either a latent form composed of a mature peptide homodimer, a LAP homodimer, and a latent TGF-beta binding protein, or in an active form consisting solely of the mature peptide homodimer. The mature peptide may also form heterodimers with other TGFB family members. This encoded protein regulates cell proliferation, differentiation and growth, and can modulate expression and activation of other growth factors including interferon gamma and tumor necrosis factor alpha. This gene is frequently upregulated in tumor cells, and mutations in this gene result in Camurati-Engelmann disease. [provided by RefSeq, Aug 2016]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:transforming growth factor beta-1
Source:NCBIAccessed: 11 March, 2017

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: TGFB1 (cancer-related)

Ryu SH, Heo SH, Park EY, et al.
Selumetinib Inhibits Melanoma Metastasis to Mouse Liver via Suppression of EMT-targeted Genes.
Anticancer Res. 2017; 37(2):607-614 [PubMed] Related Publications
AIM: We investigated the therapeutic effects of a mitogen-activated protein (MEK) inhibitor, selumetinib, in a hepatic melanoma metastasis model and studied its possible mechanism of action.
MATERIALS AND METHODS: Melanoma cell lines were exposed to selumetinib under different experimental conditions. We established a mouse model of liver metastasis and treated mice orally with vehicle or selumetinib and then evaluated metastasis progress.
RESULTS: Growth inhibition was observed in melanoma cells as a consequence of G1-phase cell-cycle arrest and the subsequent induction of apoptosis in a dose- and time-dependent manner. Mice with established liver metastases that were treated with selumetinib exhibited significantly less tumor progression than vehicle-treated mice. c-Myc expression in metastasized liver tissues were suppressed by selumetinib. Moreover, oral treatment with selumetinib modulated expression of epithelial-to-mesenchymal transition- and metastasis-related genes, including integrin alpha-5 (ITGA5), jagged 1 (JAG1), zinc finger E-box-binding homeobox 1 (ZEB1), NOTCH, and serpin peptidase inhibitor clade E (SERPINE1).
CONCLUSION: We established a mouse model of hepatic metastasis using a human melanoma cell line, such models are essential in elucidating the therapeutic effects of anti-metastatic drugs. Our data suggest the possibility that selumetinib presents a new strategy to treat liver metastasis in patients with melanoma by suppressing epithelial-to-mesenchymal transition-related genes.

Bauer G
Central Signaling Elements of Intercellular Reactive Oxygen/Nitrogen Species-dependent Induction of Apoptosis in Malignant Cells.
Anticancer Res. 2017; 37(2):499-513 [PubMed] Related Publications
Intercellular reactive oxygen/reactive nitrogen species-(ROS/RNS)-dependent induction of apoptosis in malignant cells is discussed as a potential control step during oncogenesis. In previous studies, the mechanism of intercellular apoptosis-inducing signaling was mainly established through the use of specific inhibitors and scavengers. Here, a detailed analysis was carried out based on small interfering ribonucleic acid (siRNA)-mediated knockdown of central players of intercellular ROS/RNS signaling and of the mitochondrial and the FAS receptor-dependent pathway of apoptosis. The data show that transforming growth factor β1, transforming growth factor β receptor, NADPH oxidase-1 (NOX1), NOX1 organizer, and NOX1 activator control the HOCl and the NO/peroxynitrite signaling pathways. Dual oxidase-1 (DUOX1) is specifically involved in HOCl signaling, and NO synthase in NO/peroxynitrite signaling. Both pathways utilize intracellular signal transduction through protein kinase C zeta, sphingomyelinase and central elements of the mitochondrial pathway of apoptosis, whereas the FAS receptor and FAS ligand do not seem to play a role.

Zuo ZK, Gong Y, Chen XH, et al.
TGFβ1-Induced LncRNA UCA1 Upregulation Promotes Gastric Cancer Invasion and Migration.
DNA Cell Biol. 2017; 36(2):159-167 [PubMed] Related Publications
According to recent studies, long noncoding RNA urothelial carcinoma associated 1 (UCA1) is involved in the development and progression of many malignant tumors, including gastric cancer (GC). We validated the detailed role of UCA1 in human GC cell lines and GC tissues so as to determine its exact function and the underlying mechanism of GC invasion and migration. In our research, lncRNA-UCA1 was specifically upregulated in GC tissues and cell lines, and augmented GC cell proliferation, and invasive and migratory capabilities. High UCA1 expression in GC was related with poorer prognosis (poorer invasion depth, lymph node metastasis, advanced TNM [T is for the original (primary) tumor, N for nearby (regional) lymph nodes that are involved, and M for distant metastasis] stage, and shorter overall survival). Epithelial mesenchymal transition (EMT), associated with malignancy of cancers, was reported to be responsible for invasion and migration of cancer cells. Transforming growth factor β1 (TGFβ1)-induced EMT was well evaluated. UCA1 silence reduced the protein levels of EMT-related factors, vimentin and snail, while promoted E-cadherin and zonula occludens-1 protein levels in GC cells; the effect of UCA1 could be partly restored by TGFβ1 treatment. Taken together, UCA1 might regulate the tumor proliferation, invasion, and metastasis under TGFβ1 induction. Taken together, UCA1 might present a potential oncogenic factor by promoting GC cell proliferation, invasion, and migration. UCA1 could serve as a novel biomarker for prognosis and a novel therapeutic target of GC treatment.

Wang SH, Zhang MD, Wu XC, et al.
Overexpression of LncRNA-ROR predicts a poor outcome in gallbladder cancer patients and promotes the tumor cells proliferation, migration, and invasion.
Tumour Biol. 2016; 37(9):12867-12875 [PubMed] Related Publications
LncRNA-ROR has been reported to be involved in many kinds of human cancers. However, whether LncRNA-ROR is involved in gallbladder cancer progression remains largely unknown. The objective of this study is to investigate the role of LncRNA-ROR in gallbladder cancer. We found that LncRNA-ROR expression level was upregulated in gallbladder cancer tissues (P < 0.05) and was significantly associated with tumor sizes (P < 0.05) and lymph node metastasis (P < 0.05). High expression of LncRNA-ROR was significantly associated with poor prognosis in gallbladder cancer patients (P < 0.05). Moreover, knockdown of LncRNA-ROR inhibited cell proliferation, migration, and invasion. The epithelial-mesenchymal transition (EMT) phenotype induced by TGF-β1 was reversed after LncRNA-ROR knocking down in SGC-996 and Noz cells. LncRNA-ROR plays an important role in the development of gallbladder cancer and mediates the EMT in gallbladder cancer. LncRNA-ROR might act as a marker of prognosis and therapeutic target for gallbladder cancer.

Xu L, Yan Y, Xue X, et al.
Angiogenin elevates the invasive potential of squamous cell lung carcinoma cells through epithelial‑mesenchymal transition.
Oncol Rep. 2016; 36(5):2836-2842 [PubMed] Related Publications
Squamous cell carcinoma of the lung is one of the most aggressive cancers, and its aggressiveness is in part due to its intrinsic high rate of metastasis. Moreover, the process of epithelial-mesenchymal transition (EMT) appears to be involved in these neoplastic processes. Furthermore, EMT-type cells share many biological characteristics with the function of angiogenin (ANG) in squamous cell lung carcinoma. We conducted immunohistochemical analysis to detect the expression of ANG, E-cadherin, vimentin, N-cadherin, β-catenin and TGF-β1 in 60 cases of squamous cell lung carcinoma tissues. Western blot analysis was adopted to detect the protein expression levels of ANG and EMT markers. The effects of ANG on proliferation, migration and invasion of squamous cell lung carcinoma cells was analyzed by Cell Counting Kit-8, scratch assay and Transwell invasion chamber in order to reveal the role of ANG in the process of EMT in squamous cell lung carcinoma. The results revealed that ANG was aberrantly expressed in the squamous cell lung carcinoma specimens and was closely correlated with the differentiation of the cell lines. The expression of ANG was also significantly associated with metastasis and the stage of the squamous cell lung carcinoma cases. In addition, we validated that ANG influenced the expression of vimentin, E-cadherin, N-cadherin, β-catenin and TGF-β1 in SK-MES-1 cells. Most importantly, overexpression of ANG enhanced the migration and invasion of SK-MES-1 cells, while knockdown resulted in opposite effects. In the present study, we found that ANG plays an important role in EMT in squamous cell lung carcinoma and may be a valuable therapeutic target for squamous cell lung carcinoma.

Ezzoukhry Z, Henriet E, Piquet L, et al.
TGF-β1 promotes linear invadosome formation in hepatocellular carcinoma cells, through DDR1 up-regulation and collagen I cross-linking.
Eur J Cell Biol. 2016; 95(11):503-512 [PubMed] Related Publications
Transforming growth factor-β1 (TGF-β1) is an important player in chronic liver diseases inducing fibrogenesis and hepatocellular carcinoma (HCC) development. TGF-β1 promotes pleiotropic modifications at the cellular and matrix microenvironment levels. TGF-β1 was described to enhance production of type I collagen and its associated cross-linking enzyme, the lysyl oxidase-like2 (LOXL2). In addition, TGF-β1 and type I collagen are potent inducers of invadosomes. Indeed, type I collagen fibers induce the formation of active linear invadosomes through the discoidin domain receptor 1 (DDR1). The goal of our study was to address the role of TGF-β1 in collagen cross-linking and its impact on the formation of linear invadosomes in liver cancer cells. We first report a significant correlation between expressions of TGF-β1, and type I collagen, LOXL2, DDR1 and MT1-MMP in human HCCs. We demonstrate that TGF-β1 promotes a Smad4-dependent up-regulation of DDR1, together with LOXL2, in cultured HCC cells. Moreover, we show that LOXL2-induced collagen cross-linking enhances linear invadosome formation. Altogether, our data demonstrate that TGF-β1 favors linear invadosome formation through the expressions of both the inducers, such as collagen and LOXL2, and the components such as DDR1 and MT1-MMP of linear invadosomes in cancer cells. Meanwhile, our data uncover a new TGF-β1-dependent regulation of DDR1 expression.

Yang Q, Cao X, Tao G, et al.
Effects of FOXJ2 on TGF-β1-induced epithelial-mesenchymal transition through Notch signaling pathway in non-small lung cancer.
Cell Biol Int. 2017; 41(1):79-83 [PubMed] Related Publications
As one member of Forkhead box transcription factors, Forkhead box J2 (FOXJ2) has been found to be involved in epithelial-mesenchymal transition (EMT) process. However, the role and mechanism of FOXJ2 in non-small cell lung cancer (NSCLC) and EMT regulation have not been fully revealed. In this paper, it was revealed that the expression of FOXJ2 was lower in NSCLC samples compared with matched peritumoral lung tissue. We demonstrated that FOXJ2 expression was down-regulated by transforming growth factor-β1 (TGF-β1) treated, and overexpression of FOXJ2 inhibited TGF-β1-induced EMT. Mechanistically, knocking out the expression of FOXJ2 promoted EMT by increasing the expression of Notch1 and NICD. This study implicates the potential value of FOXJ2 as a molecular marker for NSCLC.

Kondratyeva LG, Sveshnikova AA, Grankina EV, et al.
Downregulation of expression of mater genes SOX9, FOXA2, and GATA4 in pancreatic cancer cells stimulated with TGFβ1 epithelial-mesenchymal transition.
Dokl Biochem Biophys. 2016; 469(1):257-9 [PubMed] Related Publications
We show characteristic morphological changes corresponding to epithelial-mesenchymal transition (EMT) program fulfillment in PANC1 cell line stimulated with TGFβ1. Our results support downregulation of E-cadherin protein. We show 5- and 28-fold increase in SNAI1 and SNAI2 expression levels and 25- and 15-fold decrease in CDH1 and KRT8 expression levels, respectively, which confirms the EMT-program fulfillment. We demonstrate downregulation of expression of pancreatic master genes SOX9, FOXA2, and GATA4 (2-, 5-, and 4-fold, respectively) and absence of significant changes in HES1, NR5A2, and GATA6 expression levels in the cells stimulated with TGFβ1. Our results indicate the absence of induction of expression of PTF1A, PDX1, HNF1b, NEUROG3, RPBJL, NKX6.1, and ONECUT1 genes, which are inactive in PANC1 cell line after the EMT stimulated by TGFβ1.

Yin H, Wang Y, Chen W, et al.
Drug-resistant CXCR4-positive cells have the molecular characteristics of EMT in NSCLC.
Gene. 2016; 594(1):23-29 [PubMed] Related Publications
High expression of Chemokine receptor 4 (CXCR4) is important in tumor invasion, metastasis, drug-resistance and maintenance of stemness in non-small cell lung cancer (NSCLC). We therefore studied the molecular characteristics of drug-resistant CXCR4-positive cells on epithelial-mesenchymal transition (EMT) for the future identification of the tumor cells with the properties of both EMT and stemness. EMT RT(2) Profier PCR Array was performed to determine the expression levels of mRNA genes in A549 with TGF-β1 induced EMT (A549/TGF-β1) and gefitinib-resistant CXCR4-positive cells (A549/GR). TCGA database on the cBio Cancer Genomics Portal website and Gene Network Central (GNC) Pro Tutorial were used to analyze their clinical relevance and pathway interactions. CXCR4 was up-regulated both in TGF-β induced EMT cells and in gefitinib-resistant cells. In 84 mRNA genes related to EMT, 17 mRNA genes were up-regulated in CXCR4-positive population of A549/GR when compared to those in CXCR4 negative fraction, while 66 mRNA genes were up-regulated during TGF-β induced EMT. ITGA5, BMP7, MMP3, VIM, RGS2, ZEB2, TCF3, SNAI2, VCAN, PLEK2, WNT5A, COL3A1, SPARC and FOXC2 were doubly up-regulated during the two biological processes. Kaplan-Meier analysis indicated that the doubly up-regulated ITGA5, RGS2, SNAI2 and PLEK2 mRNA genes were related to poor overall survival in lung adenocarcinoma patients (P=9.291e-6, 0.0090, 3.81e-7 and 0.0013, respectively). In GNC analysis, SNAI2 mRNA gene but not ITGA5, RGS2 and PLEK2 was dependent on the signaling pathway of CXCR4. The molecular characteristics of drug-resistant CXCR4-positive cells have a crosstalk with EMT, which has the potential to find the marker with prognostic value on multiple signaling pathways in NSCLC.

Zhuang X, Qiao T, Xu G, et al.
Combination of nadroparin with radiotherapy results in powerful synergistic antitumor effects in lung adenocarcinoma A549 cells.
Oncol Rep. 2016; 36(4):2200-6 [PubMed] Related Publications
Low-molecular-weight heparins (LMWHs), which are commonly used in venous thromboprophylaxis and treatment, have recently been reported to have effects on cancer metastasis in pre-clinical research studies. This study was planned to define the synergistic antitumor effects of nadroparin (a kind of LMWH) combined with radiotherapy in A549 cells. Six experimental groups were set up in our study according to the different treatment: control group; irradiation (IR) group; low dose of nadroparin group (LMWH50, L50); high dose of nadroparin group (LMWH100, L100); LMWH50+IR group; LMWH100+IR group. The viability of A549 cells was assessed by Cell Counting Kit-8 (CCK-8) assay. The apoptosis of tumor cells was analyzed by flow cytometry (FCM) after treatment. The concentration of transforming growth factor-β1 (TGF-β1) in the culture supernatants was measured by enzyme-linked immunosorbent assay (ELISA). The migration and invasion of the A549 cells were tested by the Transwell chamber assay. The expression of survivin, CD147 and matrix metalloproteinase-2 (MMP-2) was analyzed by western blotting. CCK-8 assay showed that irradiation or nadroparin alone slightly inhibited the cell viability while the combined treatments significantly inhibited the cell viability in a dose- and time-dependent manner. The apoptosis rate showed greater improvement dose- and time‑dependently in the groups receiving combination therapy of nadroparin and irradiation than the control group or the group receiving nadroparin or irradiation alone by FCM. ELISA assay showed that the decreased TGF-β1 secretion was found after combined treatments with nadroparin and irradiation compared to either treatment alone. The Transwell chamber assay showed that nadroparin not only significantly suppressed the migration and invasion of A549 cells but also inhibited the enhanced ability of migration and invasion induced by X-ray irradiation. Western blotting showed that nadroparin inhibited the upregulated effects of survivin and MMP-2 expression induced by radiation in the combined treatment groups in a dose- and time-dependent manner. Moreover, the expression level of CD147 was the lowest in the combined treatment groups. This study identified that combination of nadroparin and irradiation had a strong synergistic antitumor effect in a dose- and time-related manner in vitro, which was reflected in the inhibition of cell viability, invasion and metastasis, promotion of apoptosis, inhibited secretion level of TGF-β1 and downregulation of CD147, MMP-2 and survivin expression.

Li Y, Tian X, Sui CG, et al.
Interference of lysine-specific demethylase 1 inhibits cellular invasion and proliferation in vivo in gastric cancer MKN-28 cells.
Biomed Pharmacother. 2016; 82:498-508 [PubMed] Related Publications
BACKGROUND: Lysine-specific demethylase 1(LSD1), the first identified histone demethylase, plays an important role in the epigenetic regulation of gene activation and repression. Up-regulated LSD1expression has been reported in several malignant tumors.Our aim, therefore, was to better understand the mechanisms underlying the upregulation of LSD1 in gastric cancer.
METHODS: We used lentiviral shRNA to knockdown LSD1 in the gastric cancer MKN-28 cell line. Cell proliferation was measured by MTT assay while cell apoptosis was assessed by Annexin V-FITC/PI double staining flow cytometry. The invasive potential of gastric cancer cells was determined by matrigel invasion assay. Protein expression was detected by Western blot. In vivo, the effect of knocking down LSD1 on tumor growth and protein expression in gastric cancer cells in nude mice was investigated.
RESULTS: LSD1 knockdown in MKN-28 cell lines resulted in increasing the activity of cisplatin in vitro and the inhibition of cancer cell proliferation and invasion, and induced cell apoptosis. The expression of TGF-β1, VEGF, Bcl-2, β-catenin, p-ERK and p-Smad 2/3 proteins was inhibited in LSD1 knockdown cells. Moreover, in an in vivo model of gastric cancer, LSD1 knockdown suppressed tumor growth and protein expression.
CONCLUSION: LSD1 knockdown affected the fuction of gastric cancer MKN-28 cell line. LSD1 may be a latent target in the diagnosis and therapy of gastric cancer.

Ilhan N, Gungor H, Gul HF, Eroksuz H
Expression of Endoglin and Vascular Endothelial Growth Factor as Prognostic Markers in Experimental Colorectal Cancer.
Anticancer Res. 2016; 36(8):3953-9 [PubMed] Related Publications
BACKGROUND/AIM: Endoglin (CD105) is a receptor for the transforming growth factor-beta 1 (TGFβ1) with crucial role in vascular development and angiogenesis. Additionally, vascular endothelial growth factor (VEGF) overexpression has been associated with advanced stage and poor survival for several cancer types. These molecules have been shown to be useful markers for identifying proliferating endothelium involved in tumor angiogenesis, especially in patients with cancer at risk of developing metastases. The aim of this study was to evaluate the relationship between VEGF and endoglin expression in an experimental model of colorectal cancer, as well as to investigate the effect of cyclooxygenase-2 (COX2) inhibitors on tumor development incidence.
MATERIALS AND METHODS: Colon cancer was induced with 1,2-dimethylhydrazine dihydrochloride (DMH). Celecoxib and diclofenac treatment was started simultaneously with DMH induction. Endoglin protein expression was performed using western blot analysis. VEGF plasma concentrations were measured by enzyme-linked immunosorbent assay.
RESULTS: In histopathological evaluations, no pathological change was observed in control rats, while adenocarcinoma (62.5%), dysplasia (31.25%) and inflammation (6.25%) were detected in the group given DMH. In treatment groups, a marked decrease was observed in adenocarcinoma rate. Expression of endoglin protein was significantly elevated in the DMH group compared to controls (p<0.001). No statistically significant difference was noted between treatment groups and DMH group regarding endoglin expression but a decrease was detected in the celecoxib-treated groups.
CONCLUSION: It was confirmed by histopathology and western blotting that COX2 inhibitors, particularly celecoxib, decrease the rate of disease and slow-down progression of existing CRC. These data show that endoglin expression may have an important role in tumor angiogenesis and predict of tumor invasion.

Huang C, Wen B
Phenotype transformation of immortalized NCM460 colon epithelial cell line by TGF-β1 is associated with chromosome instability.
Mol Biol Rep. 2016; 43(10):1069-78 [PubMed] Related Publications
Transforming growth factor-β1 (TGF-β1) within tumor microenvironment has a pivotal function in cancer initiation and tumorigenesis, and hence this study was to observe the malignant transformation induced by TGF-β1 in an immortalized colon epithelial cell line NCM460 for better understanding the mechanisms of colon carcinogenesis. Immortalized colon epithelial cell line NCM460 was used as the model of this study, and was treated with different concentrations of TGF-β1 for different time. Then, immunofluorescence was performed to observe the change of phenotype hallmarks including adherent junction protein E-cadherin, cytoskeleton protein vimentin, and tight junction marker ZO-1, western blotting analysis was performed to detect the expression of the above three markers and two transcription factors (Snail and Slug) involved in the transformation by TGF-β1. In addition, chromosome instability (CHI) including analysis of DNA-ploid was detected by flow cytometry. Our results revealed significant loss or reduction of ZO-1 and E-cadherin, and robust emergence of vimentin in the cell line NCM460 after a 15-, 20-, and 25-day treatment with 10 ng/ml TGF-β1. Interestingly, 20 and 25 days after stimulation with 5 ng/ml TGF-β1, expression of E-cadherin and ZO-1 revealed a pattern roughly similar to that of 10 ng/ml TGF-β1, especially, both expressions was vanished and vimentin expression was dramatically increased at days 25 after TGF-β1 stimulation. After a stimulation with 10 ng/ml TGF-β1 for 15, 20, and 25 days, the levels of Snail and Slug expression in the cells were significantly up-regulated, compared with the cells treated with TGF-β1 inhibitor LY364947, PBS or balnk control (P < 0.01). Our results found that many abnormal mitotic patterns including lagging chromosomes and anaphase bridges in NCM460 cells were induced by TGF-β1 after its stimulation for 15, 20, and 25 days. Very few mitotic cells with treatment of PBS for 15, 20 and 25 days were non-diploid whose DNA content was greater or less than 4 N, but these cells were significantly increased after exposure to TGF-β1 for 15, 20, and 25 days, which was associated with the induction of hypo-diploid, hyper-diploid, and poly-diploid (P < 0.05).These data indicate that TGF-β1 induces a phenotypic transformation of normal colon epithelium similar to its pro-tumoral behaviors in TME, involving in alteration of chromosome stability.

Zhang L, Yan L, Cao M, et al.
SPAG9 promotes endometrial carcinoma cell invasion through regulation of genes related to the epithelial-mesenchymal transition.
Eur J Gynaecol Oncol. 2016; 37(3):312-9 [PubMed] Related Publications
OBJECTIVE: To investigate the impact of sperm-associated antigen 9 (SPAG9) on proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) in endometrial cancer.
MATERIALS AND METHODS: The present authors' previous study demonstrated that SPAG9 is highly expressed in endometrial cancer tissues. They analyzed correlation between the levels of SPAG9 and mRNA of EMT-related genes in endometrial carcinoma tissue by using quantitative real-time PCR. They induced EMT process in ECC endometrial cancer cell lines by TGF-beta1 treatment and spheroids formation assay, and analyzed SPAG9 expression as well as correlation with EMT-related genes. In addition, they performed SPAG9 gene silencing in KLE and ECC endometrial cancer cells and evaluated the expression of genes involved in EMT, using real time PCR and Western blot analysis. Cell proliferation, colony formation, and transwell assays were employed to evaluate the functional role of SPAG9 in endometrial cancer.
RESULTS: The results showed that SPAG9 expression was positively correlated with Slug and N-cadherin (NcaD) in human endometrial cancer tissues. The expression of SPAG9 in ECC cells with TGF-β1 treatment and spheroids formation was increased, which was correlated with EMT-related genes. SPAG9 knockdown significantly inhibited cell growth and proliferation and reduced the motility and invasion of endometrial cancer cells. These phenotypes may partly be explained by decreased expression of EMT-related genes, including Twist, Slug, and Vimentin, after SPAG9 depletion.
CONCLUSIONS: SPAG9 may be required for cellular invasion and migration in endometrial cancer through regulation of EMT-related genes.

Zhang N, Bi X, Zeng Y, et al.
TGF-β1 promotes the migration and invasion of bladder carcinoma cells by increasing fascin1 expression.
Oncol Rep. 2016; 36(2):977-83 [PubMed] Related Publications
Transforming growth factor-β1 (TGF-β1) is a multifunctional cytokine that is reported to regulate cellular motility and invasive capability during tumor progression. Fascin1, an actin-bundling protein, increases cell motility, migration and adhesion. To investigate the function of TGF-β1 and test whether fascin1 is an important mediator of the tumor response to TGF-β1 in bladder carcinoma cells, real-time RT-PCR and western blot analysis were used to test changes in fascin1 expression after TGF-β1 (10 ng/ml) treatment in T24 and BIU87 cells. Small interfering RNA (siRNA) technique was performed to silence fascin1. Cell viability and biological behavior changes were evaluated by cell growth (MTT), wound-healing and Matrigel invasion assays. In the present study, we found that the mRNA and protein levels of fascin1 in the T24 and BIU87 cells were significantly increased after 10 ng/ml TGF-β1 treatment (p<0.05). The proliferation of T24 cells (p=0.005) was also significantly increased, while no significant change was observed in BIU87 cells (p=0.318). In addition, the migratory and invasive potential of the two cell lines were promoted. Furthermore, we successfully silenced fascin1, and observed that fascin1 siRNA significantly attenuated the migration and invasiveness induced by TGF-β1. The findings suggested that TGF-β1 can promote invasion and migration of T24 and BIU87 bladder carcinoma cells, and the increase in fascin1 expression may be the key point of this impact of TGF-β1.

Fan Z, Jiang H, Wang Z, Qu J
Atorvastatin partially inhibits the epithelial-mesenchymal transition in A549 cells induced by TGF-β1 by attenuating the upregulation of SphK1.
Oncol Rep. 2016; 36(2):1016-22 [PubMed] Related Publications
Statins are the most effective drugs used in the reduction of intracellular synthesis of cholesterol. Numerous studies have confirmed that statins reduce the risk of multiple types of cancers. Statin use in cancer patients is associated with reduced cancer-related mortality. Epithelial-to-mesenchymal transition (EMT), a complicated process programmed by multiple genes, is an important mechanism of cancer metastasis. We explored the effect and mechanism of atorvastatin on the EMT process in A549 cells by establishing an EMT model in vitro induced by TGF-β1, and evaluated the effects of atorvastatin on the lower signaling pathway of TGF-β1 stimulation. Our results showed that atorvastatin partially inhibited the EMT process, and inhibited cell migration and actin filament remodeling. Transcriptional upregulation of ZEB1 and protein sphingosine kinase 1 (SphK1) induced by TGF-β1 was also suppressed. SphK1 plasmid transient transfection strengthened the EMT process induced by TGF-β1 in the presence of atorvastatin. Our experiments confirmed that atorvastatin can partially inhibit the EMT process of non-small cell lung cancer cells induced by TGF-β1 by attenuating the upregulation of SphK1.

Wu J, Liu B, Wu H, et al.
A Gold Nanoparticle Platform for the Delivery of Functional TGF-β1 siRNA Into Cancer Cells.
J Biomed Nanotechnol. 2016; 12(4):800-10 [PubMed] Related Publications
Nanoparticles, especially gold nanoparticles (AuNPs), have been shown to be an efficient carrier to deliver small RNAs into cancer cells. In this study, we used cysteamine-functionalized AuNPs to effectively deliver TGF-β1 siRNA into hepatoma HepG2 cells in vitro and in vivo. We found that, compared with AuNPs-mediated NC siRNA (AuNP-siNC), AuNPs-delivered TGF-β1 siRNA (AuNP-siTGFβ1) efficiently decreased the level of TGF-β1, increased cell apoptosis, and significantly inhibited the proliferation of recipient tumour cells. Systemic administration of the AuNP-siTGFβ1 complexes into human HepG2 xenografted mice likewise reduced TGF-β1 expression and downstream TGF-β1 signalling. Functionally, AuNP-siTGFβ1 strongly inhibited tumour growth and improved the survival rate of tumour-bearing mice compared with the control groups. In conclusion, our results demonstrate that the siRNA delivery system with AuNP described here appears to be a highly effective method to deliver RNAi therapeutics into tumour cells for oncotherapy.

Teama S, Fawzy A, Teama S, et al.
Increased Serum Endoglin and Transforming Growth Factor β1 mRNA Expression and Risk of Hepatocellular Carcinoma in Cirrhotic Egyptian Patients.
Asian Pac J Cancer Prev. 2016; 17(5):2429-34 [PubMed] Related Publications
Transforming growth factor-B1 (TGF-β1 )and its coreceptor endoglin (ENG) have been shown to contribute to hepatocellular tumor development and malignant progression. Our aim was to evaluate the serum expression levels of ENG/ TGF-β1 mRNAs and risk of hepatocellular carcinoma in cirrhotic Egyptian patients. Our study included 77 subjects. Real time polymerase chain reaction was used to evaluate the expression level of ENG and TGF-β1mRNAs. The relative expression ratio of ENG mRNA was 0.82 (0.1 -3.2), 0.66 (0.15-5.3), 0.38(0.007-2.8) and 0.12 (0.00-0.22) and the relative expression ratio of TGF-β1mRNA was 1.4 (0.19 -6.2), 1.2 (0.22-4.3), 1.0 (0.15-4.4) and 0.6 (0.00-2.2) for cirrhotic HCC cirrhotic, HCC only and healthy control groups respectively. Increased ENG and TGF-β1 mRNA gene expression was correlated with TNM clinical stage. The expression ratio in TNM stage III-IV 1.1 (0.07-3.2), 1.55 (0.15-6.2) was statistically significantly higher than that in stage I-II 0.47 (0.007-2.8), 1.0 (0.31-4.4) (<0.05). Our data suggested that increased ENG and TGF-β1 gene expression may participate in hepatocarcinogenesis and increased risk of HCC in individuals with cirrhosis. Early screening for evidence of cirrhosis and consideration of ENG and TGF-β1 as targets for therapy and treatment strategies are warranted.

Choi YJ, Kim N, Jang W, et al.
Familial Clustering of Gastric Cancer: A Retrospective Study Based on the Number of First-Degree Relatives.
Medicine (Baltimore). 2016; 95(20):e3606 [PubMed] Free Access to Full Article Related Publications
This comprehensive cross-sectional study aimed to identify factors contributing to familial aggregation of gastric cancer (GC). A total of 1058 GC patients and 1268 controls were analyzed separately according to the presence or absence of a first-degree relative of GC (GC-relative). Logistic regression analysis adjusted for age, gender, residence during childhood, smoking, alcohol intake, monthly income, spicy food ingestion, Helicobacter pylori status and host cytokine polymorphisms was performed. Cytotoxin-associated gene A (cagA) positivity was a distinctive risk factor for GC in the family history (FH)-positive group (odds ratio [OR], 2.39; 95% confidence interval [CI], 1.42-4.00), while current/ex-smoker, moderate to strong spicy food ingestion, and non-B blood types were more closely associated with GC in the FH-negative group. Among the FH-positive group, alcohol consumption showed a synergistic carcinogenic effect in the at least 2 GC-relatives group compared to the 1 GC-relative group (1.71 vs. 9.58, P for interaction = 0.026), and this was dose-dependent. In the subjects with ≥2 GC-relatives, TGFB1-509T/T was a risk factor for GC (OR 23.74; 95% CI 1.37-410.91), as were rural residency in childhood, alcohol consumption, spicy food ingestion, and cagA positivity. These results suggest that subjects with FH may be a heterogeneous group in terms of gastric cancer susceptibility. Especially, subjects with ≥2 GC-relatives should undergo risk stratification including TGFB1-509T/T and alcohol consumption.

Zhang GY, Liu AH, Li GM, Wang JR
HPIP Silencing Prevents Epithelial-Mesenchymal Transition Induced by TGF-β1 in Human Ovarian Cancer Cells.
Oncol Res. 2016; 24(1):33-9 [PubMed] Related Publications
Hematopoietic pre-B-cell leukemia transcription factor (PBX)-interacting protein (HPIP/PBXIP1) is a nucleo-cytoplasmic shuttling protein, and its expression is associated with cancer aggressiveness. However, the role of HPIP in ovarian cancer is still unclear. Here, we aimed to clarify the role of HPIP in epithelial-mesenchymal transition (EMT) process of ovarian cancer cells, stimulated by transforming growth factor (TGF)-β1. In this study, we found that HPIP was highly expressed in ovarian cancer cells, and TGF-β1 treatment induced HPIP expression in ovarian cancer cells. In addition, knockdown of HPIP suppressed TGF-β1-induced EMT and migration/invasion in ovarian cancer cells. Moreover, knockdown of HPIP significantly blocked the phosphorylated pattern of both PI3K and Akt induced by TGF-β1 in SKOV3 cells. In conclusion, the present study showed that HPIP silencing might prevent TGF-β1-induced EMT in ovarian cancer cells. Thus, HPIP may be a potential therapeutic target for the treatment of ovarian cancer.

Zong W, Yu C, Wang P, Dong L
Overexpression of SASH1 Inhibits TGF-β1-Induced EMT in Gastric Cancer Cells.
Oncol Res. 2016; 24(1):17-23 [PubMed] Related Publications
The epithelial-mesenchymal transition (EMT) is considered to be one of the critical steps in gastric cancer cell invasion and metastasis. SAM- and SH3-domain containing 1 (SASH1), a member of the SLY family of signal adapter proteins, is a candidate for tumor suppression in several cancers. However, the biological role of SASH1 in gastric cancer remains largely unknown. Therefore, the purpose of this study was to investigate the impact of SASH1 on the biological behavior of gastric cancer cells treated with transforming growth factor (TGF)-β1. In the current study, we provide evidence that SASH1 was lowly expressed in human gastric cancer cells, and TGF-β1 also inhibited the expression of SASH1 in TSGH cells. We found that SASH1 inhibited TGF-β1-mediated EMT in TSGH cells, as well as cell migration and invasion. Furthermore, SASH1 obviously inhibited the phosphorylation of PI3K and Akt in TGF-β1-stimulated TSGH cells. In summary, our study is the first to show that overexpression of SASH1 inhibits TGF-β1-induced EMT in gastric cancer cells through the PI3K/Akt signaling pathway. These results suggest that SASH1 may be a potential therapeutic target for the treatment of gastric cancer.

Li J, Yu Q, Fu S, et al.
A novel genetic score model of UGT1A1 and TGFB pathway as predictor of severe irinotecan-related diarrhea in metastatic colorectal cancer patients.
J Cancer Res Clin Oncol. 2016; 142(7):1621-8 [PubMed] Related Publications
PURPOSE: UGT1A1*28/*6 as predictors of severe irinotecan-related diarrhea (SIRD) were duplicated by many studies. However, some patients of lower risk genotype (UGT1A1*1/*1) still suffered SIRD and the extremely low frequency of UGT1A1*6/*6 limited its clinical usage. Previous studies proved that the transforming growth factor (TGFB) family may have some effect on MTX-induced mucositis. However, the associations between TGFB gene variants and SIRD have never been reported so far. Our aim was to improve the predictive value of UGT1A1 gene variants on SIRD.
METHODS: Six SNPs (TGFB1 rs1800469; TGFBR1 rs10733710, rs334354 and rs6478974; TGFBR2 rs3087465; UGT1A1*6) and UGT1A1*28 were selected for genotyping in 160 metastatic colorectal cancer patients treated with irinotecan in a prospective multicenter trial (NCT01282658).
RESULTS: UGT1A1*6, UGT1A1*28, rs1800469 and rs3087465 were all associated with SIRD (p = 0.026, 0.014, 0.047 and 0.045 respectively). A novel genetic score model (with a cut off value of 1.5) based on them was created to predict SIRD (OR = 11.718; 95 % CI 2.489-55.157, p = 0.002). In patients of gene score > 1.5, the risk of SIRD was much higher (23.5 vs. 2.8 %, p = 2.24E-04) and continued in the first 6 cycles of chemotherapy, while in patients with gene score ≤1.5, the risk was much lower and none of them suffered SIRD after the first cycle of chemotherapy (p = 0.0003).
CONCLUSIONS: The novel genetic score model improved the predictive value of UGT1A1 on SIRD. If validated, it will provide valuable information for clinical use of irinotecan.

Ye Z, Li J, Han X, et al.
TET3 inhibits TGF-β1-induced epithelial-mesenchymal transition by demethylating miR-30d precursor gene in ovarian cancer cells.
J Exp Clin Cancer Res. 2016; 35:72 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Abnormal DNA methylation/demethylation is recognized as a hallmark of cancer. TET (ten-eleven translocation) family members are novel DNA demethylation related proteins that dysregulate in multiple malignances. However, their effects on ovarian cancer remain to be elucidated.
METHODS: The changes of TET family members during TGF-β1-induced epithelial-mesenchymal transition (EMT) in SKOV3 and 3AO ovarian cancer cells were detected. TET3 was ectopically expressed in TGF-β1-treated ovarian cancer cells to examine its effect on TGF-β1-induced EMT phenotype. The downstream target of TET3 was further identified. Finally, the relationships of TET3 expression to clinic-pathological parameters of ovarian cancer were investigated with a tissue microarray using immunohistochemistry.
RESULTS: TET3 was downregulated during TGF-β1-initiatd epithelial-mesenchymal transition (EMT) in SKOV3 and 3AO ovarian cancer cells. Overexpression of TET3 reversed TGF-β1-induced EMT phenotypes including the expression pattern of molecular markers (E-cadherin, Vimentin, N-cadherin, Snail) and migratory and invasive capabilities of ovarian cancer cells. miR-30d was identified as a downstream target of TET3, and TET3 overexpression resumed the demethylation status in the promoter region of miR-30d precursor gene, resulting in restoration of miR-30d (an EMT suppressor of ovarian cancer cells proven in our previous study) level in TGF-β1-induced EMT. We further found that TET3 expression was decreased in ovarian cancer tissues, especially in serous ovarian cancers. The overall positivity of TET3 was inversely correlated with the grade of differentiation status of ovarian cancer.
CONCLUSION: Our results revealed that TET3 acted as a suppressor of ovarian cancer by demethylating miR-30d precursor gene promoter to block TGF-β1-induced EMT.

Schulten HJ, Hussein D, Al-Adwani F, et al.
Microarray Expression Data Identify DCC as a Candidate Gene for Early Meningioma Progression.
PLoS One. 2016; 11(4):e0153681 [PubMed] Free Access to Full Article Related Publications
Meningiomas are the most common primary brain tumors bearing in a minority of cases an aggressive phenotype. Although meningiomas are stratified according to their histology and clinical behavior, the underlying molecular genetics predicting aggressiveness are not thoroughly understood. We performed whole transcript expression profiling in 10 grade I and four grade II meningiomas, three of which invaded the brain. Microarray expression analysis identified deleted in colorectal cancer (DCC) as a differentially expressed gene (DEG) enabling us to cluster meningiomas into DCC low expression (3 grade I and 3 grade II tumors), DCC medium expression (2 grade I and 1 grade II tumors), and DCC high expression (5 grade I tumors) groups. Comparison between the DCC low expression and DCC high expression groups resulted in 416 DEGs (p-value<0.05; fold change>2). The most significantly downregulated genes in the DCC low expression group comprised DCC, phosphodiesterase 1C (PDE1C), calmodulin-dependent 70kDa olfactomedin 2 (OLFM2), glutathione S-transferase mu 5 (GSTM5), phosphotyrosine interaction domain containing 1 (PID1), sema domain, transmembrane domain (TM) and cytoplasmic domain, (semaphorin) 6D (SEMA6D), and indolethylamine N-methyltransferase (INMT). The most significantly upregulated genes comprised chromosome 5 open reading frame 63 (C5orf63), homeodomain interacting protein kinase 2 (HIPK2), and basic helix-loop-helix family, member e40 (BHLHE40). Biofunctional analysis identified as predicted top upstream regulators beta-estradiol, TGFB1, Tgf beta complex, LY294002, and dexamethasone and as predicted top regulator effectors NFkB, PIK3R1, and CREBBP. The microarray expression data served also for a comparison between meningiomas from female and male patients and for a comparison between brain invasive and non-invasive meningiomas resulting in a number of significant DEGs and related biofunctions. In conclusion, based on its expression levels, DCC may constitute a valid biomarker to identify those benign meningiomas at risk for progression.

Wang XT, Lv M, Guo HY
Effects of epidural block combined with general anesthesia on antitumor characteristics of T helper cells in hepatocellular carcinoma patients.
J Biol Regul Homeost Agents. 2016 Jan-Mar; 30(1):67-77 [PubMed] Related Publications
This study discusses the changes of T helper cells (Th cells) of patients who received different anesthesia methods in liver cancer resection. We selected 122 patients who were diagnosed with hepatocellular carcinoma and underwent liver cancer resection and divided them into a general anesthesia combined with epidural anesthesia group (group A) and general anesthesia group (group B). Peripheral blood was collected to detect Th cells on the day of surgery, and on the second and seventh days after surgery. Th1 and Th2 cell frequency and mRNA expression of interferon-γ (IFN-γ) of all patients significantly rose on the second day but recovered to the previous level on the seventh day. Th1/Th2 increased remarkably on the seventh day compared to the second day. Compared to the day of surgery, Th17, regulatory T (Treg)cells as well as mRNA expression of interleukin-17 (IL-17) and FoxP3 had no obvious changes on the second day, but dramatically declined on the seventh day. Compared to group B, Th1 cell frequency and Th1/Th2 in group A had a slight increase on the second day, and a remarkable increase on the seventh day; but Th2, Th17 and Treg cell frequency in group A slightly decreased on the second day and remarkably decreased on the seventh day. mRNA of IFN-γ, cytokine levels and IFN-γ/IL-4 of group A were all higher than group B on the seventh day, while mRNA of IL-17, concentration of IL-17 as well as concentration of transforming growth factor-β1 (TGF-β1) in group A were much lower than group B. These findings suggest that improving antitumor activity of Th cells can benefit patients who receive liver cancer resection.

Zhang F, Dong W, Zeng W, et al.
Naringenin prevents TGF-β1 secretion from breast cancer and suppresses pulmonary metastasis by inhibiting PKC activation.
Breast Cancer Res. 2016; 18(1):38 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Targeting the TGF-β1 pathway for breast cancer metastasis therapy has become an attractive strategy. We have previously demonstrated that naringenin significantly reduced TGF-β1 levels in bleomycin-induced lung fibrosis and effectively prevented pulmonary metastases of tumors. This raised the question of whether naringenin can block TGF-β1 secretion from breast cancer cells and inhibit their pulmonary metastasis.
METHODS: We transduced a lentiviral vector encoding the mouse Tgf-β1 gene into mouse breast carcinoma (4T1-Luc2) cells and inoculated the transformant cells (4T1/TGF-β1) into the fourth primary fat pat of Balb/c mice. Pulmonary metastases derived from the primary tumors were monitored using bioluminescent imaging. Spleens, lungs and serum (n = 18-20 per treatment group) were analyzed for immune cell activity and TGF-β1 level. The mechanism whereby naringenin decreases TGF-β1 secretion from breast cancer cells was investigated at different levels, including Tgf-β1 transcription, mRNA stability, translation, and extracellular release.
RESULTS: In contrast to the null-vector control (4T1/RFP) tumors, extensive pulmonary metastases derived from 4T1/TGF-β1 tumors were observed. Administration of the TGF-β1 blocking antibody 1D11 or naringenin showed an inhibition of pulmonary metastasis for both 4T1/TGF-β1 tumors and 4T1/RFP tumors, resulting in increased survival of the mice. Compared with 4T1/RFP bearing mice, systemic immunosuppression in 4T1/TGF-β1 bearing mice was observed, represented by a higher proportion of regulatory T cells and myeloid-derived suppressor cells and a lower proportion of activated T cells and INFγ expression in CD8(+) T cells. These metrics were improved by administration of 1D11 or naringenin. However, compared with 1D11, which neutralized secreted TGF-β1 but did not affect intracellular TGF-β1 levels, naringenin reduced the secretion of TGF-β1 from the cells, leading to an accumulation of intracellular TGF-β1. Further experiments revealed that naringenin had no effect on Tgf-β1 transcription, mRNA decay or protein translation, but prevented TGF-β1 transport from the trans-Golgi network by inhibiting PKC activity.
CONCLUSIONS: Naringenin blocks TGF-β1 trafficking from the trans-Golgi network by suppressing PKC activity, resulting in a reduction of TGF-β1 secretion from breast cancer cells. This finding suggests that naringenin may be an attractive therapeutic candidate for TGF-β1 related diseases.

Long J, Liu Z, Wu X, et al.
Gene expression profile analysis of pancreatic cancer based on microarray data.
Mol Med Rep. 2016; 13(5):3913-9 [PubMed] Free Access to Full Article Related Publications
The present study identified differentially‑expressed genes (DEGs) between pancreatic cancer (PC) tissues and normal tissues, and assessed genetic factors associated with the pathogenesis of PC. The mRNA expression microarray dataset, GSE16515, containing 52 samples, including 16 paired tumor and normal tissue samples, and 20 tumor samples, was downloaded from Gene Expression Omnibus. Raw data were normalized and DEGs were identified. Subsequently, clustering was performed, protein‑protein interaction networks were drawn, and functional and pathway enrichment analyses of the DEGs were performed. Copy number variations of DEGs were also identified. A total of 1,765 DEGs between PC and normal tissues were identified, including 1,312 upregulated and 453 downregulated DEGs. Upregulated DEGs were associated with the regulation of nucleocytoplasmic and intracellular transport, whereas downregulated DEGs were associated with the response to organic substances and hormone stimulus. The pancreatic cancer pathway was connected to three DEGs, namely transforming growth factor β1 (TGFB1), TGFβ receptor 1 (TGFBR1) and epidermal growth factor (EGF), which had 2, 3 and 5 CNVs, respectively. These results indicated the important roles of TGFB1, TGFBR1 and EGF in the pathogenesis of PC. These genes may be potential therapeutic targets for the treatment of PC.

Zhu X, Wang K, Zhang K, et al.
Galectin-1 knockdown in carcinoma-associated fibroblasts inhibits migration and invasion of human MDA-MB-231 breast cancer cells by modulating MMP-9 expression.
Acta Biochim Biophys Sin (Shanghai). 2016; 48(5):462-7 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
Carcinoma-associated fibroblasts (CAFs) play central roles in facilitating tumor progression and metastasis in breast cancer. Galectin-1 (Gal-1), a marker of CAFs, was previously reported to be associated with tumorigenesis and metastasis of various types of tumors. The aim of this study is to investigate the role of Gal-1 in CAF-mediated breast cancer metastasis and its underlying molecular mechanisms. Our results showed that CAFs isolated from human breast tumor tissues expressed higher level of Gal-1 compared with paired normal fibroblasts, and the conditioned medium (CM) of CAFs significantly induced the migration and invasion of human MDA-MB-231 breast cancer cells. Knockdown of Gal-1 in CAFs dramatically inhibited CAF-CM-induced cell migration and invasion, probably by inhibiting the expression of matrix metalloprotein 9 (MMP-9). Our findings demonstrate that Gal-1-regulated CAFs activation promotes breast cancer cell metastasis by upregulating MMP-9 expression, which indicated that Gal-1 in CAFs might be a potential novel target for breast cancer therapy.

Ma M, He M, Jiang Q, et al.
MiR-487a Promotes TGF-β1-induced EMT, the Migration and Invasion of Breast Cancer Cells by Directly Targeting MAGI2.
Int J Biol Sci. 2016; 12(4):397-408 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
Tumor metastasis is a complex and multistep process and its exact molecular mechanisms remain unclear. We attempted to find novel microRNAs (miRNAs) contributing to the migration and invasion of breast cancer cells. In this study, we found that the expression of miR-487a was higher in MDA-MB-231breast cancer cells with high metastasis ability than MCF-7 breast cancer cells with low metastasis ability and the treatment with transforming growth factor β1 (TGF-β1) significantly increased the expression of miR-487a in MCF-7 and MDA-MB-231 breast cancer cells. Subsequently, we found that the transfection of miR-487a inhibitor significantly decreased the expression of vimentin, a mesenchymal marker, while increased the expression of E-cadherin, an epithelial marker, in both MCF-7 cells and MDA-MB-231 cells. Also, the inactivation of miR-487a inhibited the migration and invasion of breast cancer cells. Furthermore, our findings demonstrated that miR-487a directly targeted the MAGI2 involved in the stability of PTEN. The down-regulation of miR-487a increased the expression of p-PTEN and PTEN, and reduced the expression of p-AKT in both cell lines. In addition, the results showed that NF-kappaB (p65) significantly increased the miR-487a promoter activity and expression, and TGF-β1 induced the increased miR-487a promoter activity via p65 in MCF-7 cells and MDA-MB-231 cells. Moreover, we further confirmed the expression of miR-487a was positively correlated with the lymph nodes metastasis and negatively correlated with the expression of MAGI2 in human breast cancer tissues. Overall, our results suggested that miR-487a could promote the TGF-β1-induced EMT, the migration and invasion of breast cancer cells by directly targeting MAGI2.

Zhu H, Luo H, Shen Z, et al.
Transforming growth factor-β1 in carcinogenesis, progression, and therapy in cervical cancer.
Tumour Biol. 2016; 37(6):7075-83 [PubMed] Related Publications
Transforming growth factor β1 (TGF-β1) is a multifunctional cytokine that plays important roles in cervical tumor formation, invasion, progression, and metastasis. TGF-β1 functions as a tumor inhibitor in precancerous lesions and early stage cancers of cervix whereas as a tumor promoter in later stage. This switch from a tumor inhibitor to a tumor promoter might be due to various alterations in TGF-β signaling pathway, such as mutations or loss of expression of TGF-β receptors and SMAD proteins. Additionally, the oncoproteins of human papillomaviruses have been shown to stimulate TGF-β1 expression, which in turn suppresses host immune surveillance. Thus, in addition to driving tumor cell migration and metastasis, TGF-β1 is believed to play a key role in promoting human papillomavirus infection by weakening host immune defense. In this article, we will discuss the role of TGF-β1 in the expression, carcinogenesis, progression, and therapy in cervical cancers. A better understanding of this cytokine in cervical carcinogenesis is essential for critical evaluation of this cytokine as a potential prognostic marker and therapeutic target.

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