TGFB1; transforming growth factor, beta 1 (19q13.1)

Gene Summary

Gene:TGFB1; transforming growth factor, beta 1
Aliases: CED, LAP, DPD1, TGFB, TGFbeta
Summary:This gene encodes a member of the transforming growth factor beta (TGFB) family of cytokines, which are multifunctional peptides that regulate proliferation, differentiation, adhesion, migration, and other functions in many cell types. Many cells have TGFB receptors, and the protein positively and negatively regulates many other growth factors. The secreted protein is cleaved into a latency-associated peptide (LAP) and a mature TGFB1 peptide, and is found in either a latent form composed of a TGFB1 homodimer, a LAP homodimer, and a latent TGFB1-binding protein, or in an active form composed of a TGFB1 homodimer. The mature peptide may also form heterodimers with other TGFB family members. This gene is frequently upregulated in tumor cells, and mutations in this gene result in Camurati-Engelmann disease.[provided by RefSeq, Oct 2009]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:transforming growth factor beta-1
Updated:14 December, 2014


What does this gene/protein do?
Show (162)


What pathways are this gene/protein implicaed in?
- ALK in cardiac myocytes BIOCARTA
- Cell Cycle BIOCARTA
- Cytokines and Inflammatory Response BIOCARTA
- Erythrocyte Differentiation Pathway BIOCARTA
- Function of SLRP in Bone BIOCARTA
- MAPKinase Signaling Pathway BIOCARTA
- p38 MAPK Signaling Pathway BIOCARTA
- Role of Tob in T-cell activation BIOCARTA
- Selective expression of chemokine receptors during T-cell polarization BIOCARTA
- Signal transduction through IL1R BIOCARTA
- TGF beta signaling pathway BIOCARTA
- Cell cycle KEGG
- Colorectal cancer KEGG
- Cytokine-cytokine receptor interaction KEGG
- MAPK signaling pathway KEGG
- TGF-beta signaling pathway KEGG
Data from KEGG and BioCarta [BIOCARTA terms] via CGAP

Cancer Overview

Research Indicators

Publications Per Year (1989-2014)
Graph generated 14 December 2014 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 14 December, 2014 using data from PubMed, MeSH and CancerIndex

Notable (5)

Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Breast CancerTGFB1 and Breast Cancer View Publications118
Prostate CancerTGFB1 and Prostate Cancer View Publications79
Liver CancerTGFB1 and Liver Cancer View Publications61
Lung CancerTGFB1 and Lung Cancer View Publications55
Colorectal CancerTGFB1 and Bowel Cancer View Publications37

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

Related Links

Latest Publications: TGFB1 (cancer-related)

Rolland Y, Marighetti P, Malinverno C, et al.
The CDC42-interacting protein 4 controls epithelial cell cohesion and tumor dissemination.
Dev Cell. 2014; 30(5):553-68 [PubMed] Related Publications
The role of endocytic proteins and the molecular mechanisms underlying epithelial cell cohesion and tumor dissemination are not well understood. Here, we report that the endocytic F-BAR-containing CDC42-interacting protein 4 (CIP4) is required for ERBB2- and TGF-β1-induced cell scattering, breast cancer (BC) cell motility and invasion into 3D matrices, and conversion from ductal breast carcinoma in situ to invasive carcinoma in mouse xenograft models. CIP4 promotes the formation of an E-cadherin-CIP4-SRC complex that controls SRC activation, E-cadherin endocytosis, and localized phosphorylation of the myosin light chain kinase, thereby impinging on the actomyosin contractility required to generate tangential forces to break cell-cell junctions. CIP4 is upregulated in ERBB2-positive human BC, correlates with increased distant metastasis, and is an independent predictor of poor disease outcome in subsets of BC patients. Thus, it critically controls cell-cell cohesion and is required for the acquisition of an invasive phenotype in breast tumors.

Liszka L
Ductal adenocarcinoma of the pancreas usually retained SMAD4 and p53 protein status as well as expression of epithelial-to-mesenchymal transition markers and cell cycle regulators at the stage of liver metastasis.
Pol J Pathol. 2014; 65(2):100-12 [PubMed] Related Publications
There are limited data on the biology of metastatic pancreatic ductal adenocarcinoma (PDAC). The aim of the present study was to compare the expression of immunohistochemical markers that may be involved in the development of metastatic disease in primary PDAC and in synchronous liver metastatic tissues. Thirty-two stains (corresponding to proteins encoded by 31 genes: SMAD4, TP53, ACTA2, CDH1, CDKN1A, CLDN1, CLDN4, CLDN7, CTNNB1, EGFR, ERBB2, FN1, KRT19, MAPK1/MAPK3, MAPK14, MKI67, MMP2, MMP9, MUC1 (3 antibodies), MUC5AC, MUC6, MTOR, MYC, NES, PTGS2, RPS6, RPS6KB1, TGFB1, TGFBR1, VIM) were evaluated using tissue microarray of 26 pairs of primary PDACs and their liver metastases. There were no significant differences in expression levels of examined proteins between primary and secondary lesions. In particular, metastatic PDAC retained the primary tumour's SMAD4 protein status in all and p53 protein status in all but one case. This surprising homogeneity also involved expression levels of markers of epithelial-to-mesenchymal transition as well as cell cycle regulators studied. In conclusion, the biological profiles of primary PDACs and their liver metastases seemed to be similar. Molecular alterations of PDAC related to a set of immunohistochemical markers examined in the present study were already present at the stage of localized disease.

Related: Cancer of the Pancreas Pancreatic Cancer MADH4 TP53

Xu S, Wei J, Wang F, et al.
Effect of miR-142-3p on the M2 macrophage and therapeutic efficacy against murine glioblastoma.
J Natl Cancer Inst. 2014; 106(8) [PubMed] Related Publications
BACKGROUND: The immune therapeutic potential of microRNAs (miRNAs) in the context of tumor-mediated immune suppression has not been previously described for monocyte-derived glioma-associated macrophages, which are the largest infiltrating immune cell population in glioblastomas and facilitate gliomagenesis.
METHODS: An miRNA microarray was used to compare expression profiles between human glioblastoma-infiltrating macrophages and matched peripheral monocytes. The effects of miR-142-3p on phenotype and function of proinflammatory M1 and immunosuppressive M2 macrophages were determined. The therapeutic effect of miR-142-3p was ascertained in immune-competent C57BL/6J mice harboring intracerebral GL261 gliomas and in genetically engineered Ntv-a mice bearing high-grade gliomas. Student t test was used to evaluate the differences between ex vivo datasets. Survival was analyzed with the log-rank test and tumor sizes with linear mixed models and F test. All statistical tests were two-sided.
RESULTS: miR-142-3p was the most downregulated miRNA (approximately 4.95-fold) in glioblastoma-infiltrating macrophages. M2 macrophages had lower miR-142-3p expression relative to M1 macrophages (P = .03). Overexpression of miR-142-3p in M2 macrophages induced selective modulation of transforming growth factor beta receptor 1, which led to subsequent preferential apoptosis in the M2 subset (P = .01). In vivo miR-142-3p administration resulted in glioma growth inhibition (P = .03, n = 5) and extended median survival (miR-142-3p-treated C57BL/6J mice vs scramble control: 31 days vs 23.5 days, P = .03, n = 10; miR-142-3p treated Ntv-a mice vs scramble control: 32 days vs 24 days, P = .03, n = 9), with an associated decrease in infiltrating macrophages (R (2) = .303).
CONCLUSIONS: These data indicate a unique role of miR-142-3p in glioma immunity by modulating M2 macrophages through the transforming growth factor beta signaling pathway.

Related: Apoptosis Signal Transduction

Mincione G, Tarantelli C, Vianale G, et al.
Mutual regulation of TGF-β1, TβRII and ErbB receptors expression in human thyroid carcinomas.
Exp Cell Res. 2014; 327(1):24-36 [PubMed] Related Publications
The role of EGF and TGF-β1 in thyroid cancer is still not clearly defined. TGF-β1 inhibited the cellular growth and migration of follicular (FTC-133) and papillary (B-CPAP) thyroid carcinoma cell lines. Co-treatments of TGF-β1 and EGF inhibited proliferation in both cell lines, but displayed opposite effect on their migratory capability, leading to inhibition in B-CPAP and promotion in FTC-133 cells, by a MAPK-dependent mechanism. TGF-β1, TβRII and EGFR expressions were evaluated in benign and malignant thyroid tumors. Both positivity (51.7% and 60.0% and 80.0% in FA and PTC and FTC) and overexpression (60.0%, 77.7% and 75.0% in FA, PTC and FTC) of EGFR mRNA correlates with the aggressive tumor behavior. The moderate overexpression of TGF-β1 and TβRII mRNA in PTC tissues (61.5% and 62.5%, respectively), counteracted their high overexpression in FTC tissues (100% and 100%, respectively), while EGFR overexpression was similar in both carcinomas. Papillary carcinomas were positive to E-cadherin expression, while the follicular carcinomas lose E-cadherin staining. Our findings of TGF-β1/TβRII and EGFR overexpressions together with a loss of E-cadherin observed in human follicular thyroid carcinomas, and of increased migration ability MAPK-dependent after EGF/TGF-β1 treatments in the follicular thyroid carcinoma cell line, reinforced the hypothesis of a cross-talk between EGF and TGF-β1 systems in follicular thyroid carcinomas phenotype.

Related: Thyroid Cancer EGFR TGFBR2

Nemunaitis J, Barve M, Orr D, et al.
Summary of bi-shRNA/GM-CSF augmented autologous tumor cell immunotherapy (FANG™) in advanced cancer of the liver.
Oncology. 2014; 87(1):21-9 [PubMed] Related Publications
Therapies for advanced hepatocellular carcinoma (HCC) are limited. We carried out a phase I trial of a novel autologous whole-cell tumor cell immunotherapy (FANG™), which incorporates a dual granulocyte macrophage colony-stimulating factor (GM-CSF) expressive/bifunctional small hairpin RNA interference (bi-shRNAi) vector. The bi-shRNAi DNA targets furin, which is a proconvertase of transforming growth factors beta (TGFβ) 1 and 2. Safety, mechanism, immunoeffectiveness, and suggested benefit were previously shown [Senzer et al.: Mol Ther 2012;20:679-689; Senzer et al.: J Vaccines Vaccin 2013;4:209]. We now provide further follow-up of a subset of 8 HCC patients. FANG manufacturing was successful in 7 of 8 attempts (one failure due to insufficient cell yield). Median GM-CSF expression was 144 pg/10(6) cells, TGFβ1 knockdown was 100%, and TGFβ2 knockdown was 93% of the vector-transported cells. Five patients were vaccinated (1 or 2.5×10(7) cells/intradermal injection, 6-11 vaccinations). No FANG toxicity was observed. Three of these patients demonstrated evidence of an immune response to the autologous tumor cell sample. Long-term follow-up demonstrated survival of 319, 729, 784, 931+, and 1,043+ days of the FANG-treated patients. In conclusion, evidence supports further assessment of the FANG immunotherapy in HCC.

Related: Liver Cancer TGFB2

Fan QM, Jing YY, Yu GF, et al.
Tumor-associated macrophages promote cancer stem cell-like properties via transforming growth factor-beta1-induced epithelial-mesenchymal transition in hepatocellular carcinoma.
Cancer Lett. 2014; 352(2):160-8 [PubMed] Related Publications
Tumor-associated macrophages (TAMs), a crucial component of immune cells infiltrated in tumor microenvironment, have been found to be associated with progression and metastasis of hepatocellular carcinoma (HCC). In this study, we aimed to clarify the mechanism underlying the crosstalk between TAMs and cancer stem cells (CSCs) in HCC. Mouse macrophage cell line RAW264.7 cells were used to investigate the effects of TAMs on mouse hepatoma cell line Hepa1-6 cells in vivo and vitro. A total of 90 clinical samples had pathology-proven HCC were used to evaluate the distribution of TAMs and CSCs and analyze their value in predicting the prognosis. In the study, we have found that the number of TAMs has a positive correlation with the density of CSCs in the marginal of human HCC. Our results show that, cocultured with TAM-conditioned medium (CM) promoted CSC-like properties in Hepa1-6 cells, which underwent EMT and gained higher invasive capability. TAMs secreted more transforming growth factor- beta1 (TGF-beta1) than other phenotypes of macrophage. Furthermore, depletion of TGF-beta1 blocked acquisition of CSC-like properties by inhibition of TGF-beta1-induced EMT. High expression of CD68 in the EpCAM positive expression HCC tissues was strongly associated with both poor cancer-free survival and overall survival in patients. Our results indicate that the TAMs promote CSC-like properties via TGF-beta1-induced EMT and they may contribute to investigate the prognosis of HCC.

Related: Liver Cancer Signal Transduction EPCAM

Xu Y, Gao XD, Lee JH, et al.
Cell type-restricted activity of hnRNPM promotes breast cancer metastasis via regulating alternative splicing.
Genes Dev. 2014; 28(11):1191-203 [PubMed] Free Access to Full Article Related Publications
Tumor metastasis remains the major cause of cancer-related death, but its molecular basis is still not well understood. Here we uncovered a splicing-mediated pathway that is essential for breast cancer metastasis. We show that the RNA-binding protein heterogeneous nuclear ribonucleoprotein M (hnRNPM) promotes breast cancer metastasis by activating the switch of alternative splicing that occurs during epithelial-mesenchymal transition (EMT). Genome-wide deep sequencing analysis suggests that hnRNPM potentiates TGFβ signaling and identifies CD44 as a key downstream target of hnRNPM. hnRNPM ablation prevents TGFβ-induced EMT and inhibits breast cancer metastasis in mice, whereas enforced expression of the specific CD44 standard (CD44s) splice isoform overrides the loss of hnRNPM and permits EMT and metastasis. Mechanistically, we demonstrate that the ubiquitously expressed hnRNPM acts in a mesenchymal-specific manner to precisely control CD44 splice isoform switching during EMT. This restricted cell-type activity of hnRNPM is achieved by competition with ESRP1, an epithelial splicing regulator that binds to the same cis-regulatory RNA elements as hnRNPM and is repressed during EMT. Importantly, hnRNPM is associated with aggressive breast cancer and correlates with increased CD44s in patient specimens. These findings demonstrate a novel molecular mechanism through which tumor metastasis is endowed by the hnRNPM-mediated splicing program.

Related: Signal Transduction

Zhang B, Jia WH, Matsuda K, et al.
Large-scale genetic study in East Asians identifies six new loci associated with colorectal cancer risk.
Nat Genet. 2014; 46(6):533-42 [PubMed] Free Access to Full Article Related Publications
Known genetic loci explain only a small proportion of the familial relative risk of colorectal cancer (CRC). We conducted a genome-wide association study of CRC in East Asians with 14,963 cases and 31,945 controls and identified 6 new loci associated with CRC risk (P = 3.42 × 10(-8) to 9.22 × 10(-21)) at 10q22.3, 10q25.2, 11q12.2, 12p13.31, 17p13.3 and 19q13.2. Two of these loci map to genes (TCF7L2 and TGFB1) with established roles in colorectal tumorigenesis. Four other loci are located in or near genes involved in transcriptional regulation (ZMIZ1), genome maintenance (FEN1), fatty acid metabolism (FADS1 and FADS2), cancer cell motility and metastasis (CD9), and cell growth and differentiation (NXN). We also found suggestive evidence for three additional loci associated with CRC risk near genome-wide significance at 8q24.11, 10q21.1 and 10q24.2. Furthermore, we replicated 22 previously reported CRC-associated loci. Our study provides insights into the genetic basis of CRC and suggests the involvement of new biological pathways.

Related: Colorectal (Bowel) Cancer

Yin M, Wang X, Yao G, et al.
Transactivation of micrornA-320 by microRNA-383 regulates granulosa cell functions by targeting E2F1 and SF-1 proteins.
J Biol Chem. 2014; 289(26):18239-57 [PubMed] Article available free on PMC after 27/06/2015 Related Publications
Our previous studies have shown that microRNA-320 (miR-320) is one of the most down-regulated microRNAs (miRNA) in mouse ovarian granulosa cells (GCs) after TGF-β1 treatment. However, the underlying mechanisms of miR-320 involved in GC function during follicular development remain unknown. In this study, we found that pregnant mare serum gonadotropin treatment resulted in the suppression of miR-320 expression in a time-dependent manner. miR-320 was mainly expressed in GCs and oocytes of mouse ovarian follicles in follicular development. Overexpression of miR-320 inhibited estradiol synthesis and proliferation of GCs through targeting E2F1 and SF-1. E2F1/SF-1 mediated miR-320-induced suppression of GC proliferation and of GC steroidogenesis. FSH down-regulated the expression of miR-320 and regulated the function of miR-320 in mouse GCs. miR-383 promoted the expression of miR-320 and enhanced miR-320-mediated suppression of GC proliferation. Injection of miR-320 into the ovaries of mice partially promoted the production of testosterone and progesterone but inhibited estradiol release in vivo. Moreover, the expression of miR-320 and miR-383 was up-regulated in the follicular fluid of polycystic ovarian syndrome patients, although the expression of E2F1 and SF-1 was down-regulated in GCs. These data demonstrated that miR-320 regulates the proliferation and steroid production by targeting E2F1 and SF-1 in the follicular development. Understanding the regulation of miRNA biogenesis and function in the follicular development will potentiate the usefulness of miRNA in the treatment of reproduction and some steroid-related disorders.

Related: E2F1 Transcription Factor

Turato C, Vitale A, Fasolato S, et al.
SERPINB3 is associated with TGF-β1 and cytoplasmic β-catenin expression in hepatocellular carcinomas with poor prognosis.
Br J Cancer. 2014; 110(11):2708-15 [PubMed] Article available free on PMC after 27/05/2015 Related Publications
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most important sanitary problems for its prevalence and poor prognosis. To date, no information is available on the prognostic value of the ov-serpin SERPINB3, detected in primary liver cancer but not in normal liver. The aim of the study was to analyse SERPINB3 expression in liver cancer in relation with molecular signatures of poor prognosis and with clinical outcome.
METHODS: Liver tumours of 97 patients were analysed in parallel for SERPINB3, TGF-β and β-catenin. In a subgroup of 67 patients with adequate clinical follow-up, the correlation of molecular findings with clinical outcome was also carried out.
RESULTS: High SERPINB3 levels were detectable in 22% of the patients. A significant correlation of this serpin with TGF-β at transcription and protein level was observed, whereas for β-catenin a strong correlation was found only at post-transcription level. These findings were in agreement with transcriptome data meta-analysis, showing accumulation of SERPINB3 in the poor-prognosis subclass (S1). High levels of this serpin were significantly associated with early tumour recurrence and high SERPINB3 was the only variable significantly associated with time to recurrence at multivariate analysis.
CONCLUSIONS: SERPINB3 is overexpressed in the subset of the most aggressive HCCs.

Related: Liver Cancer CTNNB1 gene

Pan D, Zeng X, Yu H, et al.
Role of cytokine gene polymorphisms on prognosis in hepatocellular carcinoma after radical surgery resection.
Gene. 2014; 544(1):32-40 [PubMed] Related Publications
This study aimed to determine whether SNPs of cytokine genes influence survival of hepatocellular carcinoma (HCC) patients after radical surgery resection. We evaluated 14 SNPs of eight cytokine genes in 263 patients treated with radical surgery resection of HCC. Categorical variables were compared by the χ(2) test and Fisher's exact test. The Kaplan-Meier methods with log-rank test and Cox regression models were used to compare survival of resected HCC patients according to the genotype. Among the 14 studied SNPs of cytokine genes, only the TNF-α-863 (CA+CC) genotypes were revealed to be significant independent predictors of prolonged overall survival (OS) after HCC radical surgery resection (HR: 0.586, 95% CI: 0.355-0.968), considering for other clinical factors in a Cox proportional hazard model. Meanwhile, no significant association was found between the 14 SNPs and relapse-free survival (RFS) of resected HCC patients. In addition, combination analysis with the Th1 cytokine (IFN-γ, IL-2, IL-12B, TGF-β1) or Th2 cytokine (IL-6, IL-10) genetic polymorphisms by the Kaplan-Meier method and Cox multivariate analysis did not reveal any significant association between OS and RFS of resected HCC patients.

Related: IL10 Interleukin 2 (Aldesleukin) Liver Cancer TNF IL12B

Santos JI, Teixeira AL, Dias F, et al.
Restoring TGFβ1 pathway-related microRNAs: possible impact in metastatic prostate cancer development.
Tumour Biol. 2014; 35(7):6245-53 [PubMed] Related Publications
In developed countries, prostate cancer (PC) is the neoplasia more frequently diagnosed in men. The signaling pathway induced by the transforming growth factor β1 (TGFβ1) has an important role in cell growth, differentiation, and development, the downregulation of this pathway being associated with cancer development. In PC, the activation of this signaling pathway is lost, resulting in favoring of tumor growth, proliferation, and evasion of apoptosis. Several studies have shown that microRNAs (miRNAs), small non-coding RNA, are closely associated with the development, invasion, and metastasis, suggesting that they have a critical role in cancer development. Recently, Smad proteins, the signal transducers of the TGFβ1 signaling pathway, were found to regulate miRNA expression, through both transcriptional and posttranscriptional mechanisms. In this review, we summarize the mechanisms underlying Smad-mediated regulation of miRNA biogenesis and the effects on cancer development, particularly in PC. We identify that TGFβ1-related miR-143, miR-145, miR-146a, and miR-199a may have a key role in the development of prostate cancer metastasis and the restoration of their expression may be a promising therapeutic strategy for PC treatment.

Related: Apoptosis Prostate Cancer Signal Transduction

Chen D, Zhang Z, Mao C, et al.
ANRIL inhibits p15(INK4b) through the TGFβ1 signaling pathway in human esophageal squamous cell carcinoma.
Cell Immunol. 2014 May-Jun; 289(1-2):91-6 [PubMed] Related Publications
The INK4b-ARF-INK4a gene cluster encodes three tumor suppressors: p15(INK4b), p14(ARF), and p16(INK4a). Antisense non-coding RNA in the INK4 locus (ANRIL) is transcribed in the opposite direction from this gene cluster. Recent studies suggest that ANRIL represses the expression of p15(INK4b), p14(ARF), and p16(INK4a); however, the underlying mechanism is unclear. In this study, the expressions of ANRIL in human esophageal squamous cell carcinoma (ESCC) tissues and matched adjacent non-tumor tissues were examined by quantitative real-time polymerase chain reaction. Compared with matched adjacent non-tumor tissues, the expression levels of ANRIL in ESCC tissues were significantly increased. Furthermore, inhibition of ANRIL was found to increase the expression of p15(INK4b) and transforming growth factor β1 (TGFβ1) and depletion of ANRIL in ESCC cell lines may inhibit cellular proliferation. Thus, our findings suggest a significant role of ANRIL in the occurrence and development of ESCC through TGFβ1 signaling pathways.

Related: Cancer of the Esophagus Esophageal Cancer Signal Transduction

Ciftci R, Tas F, Yasasever CT, et al.
High serum transforming growth factor beta 1 (TGFB1) level predicts better survival in breast cancer.
Tumour Biol. 2014; 35(7):6941-8 [PubMed] Related Publications
The transforming growth factor beta 1 (TGFB1) is a regulatory cytokine with both tumor suppressor and tumor-promoting effects in breast cancer (BC) cell lines and tissue. Data about level of circulating TGFB1 and its prognostic significance in BC patients is conflicting. The objective of this study is to determine the clinical significance of the serum TGFB1 levels in BC patients. We enrolled 96 female patients with histopathologically diagnosed BC who did not receive chemotherapy (CT) or radiotherapy. Serum TGFB1 levels were measured by ELISA method and compared with 30 healthy controls. The mean serum TGFB1 level of BC patients was significantly higher than controls (0.08 vs. 0.04 ng/ml, p < 0.001). There was no significant difference according to known disease-related clinicopathological or laboratory parameters. Serum TGFB1 level had a significant impact on overall survival in both univariate (p = 0.01) and multivariate analysis (p = 0.013). Serum TGFB1 level is elevated in BC patients and has a favorable prognostic value. However, it has no predictive role on CT response.

Related: Breast Cancer

Nye MD, Almada LL, Fernandez-Barrena MG, et al.
The transcription factor GLI1 interacts with SMAD proteins to modulate transforming growth factor β-induced gene expression in a p300/CREB-binding protein-associated factor (PCAF)-dependent manner.
J Biol Chem. 2014; 289(22):15495-506 [PubMed] Article available free on PMC after 30/05/2015 Related Publications
The biological role of the transcription factor GLI1 in the regulation of tumor growth is well established; however, the molecular events modulating this phenomenon remain elusive. Here, we demonstrate a novel mechanism underlying the role of GLI1 as an effector of TGFβ signaling in the regulation of gene expression in cancer cells. TGFβ stimulates GLI1 activity in cancer cells and requires its transcriptional activity to induce BCL2 expression. Analysis of the mechanism regulating this interplay identified a new transcriptional complex including GLI1 and the TGFβ-regulated transcription factor, SMAD4. We demonstrate that SMAD4 physically interacts with GLI1 for concerted regulation of gene expression and cellular survival. Activation of the TGFβ pathway induces GLI1-SMAD4 complex binding to the BCL2 promoter whereas disruption of the complex through SMAD4 RNAi depletion impairs GLI1-mediated transcription of BCL2 and cellular survival. Further characterization demonstrated that SMAD2 and the histone acetyltransferase, PCAF, participate in this regulatory mechanism. Both proteins bind to the BCL2 promoter and are required for TGFβ- and GLI1-stimulated gene expression. Moreover, SMAD2/4 RNAi experiments showed that these factors are required for the recruitment of GLI1 to the BCL2 promoter. Finally, we determined whether this novel GLI1 transcriptional pathway could regulate other TGFβ targets. We found that two additional TGFβ-stimulated genes, INTERLEUKIN-7 and CYCLIN D1, are dependent upon the intact GLI1-SMAD-PCAF complex for transcriptional activation. Collectively, these results define a novel epigenetic mechanism that uses the transcription factor GLI1 and its associated complex as a central effector to regulate gene expression in cancer cells.

Related: Cancer of the Pancreas Pancreatic Cancer Signal Transduction SMAD3 MADH4 GLI

Tulley S, Chen WT
Transcriptional regulation of seprase in invasive melanoma cells by transforming growth factor-β signaling.
J Biol Chem. 2014; 289(22):15280-96 [PubMed] Article available free on PMC after 30/05/2015 Related Publications
The tumor invasive phenotype driven by seprase expression/activity has been widely examined in an array of malignant tumor cell types; however, very little is known about the transcriptional regulation of this critical protease. Seprase (also named fibroblast activation protein-α, antiplasmin-cleaving enzyme, and dipeptidyl prolyl peptidase 5) is expressed at high levels by stromal fibroblast, endothelial, and tumor cells in a variety of invasive tumors but is undetectable in the majority of normal adult tissues. To examine the transcriptional regulation of the gene, we cloned the human seprase promoter and demonstrated that endogenous seprase expression and exogenous seprase promoter activity are high in invasive melanoma cells but not in non-invasive melanoma cells/primary melanocytes. In addition, we identified a crucial TGF-β-responsive cis-regulatory element in the proximal seprase promoter region that enabled robust transcriptional activation of the gene. Treatment of metastatic but not normal/non-invasive cells with TGF-β1 caused a rapid and profound up-regulation of endogenous seprase mRNA, which coincided with an abolishment of the negative regulator c-Ski, and an increase in binding of Smad3/4 to the seprase promoter in vivo. Blocking TGF-β signaling in invasive melanoma cells through overexpression of c-Ski, chemically using SB-431542, or with a neutralizing antibody against TGF-β significantly reduced seprase mRNA levels. Strikingly, RNAi of seprase in invasive cells greatly diminished their invasive potential in vitro as did blocking TGF-β signaling using SB-431542. Altogether, we found that seprase is transcriptionally up-regulated in invasive melanoma cells via the canonical TGF-β signaling pathway, supporting the roles of both TGF-β and seprase in tumor invasion and metastasis.

Related: Melanoma Signal Transduction Skin Cancer

Chen Y, Zou L, Zhang Y, et al.
Transforming growth factor-β1 and α-smooth muscle actin in stromal fibroblasts are associated with a poor prognosis in patients with clinical stage I-IIIA nonsmall cell lung cancer after curative resection.
Tumour Biol. 2014; 35(7):6707-13 [PubMed] Related Publications
The aims of this study were to investigate the expression of transforming growth factor-β1 (TGF-β1) and α-smooth muscle actin (α-SMA) in surgical resection specimens from nonsmall cell lung cancer (NSCLC) and to evaluate the prognostic significance of this gene expression in stromal fibroblasts for patients with clinical stage I-IIIA NSCLC. The immunohistochemical expression of TGF-β1 and α-SMA was evaluated in 78 formalin-fixed paraffin-embedded tumor specimens from clinical stage I-IIIA NSCLC. Correlations between this gene expression and the clinicopathologic characteristics were determined by chi-square test. The prognostic impact of this gene expression in stromal fibroblasts with regard to overall survival (OS) was determined by Kaplan-Meier and Cox hazard proportional model. The percentages of high TGF-β1 expression in stromal fibroblasts and cancer cells were 19.2 % (15/78) and 35.9 % (28/78), respectively. There were 28.2 % (22/78) of patients with high α-SMA expression in stromal fibroblasts. The analysis revealed a significant positive association between TGF-β1 expression in stromal fibroblasts and in cancer cells (χ (2) = 4.86, p = 0.03). No significant association was found between TGF-β1 in cancer cells and α-SMA expression in stromal fibroblasts (χ (2) = 0.978, p = 0.326). The 3-year OS rates with low and high TGF-β1 expression in stromal fibroblasts were 52.4 and 26.7 %, respectively (χ (2) = 5.42, p = 0.019). The 3-year OS rates with low and high α-SMA expression in stromal fibroblasts were 53.9 and 31.0 %, respectively (χ (2) =5.01, p=0.025). The multivariate analysis revealed that clinical stage and TGF-β1 and α-SMA expression levels in stromal fibroblasts were identified as independent predictive factors of OS. The results suggest that the expression level of TGF-β1 and α-SMA in stromal fibroblasts may have prognostic significance in patients with clinical stage I-IIIA NSCLC after curative resection.

Related: Non-Small Cell Lung Cancer

Ma CQ, Yang Y, Wang JM, et al.
The aPKCι blocking agent ATM negatively regulates EMT and invasion of hepatocellular carcinoma.
Cell Death Dis. 2014; 5:e1129 [PubMed] Article available free on PMC after 30/05/2015 Related Publications
Epithelial-to-mesenchymal transition (EMT) has an important role in invasion and metastasis of hepatocellular carcinoma (HCC). To explore the regulatory mechanism of atypical protein kinase C ι (aPKCι) signaling pathways to HCC development, and find an agent for targeted therapy for HCC, immortalized murine hepatocytes were employed to establish an EMT cell model of HCC, MMH-RT cells. Our study showed that EMT took place in MMH-R cells under the effect of transforming growth factor-β1 (TGF-β1) overexpressing aPKCι. Furthermore, we showed that the aPKCι blocking agent aurothiomalate (ATM) inhibited EMT and decreased invasion of hepatocytes. Moreover, ATM selectively inhibited proliferation of mesenchymal cells and HepG2 cells and induced apoptosis. However, ATM increased proliferation of epithelial cells and had little effect on apoptosis and invasion of epithelial cells. In conclusion, our result suggested that aPKCι could be an important bio-marker of tumor EMT, and used as an indicator of invasion and malignancy. ATM might be a promising agent for targeted treatment of HCC.

Related: Apoptosis Liver Cancer Signal Transduction

Zhenye L, Chuzhong L, Youtu W, et al.
The expression of TGF-β1, Smad3, phospho-Smad3 and Smad7 is correlated with the development and invasion of nonfunctioning pituitary adenomas.
J Transl Med. 2014; 12:71 [PubMed] Article available free on PMC after 30/05/2015 Related Publications
BACKGROUND: Transforming growth factor β (TGF-β) signaling functions as a suppressor or a promoter in tumor development, depending on the tumor stage and type. However, the role of TGF-β signaling in nonfunctioning pituitary adenomas (NFPAs) has not been explored.
METHODS: TGF-β1, Smad2, phospho-Smad2 (p-Smad2), Smad3, phospho-Smad3 (p-Smad3), Smad4, and Smad7 were detected in 5 cases of normal anterior pituitaries, 29 cases of invasive NFPAs, and 21 cases of noninvasive NFPAs by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), Western blot, and immunohistochemical analysis.
RESULTS: The Smad3 and p-Smad3 protein levels gradually decreased from normal anterior pituitaries, noninvasive NFPAs, to invasive NFPAs. However, there were no significant differences in Smad2 (P = 0.122) and p-Smad2 protein levels (P = 0.101) or Smad2 mRNA level (P = 0.409). In addition, the TGF-β1 mRNA level gradually decreased while the Smad7 mRNA level gradually increased from normal anterior pituitaries, noninvasive NFPAs, to invasive NFPAs. Furthermore, proliferating cell nuclear antigen (PCNA) mRNA level was markedly increased in invasive NFPAs compared to noninvasive ones (P < 0.01), and its level was negatively correlated with Smad3 mRNA level (P < 0.01).
CONCLUSION: The activity of TGF-β signaling may be restrained in NFPAs and is correlated with the development and invasion of NFPAs.

Related: Pituitary Tumors PCNA: Proliferating cell nuclear antigen SMAD3 SMAD7

Fang L, Xu Y, Zou L
Overexpressed homeobox B9 regulates oncogenic activities by transforming growth factor-β1 in gliomas.
Biochem Biophys Res Commun. 2014; 446(1):272-9 [PubMed] Related Publications
Glioma is the leading cause of deaths related to tumors in the central nervous system. The mechanisms of gliomagenesis remain elusive to date. Homeobox B9 (HOXB9) has a crucial function in the regulation of gene expression and cell survival, but its functions in glioma formation and development have yet to be elucidated. This study showed that HOXB9 expression in glioma tissues was significantly higher than that in nontumor tissues. Higher HOXB9 expression was also significantly associated with advanced clinical stage in glioma patients. HOXB9 overexpression stimulated the proliferation, migration, and sphere formation of glioma cells, whereas HOXB9 knockdown elicited an opposite effect. HOXB9 overexpression also increased the tumorigenicity of glioma cells in vivo. Moreover, the activation of transforming growth factor-β1 contributed to HOXB9-induced oncogenic activities. HOXB9 could be used as a predictable biomarker to be detected in different pathological and histological subtypes in glioma for diagnosis or prognosis.

Kang K, Song DG, Lee EH, et al.
Secretome profiling reveals the signaling molecules of apoptotic HCT116 cells induced by the dietary polyacetylene gymnasterkoreayne B.
J Agric Food Chem. 2014; 62(11):2353-63 [PubMed] Related Publications
Dietary polyacetylenes from various foods have been receiving attention as promising cancer chemopreventive agents. However, until now, the detailed molecular mechanism and the regulatory proteins underlying these effects have not been elucidated. We investigated the effects of gymnasterkoreayne B (GKB), a model dietary polyacetylene from wild vegetables, on the programmed cell death of HCT116 human colorectal cancer cells. GKB inhibited HCT116 cell proliferation by inducing apoptotic cell death. GKB treatment resulted in ROS accumulation, leading to the activation of both intrinsic and extrinsic apoptotic pathway. We also found that FN1, TGFB1, APP, SERPINE1, HSPD1, SOD1, TXN, and ACTN4 may act as secretory signaling molecules during GKB-induced apoptotic cell death using LC-MS/MS identification followed by spectrum counting, statistical calculation, and gene ontology analysis. The secretory proteins suggested in this study may be promising candidates involved in apoptotic cell death of cancer cells induced by GKB that warrant further functional study.

Related: Apoptosis Colorectal (Bowel) Cancer Signal Transduction

Lei Z, Xu G, Wang L, et al.
MiR-142-3p represses TGF-β-induced growth inhibition through repression of TGFβR1 in non-small cell lung cancer.
FASEB J. 2014; 28(6):2696-704 [PubMed] Related Publications
TGFβR1 plays an important role in TGF-β signaling transduction and serves as a tumor suppressor. Our previous studies show that reduced expression of TGFβR1 is common in non-small cell lung cancer (NSCLC) and TGFβR1 variants confer risk of NSCLC. However, the epigenetic mechanisms underlying the role of TGFβR1 in NSCLC carcinogenesis are still elusive. We investigated the function and regulation of TGF-β signaling-based miRNAs in NSCLC. Computational algorithms predicted that the 3'-untranslated region (3'-UTR) of TGFβR1 is a target of miR-142-3p. Here a luciferase reporter assay confirmed that miR-142-3p can directly bind to 3'-UTR of TGFβR1. Overexpression of miR-142-3p in NSCLC A549 cells suppressed expression of TGFβR1 mRNA and protein, while knockdown of endogenous miR-142-3p led to increased expression of TGFβR1. On TGF-β1 stimulation, stable overexpression of miR-142-3p attenuated phosphorylation of SMAD3, an indispensable downstream effector in canonical TGF-β/Smad signaling, via repression of TGFβR1 in A549 cells. Furthermore, miR-142-3p-mediated down-regulation of TGFβR1 weakened TGF-β-induced growth inhibition effect, and this effect was reversed by stable knockdown of endogenous miR-142-3p in A549 cells. In NSCLC tissues, miR-142-3p expression was increased and inversely correlated with TGFβR1 expression. These data demonstrate that miR-142-3p influences the proliferation of NSCLC cells through repression of TGFβR1.

Related: Non-Small Cell Lung Cancer Lung Cancer Signal Transduction

Sato S, Yamamoto H, Mukaisho K, et al.
Continuous taurocholic acid exposure promotes esophageal squamous cell carcinoma progression due to reduced cell loss resulting from enhanced vascular development.
PLoS One. 2014; 9(2):e88831 [PubMed] Article available free on PMC after 30/05/2015 Related Publications
BACKGROUND: Refluxogenic effects of smoking and alcohol abuse may be related to the risk of esophageal squamous cell carcinoma (ESCC). The present study attempts to clarify the effects of continuous taurocholic acid (TCA) exposure, which is neither mutagenic nor genotoxic, on ESCC progression.
METHODS: A squamous carcinoma cell line (ESCC-DR) was established from a tumor induced in a rat model of gastroduodenal reflux. ESCC-DR cells were incubated with 2 mM TCA for ≥2 months. The effects of continuous TCA exposure were evaluated in vitro on cell morphology, growth, and invasion and in vivo on xenograft tumor growth in nude mice. Moreover, the mean level of secreted transforming growth factor (TGF)-β1 and vascular endothelial growth factor (VEGF) proteins in cell culture supernatants and mRNA synthesis of TGF-β1 and VEGF-A of ESCC cells were measured. The angiogenic potential was further examined by a migration assay using human umbilical vein endothelial cells (HUVECs).
RESULTS: Continuous TCA exposure induced marked formation of filopodia in vitro. Expression levels of angiogenic factors were significantly higher in the cells treated with TCA than in control cells. Tumor xenografts derived from cells pre-exposed to TCA were larger and more vascularized than those derived from control cells. In addition, TCA exposure increased HUVEC migration.
CONCLUSION: Continuous TCA exposure enhanced ESCC progression due to reduced cell loss in vivo. Cell loss was inhibited by TCA-induced vascular endothelial cell migration, which was mediated by TGF-β1 and VEGF-A released from ESCC cells.

Related: Cancer of the Esophagus Esophageal Cancer Angiogenesis and Cancer VEGFA

Nakamura S, Yaguchi T, Kawamura N, et al.
TGF-β1 in tumor microenvironments induces immunosuppression in the tumors and sentinel lymph nodes and promotes tumor progression.
J Immunother. 2014 Feb-Mar; 37(2):63-72 [PubMed] Related Publications
In cancer patients, sentinel lymph nodes (SLNs) are crucial in the induction of antitumor T cells. However, in many cases, SLNs and tumors appear to be in immunosuppressive condition through mechanisms yet to be elucidated. In this study, the role of tumor-derived TGF-β1 in the generation of immunosuppressive microenvironments of tumors and SLNs was investigated. Murine colorectal carcinoma CT26 transduced with TGF-β1 cDNA (CT26-TGF-β1) showed enhanced tumor growth compared with mock-transduced CT26 (CT26-Mock) when implanted in syngeneic Balb/c mice, even though CT26-TGF-β1 shows slower growth in vitro. This enhanced growth was not observed when implanted in immunodeficient mice, suggesting that TGF-β1 enhanced tumor growth by suppressing antitumor T-cell responses. Analysis of immune cells in CT26-TGF-β1-implanted mice revealed impairment of dendritic cells (DCs), decrease of CD8 T cells, and increase of MDSCs and Tregs in the tumors. Similarly, the SLNs of these mice showed an increase of MDSCs, Tregs, and PD-L1 DCs, and decrease of T-cell stimulatory activity of DCs accompanied by decreased CD80 expression and TNF-α production. In addition, induction of tumor antigen-specific T cells from SLNs of the CT26-TGF-β1-implanted mice was significantly reduced. These results demonstrate that overproduction of TGF-β1 is critical for the generation of immunosuppressive microenvironments in both tumors and SLNs, which may result in suppression of spontaneous antitumor CD8 T-cell responses. Therefore, TGF-β1 is an attractive target for restoration of immunosuppressive condition in cancer patients.

Related: Colorectal (Bowel) Cancer

Wei JH, Cao JZ, Zhang D, et al.
EIF5A2 predicts outcome in localised invasive bladder cancer and promotes bladder cancer cell aggressiveness in vitro and in vivo.
Br J Cancer. 2014; 110(7):1767-77 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
BACKGROUND: EIF5A2, eukaryotic translation initiation factor 5A2, is associated with several human cancers. In this study, we investigated the role of EIF5A2 in the metastatic potential of localised invasive bladder cancer (BC) and its underlying molecular mechanisms were explored.
METHODS: The expression pattern of EIF5A2 in localised invasive BC was determined by immunohistochemistry. In addition, the function of EIF5A2 in BC and its underlying mechanisms were elucidated with a series of in vitro and in vivo assays.
RESULTS: Overexpression of EIF5A2 was an independent predictor for poor metastasis-free survival of localised invasive BC patients treated with radical cystectomy. Knockdown of EIF5A2 inhibited BC cell migratory and invasive capacities in vitro and metastatic potential in vivo and reversed epithelial-mesenchymal transition (EMT), whereas overexpression of EIF5A2 promoted BC cells motility and invasiveness in vitro and metastatic potential in vivo and induced EMT. In addition, we found that EIF5A2 might activate TGF-β1 expression to induce EMT and drive aggressiveness in BC cells. EIF5A2 stabilized STAT3 and stimulated nuclear localisation of STAT3, which resulted in increasing enrichment of STAT3 onto TGF-β1 promoter to enhance the transcription of TGF-β1.
CONCLUSIONS: EIF5A2 overexpression predicts tumour metastatic potential in patients with localised invasive BC treated with radical cystectomy. Furthermore, EIF5A2 elevated TGF-β1 expression through STAT3 to induce EMT and promotes aggressiveness in BC.

Related: Bladder Cancer Bladder Cancer - Molecular Biology

Yamasaki S, Taguchi Y, Shimamoto A, et al.
Generation of human induced pluripotent stem (Ips) cells in serum- and feeder-free defined culture and TGF-Β1 regulation of pluripotency.
PLoS One. 2014; 9(1):e87151 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
Human Embryonic Stem cells (hESCs) and human induced Pluripotent Stem cells (hiPSCs) are commonly maintained on inactivated mouse embryonic fibroblast as feeder cells in medium supplemented with FBS or proprietary replacements. Use of culture medium containing undefined or unknown components has limited the development of applications for pluripotent cells because of the relative lack of knowledge regarding cell responses to differentiating growth factors. In addition, there is no consensus as to the optimal formulation, or the nature of the cytokine requirements of the cells to promote their self-renewal and inhibit their differentiation. In this study, we successfully generated hiPSCs from human dental pulp cells (DPCs) using Yamanaka's factors (Oct3/4, Sox2, Klf4, and c-Myc) with retroviral vectors in serum- and feeder-free defined culture conditions. These hiPSCs retained the property of self-renewal as evaluated by the expression of self-renewal marker genes and proteins, morphology, cell growth rates, and pluripotency evaluated by differentiation into derivatives of all three primary germ layers in vitro and in vivo. In this study, we found that TGF-β1 increased the expression levels of pluripotency markers in a dose-dependent manner. However, increasing doses of TGF-β1 suppressed the growth rate of hiPSCs cultured under the defined conditions. Furthermore, over short time periods the hiPSCs cultured in hESF9 or hESF9T exhibited similar morphology, but hiPSCs maintained in hESF9 could not survive beyond 30 passages. This result clearly confirmed that hiPSCs cultured in hESF9 medium absolutely required TGF-β1 to maintain pluripotency. This simple serum-free adherent monoculture system will allow us to elucidate the cell responses to growth factors under defined conditions and can eliminate the risk might be brought by undefined pathogens.

Related: SOX2 gene

Mokrani M, Klibi J, Bluteau D, et al.
Smad and NFAT pathways cooperate to induce CD103 expression in human CD8 T lymphocytes.
J Immunol. 2014; 192(5):2471-9 [PubMed] Related Publications
The interaction of integrin αE(CD103)β7, often expressed on tumor-infiltrating T lymphocytes, with its cognate ligand, the epithelial cell marker E-cadherin on tumor cells, plays a major role in antitumor CTL responses. CD103 is induced on CD8 T cells upon TCR engagement and exposure to TGF-β1, abundant within the tumor microenvironment. However, the transcriptional mechanisms underlying the cooperative role of these two signaling pathways in inducing CD103 expression in CD8 T lymphocytes remain unknown. Using a human CTL system model based on a CD8(+)/CD103(-) T cell clone specific of a lung tumor-associated Ag, we demonstrated that the transcription factors Smad2/3 and NFAT-1 are two critical regulators of this process. We also identified promoter and enhancer elements of the human ITGAE gene, encoding CD103, involved in its induction by these transcriptional regulators. Overall, our results explain how TGF-β1 can participate in CD103 expression on locally TCR-engaged Ag-specific CD8 T cells, thus contributing to antitumor CTL responses and cancer cell destruction.

Related: Lung Cancer Signal Transduction SMAD3

Vonlanthen J, Okoniewski MJ, Menigatti M, et al.
A comprehensive look at transcription factor gene expression changes in colorectal adenomas.
BMC Cancer. 2014; 14:46 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
BACKGROUND: Biological processes are controlled by transcription networks. Expression changes of transcription factor (TF) genes in precancerous lesions are therefore crucial events in tumorigenesis. Our aim was to obtain a comprehensive picture of these changes in colorectal adenomas.
METHODS: Using a 3-pronged selection procedure, we analyzed transcriptomic data on 34 human tissue samples (17 adenomas and paired samples of normal mucosa, all collected with ethics committee approval and written, informed patient consent) to identify TFs with highly significant tumor-associated gene expression changes whose potential roles in colorectal tumorigenesis have been under-researched. Microarray data were subjected to stringent statistical analysis of TF expression in tumor vs. normal tissues, MetaCore-mediated identification of TF networks displaying enrichment for genes that were differentially expressed in tumors, and a novel quantitative analysis of the publications examining the TF genes' roles in colorectal tumorigenesis.
RESULTS: The 261 TF genes identified with this procedure included DACH1, which plays essential roles in the proper proliferation and differentiation of retinal and leg precursor cell populations in Drosophila melanogaster. Its possible roles in colorectal tumorigenesis are completely unknown, but it was found to be markedly overexpressed (mRNA and protein) in all colorectal adenomas and in most colorectal carcinomas. However, DACH1 expression was absent in some carcinomas, most of which were DNA mismatch-repair deficient. When networks were built using the set of TF genes identified by all three selection procedures, as well as the entire set of transcriptomic changes in adenomas, five hub genes (TGFB1, BIRC5, MYB, NR3C1, and TERT) where identified as putatively crucial components of the adenomatous transformation process.
CONCLUSION: The transcription-regulating network of colorectal adenomas (compared with that of normal colorectal mucosa) is characterized by significantly altered expression of over 250 TF genes, many of which have never been investigated in relation to colorectal tumorigenesis.

Related: Colorectal (Bowel) Cancer BIRC5 TERT

Li F, Dong L, Xing R, et al.
Homeobox B9 is overexpressed in hepatocellular carcinomas and promotes tumor cell proliferation both in vitro and in vivo.
Biochem Biophys Res Commun. 2014; 444(2):241-7 [PubMed] Related Publications
HomeoboxB9 (HOXB9), a nontransforming transcription factor that is overexpressed in multiple tumor types, alters tumor cell fate and promotes tumor progression. However, the role of HOXB9 in hepatocellular carcinoma (HCC) development has not been well studied. In this paper, we found that HOXB9 is overexpressed in human HCC samples. We investigated HOXB9 expression and its prognostic value for HCC. HCC surgical tissue samples were taken from 89 HCC patients. HOXB9 overexpression was observed in 65.2% of the cases, and the survival analysis showed that the HOXB9 overexpression group had significantly shorter overall survival time than the HOXB9 downexpression group. The ectopic expression of HOXB9 stimulated the proliferation of HCC cells; whereas the knockdown of HOXB9 produced an opposite effect. HOXB9 also modulated the tumorigenicity of HCC cells in vivo. Moreover, we found that the activation of TGF-β1 contributes to HOXB9-induced proliferation activities. The results provide the first evidence that HOXB9 is a critical regulator of tumor growth factor in HCC.

Related: Liver Cancer

Han X, Yan S, Weijie Z, et al.
Critical role of miR-10b in transforming growth factor-β1-induced epithelial-mesenchymal transition in breast cancer.
Cancer Gene Ther. 2014; 21(2):60-7 [PubMed] Related Publications
Epithelial-mesenchymal transition (EMT) is a key process in the tumor metastatic cascade that is characterized by the loss of cell-cell junctions and cell polarity, resulting in the acquisition of migratory and invasive properties. Recent evidence showed that altered microRNA-10b (miR-10b) expression was implicated in the occurrence of EMT of breast cancer. However, the exact role and underlying mechanisms of miR-10b in the EMT of breast cancer still remain unknown. In this study, miR-10b was found to be upregulated in breast cancer tissues and breast cancer cell lines and the expression of miR-10b was shown to be closely correlated with aggressiveness in breast cancer. Treating breast cancer cells with the miR-10b inhibitor increased E-cadherin expression while decreasing vimentin expression. At the same time, on inhibition of miR-10b, the invasion and proliferation ability of breast cancer cells also decreased. Transforming growth factor-β (TGF-β) is a multifunctional cytokine that induces EMT in multiple cell types. Here, we identified miR-10b as a target gene of TGF-β1. The expression of miR-10b increased during TGF-β1-induced EMT of breast cancer cells. Further study showed that inhibition of miR-10b expression partially reversed the EMT, invasion and proliferation induced by TGF-β1 in breast cancer cells. Taken together, these results demonstrated a novel function for miR-10b in TGF-β1-induced EMT in breast cancer and increased their metastatic potential. MiR-10b might become a possible target for gene therapy in breast cancer.

Related: Breast Cancer


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Cite this page: Cotterill SJ. TGFB1, Cancer Genetics Web: http://www.cancerindex.org/geneweb/TGFB1.htm Accessed: date

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