Gene Summary

Gene:TGFB1; transforming growth factor beta 1
Aliases: CED, LAP, DPD1, TGFB, IBDIMDE, TGFbeta, TGF-beta1
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:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:transforming growth factor beta-1 proprotein
Source:NCBIAccessed: 30 August, 2019


What does this gene/protein do?
Show (162)
Pathways:What pathways are this gene/protein implicaed in?
Show (17)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 30 August 2019 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 30 August, 2019 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)

Hadj-Ahmed M, Ghali RM, Bouaziz H, et al.
Transforming growth factor beta 1 polymorphisms and haplotypes associated with breast cancer susceptibility: A case-control study in Tunisian women.
Tumour Biol. 2019; 41(8):1010428319869096 [PubMed] Related Publications
Variable association of transforming growth factor beta 1 (TGFβ1) in breast cancer (BC) pathogenesis was documented, and the contribution of specific

Yan Y, Li XQ, Duan JL, et al.
Nanosized functional miRNA liposomes and application in the treatment of TNBC by silencing Slug gene.
Int J Nanomedicine. 2019; 14:3645-3667 [PubMed] Free Access to Full Article Related Publications

Kumar KJS, Vani MG, Hsieh HW, et al.
Antcin-A Modulates Epithelial-to-Mesenchymal Transition and Inhibits Migratory and Invasive Potentials of Human Breast Cancer Cells via p53-Mediated miR-200c Activation.
Planta Med. 2019; 85(9-10):755-765 [PubMed] Related Publications
Antcin-A (ATA) is a steroid-like phytochemical isolated from the fruiting bodies of a precious edible mushroom

Ando A, Hashimoto N, Sakamoto K, et al.
Repressive role of stabilized hypoxia inducible factor 1α expression on transforming growth factor β-induced extracellular matrix production in lung cancer cells.
Cancer Sci. 2019; 110(6):1959-1973 [PubMed] Free Access to Full Article Related Publications
Activation of transforming growth factor β (TGF-β) combined with persistent hypoxia often affects the tumor microenvironment. Disruption of cadherin/catenin complexes induced by these stimulations yields aberrant extracellular matrix (ECM) production, characteristics of epithelial-mesenchymal transition (EMT). Hypoxia-inducible factors (HIF), the hallmark of the response to hypoxia, play differential roles during development of diseases. Recent studies show that localization of cadherin/catenin complexes at the cell membrane might be tightly regulated by protein phosphatase activity. We aimed to investigate the role of stabilized HIF-1α expression by protein phosphatase activity on dissociation of the E-cadherin/β-catenin complex and aberrant ECM expression in lung cancer cells under stimulation by TGF-β. By using lung cancer cells treated with HIF-1α stabilizers or carrying doxycycline-dependent HIF-1α deletion or point mutants, we investigated the role of stabilized HIF-1α expression on TGF-β-induced EMT in lung cancer cells. Furthermore, the underlying mechanisms were determined by inhibition of protein phosphatase activity. Persistent stimulation by TGF-β and hypoxia induced EMT phenotypes in H358 cells in which stabilized HIF-1α expression was inhibited. Stabilized HIF-1α protein expression inhibited the TGF-β-stimulated appearance of EMT phenotypes across cell types and species, independent of de novo vascular endothelial growth factor A (VEGFA) expression. Inhibition of protein phosphatase 2A activity abrogated the HIF-1α-induced repression of the TGF-β-stimulated appearance of EMT phenotypes. This is the first study to show a direct role of stabilized HIF-1α expression on inhibition of TGF-β-induced EMT phenotypes in lung cancer cells, in part, through protein phosphatase activity.

Fu Y, Zhang P, Nan H, et al.
LncRNA CASC11 promotes TGF-β1, increases cancer cell stemness and predicts postoperative survival in small cell lung cancer.
Gene. 2019; 704:91-96 [PubMed] Related Publications
LncRNA CASC11 is a recently identified oncogenic lncRNA in colorectal cancer. This study aimed to investigate the role of lncRNA CASC11 in small cell lung cancer (SCLC). In the present study, expression levels of CASC11 and TGF-β1 were found to be positively and significantly correlated with the percentage of CDD133+ cells of SCLC cell lines. Plasma CASC11 and TGF-β1 were upregulated and positively correlated in SCLC patients, but not in healthy controls. Upregulation of plasma CASC11 and TGF-β1 predicted poor survival of SCLC patients. Overexpression of CASC11 and TGF-β1 also resulted in the increased percentage of CDD133+ cells of SCLC cell lines, while TGF-β inhibitor attenuated the effects of CASC11 overexpression. CASC11 overexpression mediated the upregulation of TGF-β1 in SCLC cells, while treatment with exogenous TGF-β1 showed no significant effect on CASC11. Therefore, lncRNA CASC11 promotes TGF-β1, increases cancer cell stemness and predicts postoperative survival in SCLC.

Singh V, Singh AP, Sharma I, et al.
Epigenetic deregulations of Wnt/β-catenin and transforming growth factor beta-Smad pathways in esophageal cancer: Outcome of DNA methylation.
J Cancer Res Ther. 2019 Jan-Mar; 15(1):192-203 [PubMed] Related Publications
Background: Promoter methylation of tumor suppressor genes (TSGs) is a well-reported portent in carcinogenesis; hence, it is worthy to investigate this in high-risk Northeast population of India. The study was designed to investigate methylation status of 94 TSGs in esophageal squamous cell carcinoma (ESCC). Further, the effect of OPCML promoter methylation on gene expression was analyzed by immunohistochemistry. Moreover, in silico protein-protein interactions were examined among 8 TSGs identified in the present study and 23 epigenetically regulated genes reported previously by our group in ESCC.
Materials and Methods: Methylation profiling was carried out by polymerase chain reaction array and OPCML protein expression was examined by tissue microarray-based immunohistochemistry.
Results: OPCML, NEUROG1, TERT, and WT1 genes were found hypermethylated and SCGB3A1, CDH1, THBS1, and VEGFA were hypomethylated in Grade 2 tumor. No significant change in OPCML expression was observed among control, Grade 1, and Grade 2 tumor. Conclusively, hypermethylation of the studied OPCML promoter in Grade 2 tumor produced no effect on expression. Unexpectedly, OPCML expression was downregulated in Grade 3 tumor in comparison to other groups signifying that downregulation of OPCML expression may lead to higher grade of tumor formation at the time of diagnosis of ESCC in patients. Significant interactions at protein level were found as VEGFA:PTK2, CTNNB1:CDH1, CTNNB1:VEGFA, CTNNB1:NEUROG1, CTNND2:CDH1, and CTNNB1:TERT. These interactions are pertinent to Wnt/β-catenin and TGF-β-Smad pathways.
Conclusions: Deranged OPCML expression may lead to high-grade ESCC as well as epigenetically regulated genes, that is, CDH1, CTNNB1, CTNND2, THBS1, PTK2, WT1, OPCML, TGFB1, and SMAD4 may alter the Wnt/β-catenin and TGF-β-Smad pathways in ESCC. Further study of these genes could be useful to understand the molecular pathology of ESCC with respect to epithelial-mesenchymal transition (EMT) mediated by Wnt/β-catenin and TGF-β signaling pathways.

Daubon T, Léon C, Clarke K, et al.
Deciphering the complex role of thrombospondin-1 in glioblastoma development.
Nat Commun. 2019; 10(1):1146 [PubMed] Free Access to Full Article Related Publications
We undertook a systematic study focused on the matricellular protein Thrombospondin-1 (THBS1) to uncover molecular mechanisms underlying the role of THBS1 in glioblastoma (GBM) development. THBS1 was found to be increased with glioma grades. Mechanistically, we show that the TGFβ canonical pathway transcriptionally regulates THBS1, through SMAD3 binding to the THBS1 gene promoter. THBS1 silencing inhibits tumour cell invasion and growth, alone and in combination with anti-angiogenic therapy. Specific inhibition of the THBS1/CD47 interaction using an antagonist peptide decreases cell invasion. This is confirmed by CD47 knock-down experiments. RNA sequencing of patient-derived xenograft tissue from laser capture micro-dissected peripheral and central tumour areas demonstrates that THBS1 is one of the gene with the highest connectivity at the tumour borders. All in all, these data show that TGFβ1 induces THBS1 expression via Smad3 which contributes to the invasive behaviour during GBM expansion. Furthermore, tumour cell-bound CD47 is implicated in this process.

Gao R, Zhang N, Yang J, et al.
Long non-coding RNA ZEB1-AS1 regulates miR-200b/FSCN1 signaling and enhances migration and invasion induced by TGF-β1 in bladder cancer cells.
J Exp Clin Cancer Res. 2019; 38(1):111 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The effect of competing endogenous RNA (ceRNA) can regulate gene expression by competitively binding microRNAs. Fascin-1 (FSCN1) plays an important role in the regulation of cellular migration and invasion during tumor progression, but how its regulatory mechanism works through the ceRNA effect is still unclear in bladder cancer (BLCA).
METHODS: The role of fascin-1, miR-200b, and ZEB1-AS1 in BLCA was investigated in vitro and in vivo. The interaction between fascin-1, miR-200b, and ZEB1-AS1 was identified using bioinformatics analysis, luciferase activity assays, RNA-binding protein immunoprecipitation (RIP), quantitative PCR, and western blotting. Loss (or gain)-of-function experiments were performed to investigate the biological roles of miR-200b and ZEB1-AS1 on migration, invasion, proliferation, cell apoptosis, and cell cycle.
RESULTS: ZEB1-AS1 functions as a competing endogenous RNA in BLCA to regulate the expression of fascin-1 through miR-200b. Moreover, the oncogenic long non-coding RNA ZEB1-AS1 was highly expressed in BLCA and positively correlated with high tumor grade, high TNM stage, and reduced survival of patients with BLCA. Moreover, ZEB1-AS1 downregulated the expression of miR-200b, promoted migration, invasion, and proliferation, and inhibited apoptosis in BLCA. Furthermore, we found TGF-β1 induced migration and invasion in BLCA by regulating the ZEB1-AS1/miR-200b/FSCN1 axis.
CONCLUSION: The observations in this study identify an important regulatory mechanism of fascin-1 in BLCA, and the TGF-β1/ZEB1-AS1/miR-200b/FSCN1 axis may serve as a potential target for cancer therapeutic purposes.

Farhan M, Malik A, Ullah MF, et al.
Garcinol Sensitizes NSCLC Cells to Standard Therapies by Regulating EMT-Modulating miRNAs.
Int J Mol Sci. 2019; 20(4) [PubMed] Free Access to Full Article Related Publications
Garcinol, a dietary factor obtained from

Teufel M, Seidel H, Köchert K, et al.
Biomarkers Associated With Response to Regorafenib in Patients With Hepatocellular Carcinoma.
Gastroenterology. 2019; 156(6):1731-1741 [PubMed] Related Publications
BACKGROUND & AIMS: In a phase 3 trial (RESORCE), regorafenib increased overall survival compared with placebo in patients with hepatocellular carcinoma (HCC) previously treated with sorafenib. In an exploratory study, we analyzed plasma and tumor samples from study participants to identify genetic, microRNA (miRNA), and protein biomarkers associated with response to regorafenib.
METHODS: We obtained archived tumor tissues and baseline plasma samples from patients with HCC given regorafenib in the RESORCE trial. Baseline plasma samples from 499 patients were analyzed for expression of 294 proteins (DiscoveryMAP) and plasma samples from 349 patients were analyzed for levels of 750 miRNAs (miRCURY miRNA PCR). Tumor tissues from 7 responders and 10 patients who did not respond (progressors) were analyzed by next-generation sequencing (FoundationOne). Forty-six tumor tissues were analyzed for expression patterns of 770 genes involved in oncogenic and inflammatory pathways (PanCancer Immune Profiling). Associations between plasma levels of proteins and miRNAs and response to treatment (overall survival and time to progression) were evaluated using a Cox proportional hazards model.
RESULTS: Decreased baseline plasma concentrations of 5 of 266 evaluable proteins (angiopoietin 1, cystatin B, the latency-associated peptide of transforming growth factor beta 1, oxidized low-density lipoprotein receptor 1, and C-C motif chemokine ligand 3; adjusted P ≤ .05) were significantly associated with increased overall survival time after regorafenib treatment. Levels of these 5 proteins, which have roles in inflammation and/or HCC pathogenesis, were not associated with survival independently of treatment. Only 20 of 499 patients had high levels and a reduced survival time. Plasma levels of α-fetoprotein and c-MET were associated with poor outcome (overall survival) independently of regorafenib treatment only. We identified 9 plasma miRNAs (MIR30A, MIR122, MIR125B, MIR200A, MIR374B, MIR15B, MIR107, MIR320, and MIR645) whose levels significantly associated with overall survival time with regorafenib (adjusted P ≤ .05). Functional analyses of these miRNAs indicated that their expression level associated with increased overall survival of patients with tumors of the Hoshida S3 subtype. Next-generation sequencing analyses of tumor tissues revealed 49 variants in 27 oncogenes or tumor suppressor genes. Mutations in CTNNB1 were detected in 3 of 10 progressors and VEGFA amplification in 1 of 7 responders.
CONCLUSION: We identified expression patterns of plasma proteins and miRNAs that associated with increased overall survival times of patients with HCC following treatment with regorafenib in the RESORCE trial. Levels of these circulating biomarkers and genetic features of tumors might be used to identify patients with HCC most likely to respond to regorafenib. number NCT01774344. NCBI GEO accession numbers: mRNA data (NanoString): GSE119220; miRNA data (Exiqon): GSE119221.

Asiri A, Raposo TP, Alfahed A, Ilyas M
TGFβ1-induced cell motility but not cell proliferation is mediated through Cten in colorectal cancer.
Int J Exp Pathol. 2018; 99(6):323-330 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Cten (C-terminal tensin-like) is a member of the tensin protein family found in complex with integrins at focal adhesions. It promotes epithelial-mesenchymal transition (EMT) and cell motility. The precise mechanisms regulating Cten are unknown, although we and others have shown that Cten could be under the regulation of several cytokines and growth factors. Since transforming growth factor beta 1 (TGF-β1) regulates integrin function and promotes EMT/cell motility, we were prompted to investigate whether TGF-β1 induces EMT and cell motility through Cten signalling in colorectal cancer. TGF-β1 signalling was modulated by either stimulation with TGF-β1 or knockdown of TGF-β1 in the CRC cell lines SW620 and HCT116. The effect of this modulation on expression of Cten, EMT markers and on cellular function was tested. The role of Cten as a direct mediator of TGF-β1 signalling was investigated in a CRC cell line in which the Cten gene had been deleted (SW620

Long NP, Park S, Anh NH, et al.
High-Throughput Omics and Statistical Learning Integration for the Discovery and Validation of Novel Diagnostic Signatures in Colorectal Cancer.
Int J Mol Sci. 2019; 20(2) [PubMed] Article available free on PMC after 01/12/2019 Related Publications
The advancement of bioinformatics and machine learning has facilitated the discovery and validation of omics-based biomarkers. This study employed a novel approach combining multi-platform transcriptomics and cutting-edge algorithms to introduce novel signatures for accurate diagnosis of colorectal cancer (CRC). Different random forests (RF)-based feature selection methods including the area under the curve (AUC)-RF, Boruta, and Vita were used and the diagnostic performance of the proposed biosignatures was benchmarked using RF, logistic regression, naïve Bayes, and k-nearest neighbors models. All models showed satisfactory performance in which RF appeared to be the best. For instance, regarding the RF model, the following were observed: mean accuracy 0.998 (standard deviation (SD) < 0.003), mean specificity 0.999 (SD < 0.003), and mean sensitivity 0.998 (SD < 0.004). Moreover, proposed biomarker signatures were highly associated with multifaceted hallmarks in cancer. Some biomarkers were found to be enriched in epithelial cell signaling in

Dudás J, Riml A, Tuertscher R, et al.
Brain-Derived Neurotrophin and TrkB in Head and Neck Squamous Cell Carcinoma.
Int J Mol Sci. 2019; 20(2) [PubMed] Article available free on PMC after 01/12/2019 Related Publications
We hypothesized that in head and neck squamous cell carcinoma (HNSCC), the neurotrophin brain-derived neurotrophic factor (BDNF) and its high affinity receptor TrkB regulate tumor cell survival, invasion, and therapy resistance. We used in situ hybridization for

Jiang J, Zheng M, Zhang M, et al.
PRRX1 Regulates Cellular Phenotype Plasticity and Dormancy of Head and Neck Squamous Cell Carcinoma Through miR-642b-3p.
Neoplasia. 2019; 21(2):216-229 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
BACKGROUND: Dormancy is one characteristic of cancer cells to make patients remain asymptomatic before metastasis and relapse, which is closely related to the survival rate of cancer patients, including head and neck squamous cell carcinoma (HNSCC). PRRX1 has previously been implicated in the invasion and metastasis of the epithelial-mesenchymal transition (EMT) process in different types of human carcinoma. However, whether PRRX1 can regulate cancer dormancy and its reactivation, leading to the migration and invasion of HNSCC cells, remains elusive. The aim of this study was to determine the role of PRRX1 in cellular phenotype plasticity and cancer dormancy of HNSCC cells and its association with miRNAs in HNSCC.
METHODS: The expression of PRRX1 was detected by immunohistochemical staining in primary HNSCC samples and the metastatic lymph nodes. Meanwhile, the role of PRRX1 and its relationship with miR-642b-3p and EMT in cellular phenotype plasticity and cancer dormancy of HNSCC were investigated in vitro and in vivo.
RESULTS: PRRX1 was significantly higher at the invasive front of HNSCC samples compared with the metastatic lymph nodes, and such switch process was accompanied by the cellular phenotype plasticity and cell dormancy activation. In HNSCC cell lines, PRRX1 positively promoted the expression of known EMT inducers and cooperated with activated TGF-β1 to contribute to EMT and migration and invasion of HNSCC cells. Then, we found that overexpression of miR-642b-3p, one of the most significantly downregulated miRNAs in PRRX1-overexpressed cells, significantly reduced the migration and invasion, and increased cell proliferation and apoptosis. And miR-642b-3p restoration reversed PRRX1-induced cell dormancy and EMT of HNSCC cells through TGF-β2 and p38. Finally, we demonstrated that overexpressed PRRX1 was closely correlated with miR-642b-3p downregulation and the upregulation of TGF-β2 and p38 in a xenograft model of HNSCC.
CONCLUSIONS: Our findings showed that PRRX1 may be one of the main driving forces for the cellular phenotype plasticity and tumor dormancy of HNSCC. Therefore, we can raise the possibility that EMT may help to keep cancer cell in dormant state and mesenchymal-epithelial transition may resurge dormancy in HNSCC.

Wu LS, Wang XW, He W, et al.
TRAIL inhibits platelet-induced colorectal cancer cell invasion.
J Int Med Res. 2019; 47(2):962-972 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
OBJECTIVE: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a pro-apoptotic ligand that activates the extrinsic apoptosis pathway of cell death receptors. This study aimed to evaluate the relationship between TRAIL and platelet-induced tumor metastasis in colorectal cancer.
METHODS: Platelet P-selectin (CD62P) was measured by immunohistochemistry in tumor and adjacent normal tissues from 90 patients with colorectal cancer undergoing resection. Tumor cell invasion was assessed by transwell assay in the presence of platelets with or without TRAIL. The expression of TRAIL receptors DR4 and DR5 on platelets was assessed by flow cytometry, real-time polymerase chain reaction, and western blotting.
RESULTS: P-selectin (CD62P) expression was significantly increased in tumor tissues compared with adjacent normal tissues. High CD62P expression was significantly correlated with tumor stage and vascular invasion. Tumor cell migration was increased by coculture with platelets, but this effect was inhibited by TRAIL. Transforming growth factor (TGF)-β1 secretion was significantly reduced in TRAIL-treated platelets. The TRAIL receptor DR5 but not DR4 was expressed in platelets according to flow cytometry.
CONCLUSIONS: TRAIL could inhibit metastasis and colon cancer cell invasion by promoting platelet apoptosis and reducing the release of TGF-β1.

Li W, Wu X, She W
LncRNA POU3F3 promotes cancer cell migration and invasion in nasopharyngeal carcinoma by up-regulating TGF-β1.
Biosci Rep. 2019; 39(1) [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Up-regulation of lncRNA POU3F3 has been observed in esophageal squamous cell carcinomas, while its expression pattern and functionality in other human disease is unknown. Our study showed that plasma levels of lncRNA POU3F3 and TGF-β1 (transforming growth factor-β) were both increased in nasopharyngeal carcinoma patients than in healthy controls. Plasma levels of lncRNA POU3F3 were not affected by the diameter of primary tumors but increased in patients with tumor metastasis. Plasma levels of lncRNA POU3F3 and TGF-β1 were positively correlated only in nasopharyngeal carcinoma patients but not in healthy controls. Follow-up study showed that high plasma levels of lncRNA POU3F3 were significantly correlated with poor overall survival. LncRNA POU3F3 overexpression and exogenous TGF-β1 treatment led to promoted, while TGF-β1 inhibitor led to inhibited migration and invasion of nasopharyngeal carcinoma cells. TGF-β1 inhibitor partially rescued the inhibited cancer cell migration and invasion caused by lncRNA POU3F3 overexpression. LncRNA POU3F3 overexpression led to down-regulated TGF-β1 expression, while exogenous TGF-β1 and TGF-β1 inhibitor treatment did not significantly change the expression level of lncRNA POU3F3. Therefore, lncRNA POU3F3 may promote cancer cell migration and invasion in nasopharyngeal carcinoma by up-regulating TGF-β1.

Wang Y, Xiang J, Wang J, Ji Y
Downregulation of TGF-β1 suppressed proliferation and increased chemosensitivity of ovarian cancer cells by promoting BRCA1/Smad3 signaling.
Biol Res. 2018; 51(1):58 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
BACKGROUND: Studies have demonstrated that transforming growth factor beta-1 (TGF-β1) exhibits oncogenic activity in different types of cancer, including ovarian cancer (OC). However, its regulatory mechanism in OC and whether TGF-β1 is involved in chemosensitivity regulation remains unclear. Thus, the aim of this study was to investigate the role of TGF-β1 in OC.
METHODS: The OC cell line SKOV3 was employed, and TGF-β1 overexpression or knockdown vectors were constructed. The cell proliferation of SKOV3 was evaluated with the cell counting kit (CCK8) kit after treatment with different concentrations of cis-platinum. Western blot and protein immunoprecipitation were employed to detect changes in BRCA1 and Smad3 expression and their interactions. Tumor growth in nude mice was evaluated.
RESULTS: The results showed that TGF-β1 knockdown increased chemosensitivity by promoting BRCA1 expression and Smad3 phosphorylation. In vivo studies showed that TGF-β1 knockdown significantly inhibited the growth of tumors, also by upregulating BRCA1 expression and Smad3 phosphorylation.
CONCLUSION: Taken together, our results suggest that TGF-β1 knockdown inhibits tumor growth and increases chemosensitivity by promotion of BRCA1/Smad3 signaling.

Liang Y, Zhang C, Ma MH, Dai DQ
Identification and prediction of novel non-coding and coding RNA-associated competing endogenous RNA networks in colorectal cancer.
World J Gastroenterol. 2018; 24(46):5259-5270 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
AIM: To identify and predict the competing endogenous RNA (ceRNA) networks in colorectal cancer (CRC) by bioinformatics analysis.
METHODS: In the present study, we obtained CRC tissue and normal tissue gene expression profiles from The Cancer Genome Atlas project. Differentially expressed (DE) genes (DEGs) were identified. Then, upregulated and downregulated miRNA-centered ceRNA networks were constructed by analyzing the DEGs using multiple bioinformatics approaches. DEmRNAs in the ceRNA networks were identified in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways using KEGG Orthology Based Annotation System 3.0. The interactions between proteins were analyzed using the STRING database. Kaplan-Meier survival analysis was conducted for DEGs and real time quantitative polymerase chain reaction (RT-qPCR) was also performed to validate the prognosis-associated lncRNAs in CRC cell lines.
RESULTS: Eighty-one DElncRNAs, 20 DEmiRNAs, and 54 DEmRNAs were identified to construct the ceRNA networks of CRC. The KEGG pathway analysis indicated that nine out of top ten pathways were related with cancer and the most significant pathway was "colorectal cancer". Kaplan-Meier survival analysis showed that the overall survival was positively associated with five DEGs (IGF2-AS, POU6F2-AS2, hsa-miR-32, hsa-miR-141, and SERPINE1) and it was negatively related to three DEGs (LINC00488, hsa-miR-375, and PHLPP2). Based on the STRING protein database, it was found that SERPINE1 and PHLPP2 interact with AKT1. Besides, SERPINE1 can interact with VEGFA, VTN, TGFB1, PLAU, PLAUR, PLG, and PLAT. PHLPP2 can interact with AKT2 and AKT3. RT-qPCR revealed that the expression of IGF2-AS, POU6F2-AS2, and LINC00488 in CRC cell lines was consistent with the
CONCLUSION: CeRNA networks play an important role in CRC. Multiple DEGs are related with clinical prognosis, suggesting that they may be potential targets in tumor diagnosis and treatment.

Li Z, Huang J, Shen S, et al.
SIRT6 drives epithelial-to-mesenchymal transition and metastasis in non-small cell lung cancer via snail-dependent transrepression of KLF4.
J Exp Clin Cancer Res. 2018; 37(1):323 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
BACKGROUND: Epithelial-to-mesenchymal transition (EMT) contributes to the invasion and metastasis of epithelial tumors. Sirtuin 6 (SIRT6), an NAD-dependent deacetylase, is known to promote metastasis of non-small cell lung cancer (NSCLC).
METHODS: In this work, we determined the role of SIRT6 in the EMT of NSCLC cells and identified the key EMT-related genes involved in the oncogenic activity of SIRT6.
RESULTS: We report that depletion of SIRT6 inhibits transforming growth factor-β1 (TGF-β1)-induced EMT in A549 and H1299 NSCLC cells, which is rescued by ectopic expression of SIRT6. Knockdown of SIRT6 leads to a reduction in Snail protein without affecting the mRNA level. Immunoprecipitation experiments demonstrate a physical association between SIRT6 and Snail. SIRT6 deacetylates Snail and prevents its proteasomal degradation. Silencing of Snail blunts SIRT6-induced NSCLC cell migration and invasion, while overexpression of Snail restores the invasion and EMT in SIRT6-depleted NSCLC cells. SIRT6 depletion leads to an upregulation of kruppel-like factor 4 (KLF4) and reduced Snail binding to the promoter of Klf4 in NSCLC cells. Knockdown of KLF4 rescues the invasive capacity in SIRT6-depleted NSCLC cells. Conversely, co-expression of KLF4 impairs SIRT6-induced aggressive behavior. In vivo data further demonstrate that SIRT6-induced NSCLC metastasis is antagonized by overexpression of KLF4.
CONCLUSIONS: These findings provide mechanistic insights into the pro-metastatic activity of SIRT6 and highlight the role of the SIRT6/Snail/KLF4 axis in regulating EMT and invasion of NSCLC cells.

Zhuang X, Wang J
Correlations of MRP1 gene with serum TGF-β1 and IL-8 in breast cancer patients during chemotherapy.
J BUON. 2018 Sep-Oct; 23(5):1302-1308 [PubMed] Related Publications
PURPOSE: To investigate the expressions of multidrug resistance-associated protein 1 (MRP1) gene, serum transforming growth factor beta-1 (TGF-β1) and interleukin-8 (IL-8) in patients with breast cancer during chemotherapy, and to analyze their correlations in chemotherapy.
METHODS: 346 breast cancer patients admitted to the Department of Surgery (Breast) of Nanjing Drum Tower Hospital from March 2015 to December 2017 were included as study subjects. All selected patients received chemotherapy in our hospital. Quantitative reverse transcription- polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) were adopted to detect the expression levels of MRP1 mRNA, as well as MRP1, TGF-β1 and IL-8 proteins in patients before chemotherapy and at 1, 2, 4 and 8 weeks after chemotherapy. Correlations of MRP1 protein/mRNA with clinical features of patients were analyzed, and Pearson's correlation analysis was performed to examine correlations of MRP1 protein/mRNA with TGF-β1 and IL-8 proteins.
RESULTS: The expressions of MRP1 mRNA as well as MRP1, TGF-β1 and IL-8 proteins were increased with the prolongation of chemotherapy time, and there were statistically significant differences between the two time points (pCONCLUSION: With the prolongation of chemotherapy time in breast cancer patients, the expression level of MRP1 also increased which may affect the therapeutic effect of chemotherapy in breast cancer patients and lead to drug resistance. TGF-β1 and IL-8 may be closely associated with the mechanism of drug resistance in MRP1-guided breast cancer chemotherapy.

Zheng X, Dong L, Wang K, et al.
MiR-21 Participates in the PD-1/PD-L1 Pathway-Mediated Imbalance of Th17/Treg Cells in Patients After Gastric Cancer Resection.
Ann Surg Oncol. 2019; 26(3):884-893 [PubMed] Related Publications
BACKGROUND: The programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) pathway has been shown to be involved in trauma-induced immunosuppression and to influence CD4
METHODS: In the present study, we analyzed the percentages of T-helper (Th)-17/regulatory T (Treg) cells and PD-1/PD-L1 expression on peripheral blood mononuclear cells (PBMCs) during the perioperative period. We also detected the secretion of interleukin (IL)-17 and transforming growth factor (TGF)-β1 using enzyme-linked immunosorbent assays (ELISAs). Furthermore, PBMCs isolated from patients were transfected with or without adenovirus-short hairpin-PD-1 (Ad-sh-PD1), pre-miR-21 or adenovirus-green fluorescent protein (Ad-GFP), and the percentages of Th17/Treg cells and related transcription factors were measured.
RESULTS: In patients who underwent gastric cancer resection, the number of Th17 cells decreased, whereas the number of Treg cells increased, accompanied by an increased expression of PD-1/PD-L1. In addition, the expression of RORγt and IL-17 decreased, whereas the expression of Foxp3 and TGF-β1 increased. In vitro, silencing PD-1 via Ad-sh-PD1 promoted the expression of miR-21 and increased the percentage of Th17 cells, but decreased the percentage of Treg cells. The overexpression of miR-21 increased the percentage of Th17 cells but decreased the percentage of Treg cells.
CONCLUSIONS: Our study demonstrated that gastric cancer resection altered the balance of Th17/Treg cells and increased PD-1/PD-L1 expression. In the in vitro experiments, the transfection of Ad-sh-PD1 ameliorated Th17/Treg cell imbalance partially by increasing the expression of miR-21.

Cultrara CN, Kozuch SD, Ramasundaram P, et al.
GRP78 modulates cell adhesion markers in prostate Cancer and multiple myeloma cell lines.
BMC Cancer. 2018; 18(1):1263 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
BACKGROUND: Glucose regulated protein 78 (GRP78) is a resident chaperone of the endoplasmic reticulum and a master regulator of the unfolded protein response under physiological and pathological cell stress conditions. GRP78 is overexpressed in many cancers, regulating a variety of signaling pathways associated with tumor initiation, proliferation, adhesion and invasion which contributes to metastatic spread. GRP78 can also regulate cell survival and apoptotic pathways to alter responsiveness to anticancer drugs. Tumors that reside in or metastasize to the bone and bone marrow (BM) space can develop pro-survival signals through their direct adhesive interactions with stromal elements of this niche thereby resisting the cytotoxic effects of drug treatment. In this study, we report a direct correlation between GRP78 and the adhesion molecule N-cadherin (N-cad), known to play a critical role in the adhesive interactions of multiple myeloma and metastatic prostate cancer with the bone microenvironment.
METHODS: N-cad expression levels (transcription and protein) were evaluated upon siRNA mediated silencing of GRP78 in the MM.1S multiple myeloma and the PC3 metastatic prostate cancer cell lines. Furthermore, we evaluated the effects of GRP78 knockdown (KD) on epithelial-mesenchymal (EMT) transition markers, morphological changes and adhesion of PC3 cells.
RESULTS: GRP78 KD led to concomitant downregulation of N-cad in both tumors types. In PC3 cells, GRP78 KD significantly decreased E-cadherin (E-cad) expression likely associated with the induction in TGF-β1 expression. Furthermore, GRP78 KD also triggered drastic changes in PC3 cells morphology and decreased their adhesion to osteoblasts (OSB) dependent, in part, to the reduced N-cad expression.
CONCLUSION: This work implicates GRP78 as a modulator of cell adhesion markers in MM and PCa. Our results may have clinical implications underscoring GRP78 as a potential therapeutic target to reduce the adhesive nature of metastatic tumors to the bone niche.

Zhang X, Cho IH, Park JH, et al.
Fascin is involved in cancer cell invasion and is regulated by stromal factors.
Oncol Rep. 2019; 41(1):465-474 [PubMed] Related Publications
The tumor microenvironment plays an important role in cancer growth, invasion and metastasis. The stroma surrounding a tumor is known to contain a variety of factors that can increase angiogenesis, cancer growth and tumor progression. The aim of the present study was to determine the role of fascin in cancer growth and invasion and identify stromal factors involved in cancer progression. A fascin‑depleted cell line (fascindep) was used to observe the role of fascin in cancer invasion. Compared with wild‑type Mock cells, cancer cell invasion in Matrigel‑coated Transwell and three‑dimensional (3D) culture system were reduced by fascin depletion. Tumor cell growth in vivo was also significantly reduced in mice injected with fascindep cells. Notably, fascin expression was increased during Transwell invasion with Matrigel compared to Transwell invasion without Matrigel. TGF‑β1, EGF and IL‑1β significantly stimulated fascin expression. Such increased expression of fascin was also observed in cultured cells using conditioned media (CM) from cancer‑associated fibroblasts (CAFs). However, no significant change in fascin expression was observed using CM from normal fibroblasts (NFs). Stimulated expression of fascin by Matrigel and CAFs was reduced by biological specific inhibitor of TGF‑β1, EGF and IL‑1β. Compared with wild‑type Mock cells, the fascindep cell line showed low RhoA and NF‑κB activity, suggesting that RhoA and NF‑κB signals are involved in fascin expression. In conclusion, stromal factors are involved in cancer invasion and progression by activating intracellular signaling of cancer cells to increase fascin expression.

Liu S, Hou H, Zhang P, et al.
Sphingomyelin synthase 1 regulates the epithelial‑to‑mesenchymal transition mediated by the TGF‑β/Smad pathway in MDA‑MB‑231 cells.
Mol Med Rep. 2019; 19(2):1159-1167 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Breast cancer is the most common cancer in women and a leading cause of cancer‑associated mortalities in the world. Epithelial‑to‑mesenchymal transition (EMT) serves an important role in the process of metastasis and invasive ability in cancer cells, and transforming growth factor β1 (TGF‑β1) have been investigated for promoting EMT. However, in the present study, the role of the sphingomyelin synthase 1 (SMS1) in TGF‑β1‑induced EMT development was investigated. Firstly, bioinformatics analysis demonstrated that the overexpression of SMS1 negatively regulated the TGFβ receptor I (TβRI) level of expression. Subsequently, the expression of SMS1 was decreased, whereas, SMS2 had no significant difference when MDA‑MB‑231 cells were treated by TGF‑β1 for 72 h. Furthermore, the present study constructed an overexpression cells model of SMS1 and these cells were treated by TGF‑β1. These results demonstrated that overexpression of SMS1 inhibited TGF‑β1‑induced EMT and the migration and invasion of MDA‑MB‑231 cells, increasing the expression of E‑cadherin while decreasing the expression of vimentin. Furthermore, the present study further confirmed that SMS1 overexpression could decrease TβRI expression levels and blocked smad family member 2 phosphorylation. Overall, the present results suggested that SMS1 could inhibit EMT and the migration and invasion of MDA‑MB‑231 cells via TGF‑β/Smad signaling pathway.

Miao F, Chen J, Shi M, et al.
LncRNA HAND2-AS1 inhibits non-small cell lung cancer migration, invasion and maintains cell stemness through the interactions with TGF-β1.
Biosci Rep. 2019; 39(1) [PubMed] Article available free on PMC after 01/12/2019 Related Publications
LncRNA HAND2-AS1 is characterized as a tumor suppressor involved in several types of malignancies, but its role in non-small cell lung cancer (NSCLC) is unknown. Our study was carried out to investigate the involvement of lncRNA HAND2-AS1 in NSCLC. In our study, we observed that levels of HAND2-AS1 were lower in tumor tissues than that in adjacent healthy tissues. Compared with healthy controls, plasma levels of HAND2-AS1 were lower, while levels of transforming growth factor β (TGF-β) were higher in NSCLC patients. A significant negative correlation between plasma levels of HAND2-AS1 and TGF-β1 was found in NSCLC patients but not in healthy controls. LncRNA HAND2-AS1 overexpression inhibits, while exogenous TGF-β1 treatment promotes cell migration and invasion ability and cancer cell stemness. Cancer cells with lncRNA HAND2-AS1 overexpression showed down-regulated TGF-β1, while TGF-β1 treatment showed no significant effects on lncRNA HAND2-AS1 expression. TGF-β1 attenuated the inhibitory effects of lncRNA HAND2-AS1 overexpression on cell migration, invasion and stemness. We concluded that lncRNA HAND2-AS1 may regulate the migration, invasion and stemness of NSCLC cells through interactions with TGF-β1.

Kwan AK, Um CY, Rutherford RE, et al.
Effects of vitamin D and calcium on expression of MSH2 and transforming growth factors in normal-appearing colorectal mucosa of sporadic colorectal adenoma patients: A randomized clinical trial.
Mol Carcinog. 2019; 58(4):511-523 [PubMed] Related Publications
Abnormal expression of the DNA mismatch repair protein MSH2 and autocrine/paracrine transforming growth factors TGFα (growth promoter) and TGFβ

Abd El-Fattah AA, Sadik NAH, Shaker OG, Mohamed Kamal A
Single Nucleotide Polymorphism in SMAD7 and CHI3L1 and Colorectal Cancer Risk.
Mediators Inflamm. 2018; 2018:9853192 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Colorectal cancer (CRC) is one of the leading cancers throughout the world. It represents the third most common cancer and the fourth in mortality. Most of CRC are sporadic, arise with no known high-penetrant genetic variation and with no previous family history. The etiology of sporadic CRC is considered to be multifactorial and arises from the interaction of genetic variants of low-penetrant genes and environmental risk factors. The most common well-studied genetic variation is single nucleotide polymorphisms (SNPs). SNP arises as a point mutation. If the frequency of the sequence variation reaches 1% or more in the population, it is referred to as polymorphism, but if it is lower than 1%, the allele is typically considered as a mutation. Lots of SNPs have been associated with CRC development and progression, for example, genes of TGF-

Zhang C, Chen B, Jiao A, et al.
miR-663a inhibits tumor growth and invasion by regulating TGF-β1 in hepatocellular carcinoma.
BMC Cancer. 2018; 18(1):1179 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
BACKGROUND: The dysregulation of miR-663a is frequently observed in many human cancers. However, the functional role and precise mechanism of miR-663a have been controversial in hepatocellular carcinoma (HCC) and need to be studied in depth.
METHODS: The expression of miR-663a was detected in human cell lines and HCC tissues by quantitative RT-PCR (qRT-PCR), and data from the Cancer Genome Atlas (TCGA). Cell proliferation was investigated using MTS, EdU, colony formation assays, and xenograft animal experiments, and the cell invasion capacity was evaluated using the transwell assay. The target gene of miR-663a was identified by qRT-PCR, Western blot, and dual-luciferase reporter assays. The clinicopathological features of miR-663a and the correlation between miR-663a and TGF-β1 expression were also investigated in the clinical samples of HCC.
RESULTS: miR-663a was significantly downregulated in HCC cells relative to immortal normal liver cells, as indicated using qRT-PCR, and the lower expression of miR-663a was also confirmed in HCC tissue samples and the data from TCGA. The expression of miR-663a in HCC tissue samples was statistically significantly associated with size and the number of tumors. In addition, the upregulation of miR-663a inhibited the proliferation and invasion of HCC cells in vitro. Further study showed that miR-663a directly targeted transforming growth factor beta 1 (TGF-β1) to suppress HCC invasion, and that the inhibitory effect of miR-663a on cell invasion could be regulated by TGF-β1. In vivo studies showed that miR-663a significantly inhibited tumor growth. A negative correlation between miR-663a and TGF-β1 expression was also confirmed from the clinical samples of HCC.
CONCLUSIONS: miR-663a acts as a tumor suppressor and exerts a substantial role in inhibiting the proliferation, invasion, and tumorigenesis of HCC by regulating TGF-β1 in vitro and in vivo. These observations indicate that miR-663a may be a suitable diagnostic, therapeutic, and prognostic target for the treatment of HCC.

Zeng K, He B, Yang BB, et al.
The pro-metastasis effect of circANKS1B in breast cancer.
Mol Cancer. 2018; 17(1):160 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
BACKGROUND: Recent studies indicate that circular RNA (circRNA) plays a pivotal role in cancer progression. Here, we sought to investigate its role in breast cancer.
METHODS: CircANKS1B (a circRNA originated from exons 5 to 8 of the ANKS1B gene, hsa_circ_0007294) was identified by RNA-sequencing and validated by qRT-PCR and Sanger sequencing. Clinical breast cancer samples were used to evaluate the expression of circANKS1B and its associations with clinicopathological features and prognosis. Gain- and loss-of-function experiments in cell lines and mouse xenograft models were performed to support clinical findings and elucidate the function and underlying mechanisms of circANKS1B in breast cancer.
RESULTS: CircANKS1B was significantly up-regulated in triple-negative breast cancer (TNBC) compared with non-TNBC tissues and cell lines. Increased circANKS1B expression was closely associated with lymph node metastasis and advanced clinical stage and served as an independent risk factor for overall survival of breast cancer patients. Functional studies revealed that circANKS1B promoted breast cancer invasion and metastasis both in vitro and in vivo by inducing epithelial-to-mesenchymal transition (EMT), while had no effect on breast cancer growth. Mechanistically, circANKS1B abundantly sponged miR-148a-3p and miR-152-3p to increase the expression of transcription factor USF1, which could transcriptionally up-regulate TGF-β1 expression, resulting in activating TGF-β1/Smad signaling to promote EMT. Moreover, we found that circANKS1B biogenesis in breast cancer was promoted by splicing factor ESRP1, whose expression was also regulated by USF1.
CONCLUSIONS: Our data uncover an essential role of the novel circular RNA circANKS1B in the metastasis of breast cancer, which demonstrate that therapeutic targeting of circANKS1B may better prevent breast cancer metastasis.

Luo Y, Huang K, Zheng J, et al.
TGF-β1 promotes cell migration in hepatocellular carcinoma by suppressing reelin expression.
Gene. 2019; 688:19-25 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and is a leading cause of worldwide cancer mortality. Intrahepatic dissemination and extrahepatic metastasis are key factors in malignant growth of HCC. Reducing HCC-associated metastasis is critically dependent on uncovering molecular signaling pathways that promote HCC metastasis. In this study, we explored the effect of TGF-β1 and RELN on cell migration, and the relationship between TGF-β1 and RELN in HCC cells. The data presented that TGF-β1 and RELN showed an opposite expression pattern, and either increased expression of TGF-β1 or decreased expression of RELN increased HCC cell migration ability. We also found TGF-β1 enhanced cell migration ability was through repressing RELN expression, as overexpression of RELN impaired TGF-β1 enhanced cell migration. Our work revealed the relationship between TGF-β1 and RELN and uncovered the important role of RELN in suppressing cell migration in HCC cells.

Disclaimer: This site is for educational purposes only; it can not be used in diagnosis or treatment.

Cite this page: Cotterill SJ. TGFB1, Cancer Genetics Web: Accessed:

Creative Commons License
This page in Cancer Genetics Web by Simon Cotterill is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Note: content of abstracts copyright of respective publishers - seek permission where appropriate.

 [Home]    Page last revised: 30 August, 2019     Cancer Genetics Web, Established 1999