Gene Summary

Gene:SMAD3; SMAD family member 3
Aliases: LDS3, LDS1C, MADH3, JV15-2, HSPC193, HsT17436
Summary:The protein encoded by this gene belongs to the SMAD, a family of proteins similar to the gene products of the Drosophila gene 'mothers against decapentaplegic' (Mad) and the C. elegans gene Sma. SMAD proteins are signal transducers and transcriptional modulators that mediate multiple signaling pathways. This protein functions as a transcriptional modulator activated by transforming growth factor-beta and is thought to play a role in the regulation of carcinogenesis. [provided by RefSeq, Apr 2009]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:mothers against decapentaplegic homolog 3
Source:NCBIAccessed: 31 August, 2019


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

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 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 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (2)

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: SMAD3 (cancer-related)

Wu TK, Chen CH, Pan YR, et al.
Cetrimonium Bromide Inhibits Cell Migration and Invasion of Human Hepatic SK-HEP-1 Cells Through Modulating the Canonical and Non-canonical TGF-β Signaling Pathways.
Anticancer Res. 2019; 39(7):3621-3631 [PubMed] Related Publications
BACKGROUND/AIM: Cetrimonium bromide (CTAB), a quaternary ammonium surfactant, is an antiseptic agent against bacteria and fungi. However, the mechanisms by which its pharmacological actions affect epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma (HCC) cells, such as adenocarcinoma in SK-HEP-1 cells, have not been investigated. We, thereby, investigated whether CTAB inhibits cellular mobility and invasiveness of human hepatic adenocarcinoma in SK-HEP-1 cells.
MATERIALS AND METHODS: SK-HEP-1 cells were treated with CTAB, and subsequent migration and invasion were measured by wound healing and transwell assays. Protein expression was detected by immunoblotting analysis.
RESULTS: Our data revealed that treatment of SK-HEP-1 cells with CTAB altered their mesenchymal spindle-like morphology. CTAB exerted inhibitory effects on the migration and invasion of SK-HEP-1 cells dose-dependently, and reduced protein levels of matrix metalloproteinase-2 (MMP-2), MMP-9, snail, slug, twist, vimentin, fibronectin, N-cadherin, Smad2, Smad3, Smad4, phosphoinositide-3-kinase (PI3K), p-PI3K, Akt, p-Akt, β-catenin, mammalian target of rapamycin (mTOR), p-mTOR, p-p70S6K, p-extracellular signal-regulated kinases (ERK)1/2, p-p38 mitogen-activated protein kinase (MAPK) and p-c-Jun N-terminal kinase (JNK), but increased protein levels of tissue inhibitor matrix metalloproteinase-1 (TIMP-1), TIMP-2, claudin-1 and p-GSK3β. Based on these observations, we suggest that CTAB not only inhibits the canonical transforming growth factor-β (TGF-β) signaling pathway though reducing SMADs (an acronym from the fusion of Caenorhabditis elegans Sma genes and the Drosophila Mad, Mothers against decapentaplegic proteins), but also restrains the non-canonical TGF-β signaling including MAPK pathways like ERK1/2, p38 MAPK, JNK and PI3K.
CONCLUSION: CTAB is involved in the suppression of TGF-β-mediated mesenchymal phenotype and could be a potent medical agent for use in controlling the migration and invasion of hepatic adenocarcinoma.

Zhang Q, Huang F, Yao Y, et al.
Interaction of transforming growth factor-β-Smads/microRNA-362-3p/CD82 mediated by M2 macrophages promotes the process of epithelial-mesenchymal transition in hepatocellular carcinoma cells.
Cancer Sci. 2019; 110(8):2507-2519 [PubMed] Free Access to Full Article Related Publications
Abnormal tumor microenvironment and the epithelial-mesenchymal transition (EMT) are important features of tumor metastasis. However, it remains unknown how signals can form complicated networks to regulate the sustainability of the EMT process. The aim of our study is to explore the possible interaction between tumor-associated macrophages and tumor cells in the EMT process mediated by microRNA (miR)-362-3p. In this study, we found that by releasing TGF-β, M2 macrophages mediate binding of Smad2/3 to miR-362-3p promoter, leading to overexpression of miR-362-3p. MicroRNA-362-3p maintains EMT by regulating CD82, one of the most important members of the family of tetraspanins. Our finding suggests that miR-362-3p can serve as a core factor mediating cross-talk between the TGF-β pathway in tumor-associated macrophages and tetraspanins in tumor cells, and thus facilitates the EMT process.

Li X, Ding D, Yao J, et al.
Chromatin remodeling factor BAZ1A regulates cellular senescence in both cancer and normal cells.
Life Sci. 2019; 229:225-232 [PubMed] Related Publications
AIMS: Cellular senescence is a well-known cancer prevention mechanism, inducing cancer cells to senescence can enhance cancer immunotherapy. However, how cellular senescence is regulated is not fully understood. Dynamic chromatin changes have been discovered during cellular senescence, while the causality remains elusive. BAZ1A, a gene coding the accessory subunit of ATP-dependent chromatin remodeling complex, showed decreased expression in multiple cellular senescence models. We aim to investigate the functional role of BAZ1A in regulating senescence in cancer and normal cells.
MATERIALS AND METHODS: Knockdown of BAZ1A was performed via lentivirus mediated short hairpin RNA (shRNA) in various cancer cell lines (A549 and U2OS) and normal cells (HUVEC, NIH3T3 and MEF). A series of senescence-associated phenotypes were quantified by CCK-8 assay, SA-β-Gal staining and EdU incorporation assay, etc. KEY FINDINGS: Knockdown (KD) of BAZ1A induced series of senescence-associated phenotypes in both cancer and normal cells. BAZ1A-KD caused the upregulated expression of SMAD3, which in turn activated the transcription of p21 coding gene CDKN1A and resulted in senescence-associated phenotypes in human cancer cells (A549 and U2OS).
SIGNIFICANCE: Our results revealed chromatin remodeling modulator BAZ1A acting as a novel regulator of cellular senescence in both normal and cancer cells, indicating a new target for potential cancer treatment.

Liu Z, He F, OuYang S, et al.
miR-140-5p could suppress tumor proliferation and progression by targeting TGFBRI/SMAD2/3 and IGF-1R/AKT signaling pathways in Wilms' tumor.
BMC Cancer. 2019; 19(1):405 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Wilms' tumor is also called nephroblastoma and is the most common pediatric renal cancer. Several genetic and epigenetic factors have been found to account for the development of Wilms' tumor. MiRNAs play important roles in this tumorigenic process. In the present study, we aimed to investigate the role of miR-140-5p in nephroblastoma by identifying its targets, as well as its underlying molecular mechanism of action.
METHODS: The miRNA expression profile of nephroblastoma samples was investigated and the targets of miR-140-5p were predicted and validated using the miRNA luciferase reporter method. Moreover, the roles of miR-140-5p in regulating nephroblastoma cell proliferation, migration and cell cycle were analyzed by the CCK8, migration and flow cytometry assays, respectively. The downstream protein of the direct target of miR-140-5p was also identified.
RESULTS: miR-140-5p was downregulated in Wilms' tumor tissues, whereas in the nephroblastoma cell lines G401 and WT-CLS1 that exhibited high levels of miRNA-140-5p, inhibition of cellular proliferation and metastasis were noted as well as cell cycle arrest at the G1/S phase. TGFBRI and IGF1R were identified as direct target genes for miRNA-140-5p. In addition, SMAD2/3 and p-AKT were regulated by TGFBRI and IGF1R separately and participated in the miRNA-140-5p regulatory network. Ectopic expression of TGFBR1 and IGF-1R could abrogate the inhibitory effect of miR-140-5p.
CONCLUSION: We demonstrated that miRNA-140-5p participates in the progression of Wilms' tumor by targeting the TGFBRI/SMAD2/3 and the IGF-1R/AKT signaling pathways.

Zhang H, Wang JS, Chen XG, et al.
Overexpression of c-Ski promotes cell proliferation, invasion and migration of gastric cancer associated fibroblasts.
Kaohsiung J Med Sci. 2019; 35(4):214-221 [PubMed] Related Publications
The present study aimed to investigate the effects of c-Ski on cell proliferation, invasion and migration of gastric cancer associated fibroblasts (CAFs). Expression of c-Ski in gastric cancer (GC) tissues was determined using immunohistochemistry. Both CAFs and non-cancerous gastric fibroblasts (NGFs) were isolated and cultured. c-Ski and Smad3 were over-expressed or knocked down using pcDNA3.0-c-Ski/Smad3 or siRNA, respectively. Cell viability, invasion and migration were measured and expression of c-Ski, α-SMA, and Smad3 in cells was determined using real time quantitative PCR (RT-qPCR) and Western blotting. Expression of c-Ski was significantly higher in both in GC tissues and cell lines, and was the highest in tissues of diffuse type. Both c-Ski and α-SMA were significantly over-expressed in CAFs compared with that in the NGFs. When c-Ski was over-expressed in NGFs, cell viability, cell invasion and migration were all enhanced and expression of Smad3 was downregulated. When c-Ski was inhibited, cell viability, cell invasion, and migration were all suppressed and expression of Smad3 was upregulated. Meanwhile, overexpression of Smad3 significantly reversed the effects of over-expressed c-Ski in NGFs, and knockdown of Smad3 dramatically reversed the effects of si-c-Ski in CAFs. Over-expressed c-Ski could enhance cell viability, promote cell invasion, and migration of GC CAFs, and the effects might be through regulation of Smad3 signaling. This study may give deeper insights for relationship between c-Ski and CAFs, as well as role of c-Ski in cancer development, and also provide some novel research targets for treatment of GC.

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.

Guo H, Ci X, Ahmed M, et al.
ONECUT2 is a driver of neuroendocrine prostate cancer.
Nat Commun. 2019; 10(1):278 [PubMed] Free Access to Full Article Related Publications
Neuroendocrine prostate cancer (NEPC), a lethal form of the disease, is characterized by loss of androgen receptor (AR) signaling during neuroendocrine transdifferentiation, which results in resistance to AR-targeted therapy. Clinically, genomically and epigenetically, NEPC resembles other types of poorly differentiated neuroendocrine tumors (NETs). Through pan-NET analyses, we identified ONECUT2 as a candidate master transcriptional regulator of poorly differentiated NETs. ONECUT2 ectopic expression in prostate adenocarcinoma synergizes with hypoxia to suppress androgen signaling and induce neuroendocrine plasticity. ONEUCT2 drives tumor aggressiveness in NEPC, partially through regulating hypoxia signaling and tumor hypoxia. Specifically, ONECUT2 activates SMAD3, which regulates hypoxia signaling through modulating HIF1α chromatin-binding, leading NEPC to exhibit higher degrees of hypoxia compared to prostate adenocarcinomas. Treatment with hypoxia-activated prodrug TH-302 potently reduces NEPC tumor growth. Collectively, these results highlight the synergy between ONECUT2 and hypoxia in driving NEPC, and emphasize the potential of hypoxia-directed therapy for NEPC patients.

Kriseman M, Monsivais D, Agno J, et al.
Uterine double-conditional inactivation of
Proc Natl Acad Sci U S A. 2019; 116(9):3873-3882 [PubMed] Free Access to Full Article Related Publications
SMAD2 and SMAD3 are downstream proteins in the transforming growth factor-β (TGF β) signaling pathway that translocate signals from the cell membrane to the nucleus, bind DNA, and control the expression of target genes. While SMAD2/3 have important roles in the ovary, we do not fully understand the roles of SMAD2/3 in the uterus and their implications in the reproductive system. To avoid deleterious effects of global deletion, and given previous data showing redundant function of

Matsui M, Kajikuri J, Kito H, et al.
Inhibition of Interleukin 10 Transcription through the SMAD2/3 Signaling Pathway by Ca
Mol Pharmacol. 2019; 95(3):294-302 [PubMed] Related Publications
The hyperpolarization induced by intermediate-conductance Ca

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] Free Access to Full Article 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.

Qian Z, Zhang Q, Hu Y, et al.
Investigating the mechanism by which SMAD3 induces PAX6 transcription to promote the development of non-small cell lung cancer.
Respir Res. 2018; 19(1):262 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: This study investigated the function of SMAD3 (SMAD family member 3) in regulating PAX6 (paired box 6) in non-small cell lung cancer.
METHODS: First, qRT-PCR was employed to detect SMAD3 expression in cancer tissues along with normal tissues and four cell lines, including BEAS-2B, H125, HCC827 and A549 cells. SMAD3 was knocked down by small interference RNA (siRNA), and then its expression was determined via qRT-PCR and Western blot analysis. The correlation between SMAD3 and PAX6 was determined by double luciferase reporter experiments and chromatin immunoprecipitation (ChIP) assay. Cell viability was evaluated by CCK-8 and colony forming assays, while cell migration and invasion were detected by Transwell analysis.
RESULTS: SMAD3 and PAX6 were upregulated in lung cancer tissues and cancer cells. Knocking down SMAD3 and PAX6 by transfection with siRNAs specifically suppressed the expression of SMAD3 and PAX6 mRNA and protein levels. SMAD3 could promote PAX6 transcriptional activity by binding to its promoter. Reduced expression of SMAD3 led to the downregulation of PAX6 mRNA and protein levels along with decreased cell migration, invasion, proliferation and viability in A549 and HCC827 cells. PAX6 overexpression altered the si-SMAD3-induced inhibition of cell migration, invasion, proliferation and viability in A549 and HCC827 cells. Additionally, PAX6 knockdown alone also repressed the cell migration, invasion, proliferation and viability of the cell lines.
CONCLUSIONS: SMAD3 promotes the progression of non-small cell lung cancer by upregulating PAX6 expression.

Fenizia C, Bottino C, Corbetta S, et al.
SMYD3 promotes the epithelial-mesenchymal transition in breast cancer.
Nucleic Acids Res. 2019; 47(3):1278-1293 [PubMed] Free Access to Full Article Related Publications
SMYD3 is a methylase previously linked to cancer cell invasion and migration. Here we show that SMYD3 favors TGFβ-induced epithelial-mesenchymal transition (EMT) in mammary epithelial cells, promoting mesenchymal and EMT transcription factors expression. SMYD3 directly interacts with SMAD3 but it is unnecessary for SMAD2/3 phosphorylation and nuclear translocation. Conversely, SMYD3 is indispensable for SMAD3 direct association to EMT genes regulatory regions. Accordingly, SMYD3 knockdown or its pharmacological blockade with the BCI121 inhibitor dramatically reduce TGFβ-induced SMAD3 association to the chromatin. Remarkably, BCI121 treatment attenuates mesenchymal genes transcription in the mesenchymal-like MDA-MB-231 cell line and reduces their invasive ability in vivo, in a zebrafish xenograft model. In addition, clinical datasets analysis revealed that higher SMYD3 levels are linked to a less favorable prognosis in claudin-low breast cancers and to a reduced metastasis free survival in breast cancer patients. Overall, our data point at SMYD3 as a pivotal SMAD3 cofactor that promotes TGFβ-dependent mesenchymal gene expression and cell migration in breast cancer, and support SMYD3 as a promising pharmacological target for anti-cancer therapy.

Jiang Z, Guo Y, Miao L, et al.
SMAD3 silencing enhances DNA damage in radiation therapy by interacting with MRE11-RAD50-NBS1 complex in glioma.
J Biochem. 2019; 165(4):317-322 [PubMed] Related Publications
Radiotherapy is the major treatment modality for malignant glioma. However, the treatment response of radiotherapy is suboptimal due to resistance. Here we aimed to explore the effect and mechanism of Mothers against decapentaplegic homologue (SMAD3) silencing in sensitizing malignant glioma to radiotherapy. Clonogenic assay was used to evaluate the sensitivity of glioma cells to increasing doses of radiation. Glioma cells were transfected with small-interfering RNAs (siRNAs) specific to SMAD3. Overexpression of SMAD3 was achieved by transfecting expression plasmid encoding SMAD3 cDNA. Changes in MRE11-RAD50-NBS1 mRNA and protein levels were assessed through qPCR analysis and western blot analysis, respectively. Chromatin immunoprecipitation (ChIP) was used to confirm the interaction between SMAD3 and MRE11-RAD50-NBS1 (MRN) complex. Silencing of SMAD3 increased sensitivity of glioma cells to radiotherapy. MRE11, RAD50 and NBS1 were overexpressed in response to radiotherapy, which was attenuated by SMAD3 silencing while boosted by SMAD3 overexpression. ChIP analysis confirmed the interaction of SMAD3 with MRE11, RAD50 and NBS1 under radiotherapy, which was inhibited by SMAD3 silencing. SMAD3 silencing is an effective strategy for sensitizing glioma to radiotherapy, which is mediated by the interaction of SMAD3 with the MRN complex.

Marques M, Jangal M, Wang LC, et al.
Oncogenic activity of poly (ADP-ribose) glycohydrolase.
Oncogene. 2019; 38(12):2177-2191 [PubMed] Free Access to Full Article Related Publications
Poly (ADP-ribosylation), known as PARylation, is a post-translational modification catalyzed by poly (ADP-ribose) polymerases (PARP) and primarily removed by the enzyme poly (ADP-ribose) glycohydrolase (PARG). While the aberrant removal of post-translation modifications including phosphorylation and methylation has known tumorigenic effects, deregulation of PARylation has not been widely studied. Increased hydrolysis of PARylation chains facilitates cancer growth through enhancing estrogen receptor (ER)-driven proliferation, but oncogenic transformation has not been linked to increased PARG expression. In this study, we find that elevated PARG levels are associated with a poor prognosis in breast cancers, especially in HER2-positive and triple-negative subtypes. Using both in vitro and in vivo models, we demonstrate that heightened expression of catalytically active PARG facilitates cell transformation and invasion of normal mammary epithelial cells. Catalytically inactive PARG mutants did not recapitulate these phenotypes. Consistent with clinical data showing elevated PARG predicts poor outcomes in HER2+ patients, we observed that PARG acts in synergy with HER2 to promote neoplastic growth of immortalized mammary cells. In contrast, PARG depletion significantly impairs the growth and metastasis of triple-negative breast tumors. Mechanistically, we find that PARG interacts with SMAD2/3 and significantly decreases their PARylation in non-transformed cells, leading to enhanced expression of SMAD target genes. Further linking SMAD-mediated transcription to the oncogenicity of PARG, we show that PARG-mediated anchorage-independent growth and invasion are dependent, at least in part, on SMAD expression. Overall, our study underscores the oncogenic impact of aberrant protein PARylation and highlights the therapeutic potential of PARG inhibition in breast cancer.

Asnaghi L, White DT, Key N, et al.
ACVR1C/SMAD2 signaling promotes invasion and growth in retinoblastoma.
Oncogene. 2019; 38(12):2056-2075 [PubMed] Free Access to Full Article Related Publications
Retinoblastoma is the most common intraocular cancer in children. While the primary tumor can often be treated by local or systemic chemotherapy, metastatic dissemination is generally resistant to therapy and remains a leading cause of pediatric cancer death in much of the world. In order to identify new therapeutic targets in aggressive tumors, we sequenced RNA transcripts in five snap frozen retinoblastomas which invaded the optic nerve and five which did not. A three-fold increase was noted in mRNA levels of ACVR1C/ALK7, a type I receptor of the TGF-β family, in invasive retinoblastomas, while downregulation of DACT2 and LEFTY2, negative modulators of the ACVR1C signaling, was observed in most invasive tumors. A two- to three-fold increase in ACVR1C mRNA was also found in invasive WERI Rb1 and Y79 cells as compared to non-invasive cells in vitro. Transcripts of ACVR1C receptor and its ligands (Nodal, Activin A/B, and GDF3) were expressed in six retinoblastoma lines, and evidence of downstream SMAD2 signaling was present in all these lines. Pharmacological inhibition of ACVR1C signaling using SB505124, or genetic downregulation of the receptor using shRNA potently suppressed invasion, growth, survival, and reduced the protein levels of the mesenchymal markers ZEB1 and Snail. The inhibitory effects on invasion, growth, and proliferation were recapitulated by knocking down SMAD2, but not SMAD3. Finally, in an orthotopic zebrafish model of retinoblastoma, a 55% decrease in tumor spread was noted (p = 0.0026) when larvae were treated with 3 µM of SB505124, as compared to DMSO. Similarly, knockdown of ACVR1C in injected tumor cells using shRNA also resulted in a 54% reduction in tumor dissemination in the zebrafish eye as compared to scrambled shRNA control (p = 0.0005). Our data support a role for the ACVR1C/SMAD2 pathway in promoting invasion and growth of retinoblastoma.

Zeinali T, Mansoori B, Mohammadi A, Baradaran B
Regulatory mechanisms of miR-145 expression and the importance of its function in cancer metastasis.
Biomed Pharmacother. 2019; 109:195-207 [PubMed] Related Publications
MicroRNAs are post-transcriptional mediators of gene expression and regulation, which play influential roles in tumorigenesis and cancer metastasis. The expression of tumor suppressor miR-145 is reduced in various cancer cell lines, containing both solid tumors and blood malignancies. However, the responsible mechanisms of its down-regulation are a complicated network. miR-145 is potentially able to inhbit tumor cell metastasis by targeting of multiple oncogenes, including MUC1, FSCN1, Vimentin, Cadherin, Fibronectin, Metadherin, GOLM1, ARF6, SMAD3, MMP11, Snail1, ZEB1/2, HIF-1α and Rock-1. This distinctive role of miR-145 in the regulation of metastasis-related gene expression may introduce miR-145 as an ideal candidate for controlling of cancer metastasis by miRNA replacement therapy. The present review aims to discuss the current understanding of the different aspects of molecular mechanisms of miR-145 regulation as well as its role in r metastasis regulation.

Tang Y, Wu B, Huang S, et al.
Downregulation of miR‑505‑3p predicts poor bone metastasis‑free survival in prostate cancer.
Oncol Rep. 2019; 41(1):57-66 [PubMed] Free Access to Full Article Related Publications
The principal issue deriving from prostate cancer (PCa) is its propensity to metastasize to bone. To date, bone metastasis remains incurable, and therapeutic strategies are limited. Therefore, it is of paramount importance to explore predictive markers for bone metastasis of PCa. In the present study, we reported that miR‑505‑3p was significantly downregulated in bone metastatic PCa tissues compared with that in non‑bone metastatic PCa tissues, but there was no significant difference in miR‑505‑3p expression between PCa and adjacent normal tissues. miR‑505‑3p expression was inversely associated with serum PSA levels, Gleason grade, N and M classification, and short bone metastasis‑free survival in PCa patients, but had no effect on overall survival in PCa patients. Furthermore, upregulation of miR‑505‑3p suppressed the activity of TGF‑β signaling by directly targeting downstream effectors of TGF‑β signaling, SMAD2 and SMAD3, further inhibiting the invasion and migration abilities of PCa cells. Therefore, our findings unraveled a novel mechanism by which miR‑505‑3p inhibits bone metastasis of PCa, supporting the notion that miR‑505‑3p may serve as a predictive marker for bone metastasis of PCa.

Cheng Z, Lei Z, Yang P, et al.
Long non-coding RNA THOR promotes liver cancer stem cells expansion via β-catenin pathway.
Gene. 2019; 684:95-103 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is a highly aggressive liver tumor containing cancer stem cells (CSCs), which participate in tumor invasion, therapeutic resistance, and tumor relapse leading to poor outcome and limited therapeutic options. Recently, a novel lncRNA, THOR (testis-associated highly conserved oncogenic long non-coding RNA), was characterized in human cancers and shown to exhibit an oncogenic role. However, the role of THOR in liver cancer stem cells (CSCs) remains obscure. Herein, we observed high expression of THOR in chemoresistant hepatocellular carcinomas (HCCs). A remarkable increase of THOR expression in OV6 or EpCAM-positive liver CSCs as well as in CSC-enriched hepatoma spheres. Interference THOR suppressed liver CSC expansion by inhibiting the dedifferentiation of hepatoma cells and decreasing the self-renewal ability of liver CSCs. Mechanistically, we found β-catenin as the downstream of THOR in HCC cells. The special β-catenin inhibitor FH535 abolished the discrepancy in liver CSC proportion and the self-renewal capacity between THOR knockdown HCC cells and control cells, which further confirmed that β-catenin was required in THOR promoted liver CSCs expansion. Moreover, interference THOR hepatoma cells were more sensitive to sorafenib treatment, indicates that HCC patients with low THOR expression may benefit from sorafenib treatment. Collectively, THOR was upregulated in liver CSCs and could promote HCC cells dedifferentiation and liver CSCs expansion by targeting β-catenin signaling.

Chakraborty S, Jiang C, Gau D, et al.
Profilin-1 deficiency leads to SMAD3 upregulation and impaired 3D outgrowth of breast cancer cells.
Br J Cancer. 2018; 119(9):1106-1117 [PubMed] Article available free on PMC after 30/10/2019 Related Publications
BACKGROUND: Adhesion-mediated activation of FAK/ERK signalling pathway, enabled by the formation of filopodial protrusions (FLP), has been shown to be an important event for triggering of dormancy-to-proliferation switch and metastatic outgrowth of breast cancer cells (BCC). We studied the role of actin-binding protein profilin1 (Pfn1) in these processes.
METHODS: Quantitative immunohistochemistry (IHC) of BC tissue microarray (TMA) and survival analyses of curated transcriptome datasets of BC patients were performed to examine Pfn1's association with certain clinicopathological features. FLP formation and single cell outgrowth of BCC were assessed using a 3D matrigel culture that accurately predicts dormant vs metastatic outgrowth phenotypes of BCC in certain microenvironment. Gene expression studies were performed to identify potential biological pathways that are perturbed under Pfn1-depleted condition.
RESULTS: Lower Pfn1 expression is correlated with lower nuclear grade of breast tumours and longer relapse-free survival of BC patients. Pfn1 depletion leads to defects in FLP and outgrowth of BCC but without impairing either FAK or ERK activation. Guided by transcriptome analyses, we further showed that Pfn1 depletion is associated with prominent SMAD3 upregulation. Although knockdown and overexpression experiments revealed that SMAD3 has an inhibitory effect on the outgrowth of breast cancer cells, SMAD3 knockdown alone was not sufficient to enhance the outgrowth potential of Pfn1-depleted BCC suggesting that other proliferation-regulatory pathways in conjunction with SMAD3 upregulation may underlie the outgrowth-deficient phenotype of BCC cells upon depletion of Pfn1.
CONCLUSION: Overall, these data suggest that Pfn1 may be a novel biomarker for BC recurrence and a possible target to reduce metastatic outgrowth of BCC.

Yeo HL, Fan TC, Lin RJ, et al.
Sialylation of vasorin by ST3Gal1 facilitates TGF-β1-mediated tumor angiogenesis and progression.
Int J Cancer. 2019; 144(8):1996-2007 [PubMed] Article available free on PMC after 30/10/2019 Related Publications
ST3Gal1 is a key sialyltransferase which adds α2,3-linked sialic acid to substrates and generates core 1 O-glycan structure. Upregulation of ST3Gal1 has been associated with worse prognosis of breast cancer patients. However, the protein substrates of ST3Gal1 implicated in tumor progression remain elusive. In our study, we demonstrated that ST3GAL1-silencing significantly reduced tumor growth along with a notable decrease in vascularity of MCF7 xenograft tumors. We identified vasorin (VASN) which was shown to bind TGF-β1, as a potential candidate that links ST3Gal1 to angiogenesis. LC-MS/MS analysis of VASN secreted from MCF7, revealed that more than 80% of its O-glycans are sialyl-3T and disialyl-T. ST3GAL1-silencing or desialylation of VASN by neuraminidase enhanced its binding to TGF-β1 by 2- to 3-fold and thereby dampening TGF-β1 signaling and angiogenesis, as indicated by impaired tube formation of HUVECs, suppressed angiogenesis gene expression and reduced activation of Smad2 and Smad3 in HUVEC cells. Examination of 114 fresh primary breast cancer and their adjacent normal tissues showed that the expression levels of ST3Gal1 and TGFB1 were high in tumor part and the expression of two genes was positively correlated. Kaplan Meier survival analysis showed a significantly shorter relapse-free survival for those with lower expression VASN, notably, the combination of low VASN with high ST3GAL1 yielded even higher risk of recurrence (p = 0.025, HR = 2.967, 95% CI = 1.14-7.67). Since TGF-β1 is known to transcriptionally activate ST3Gal1, our findings illustrated a feedback regulatory loop in which TGF-β1 upregulates ST3Gal1 to circumvent the negative impact of VASN.

Huang CC, Huang MS, Chung HJ, et al.
Impaired mammary tumor formation and metastasis by the point mutation of a Smad3 linker phosphorylation site.
Biochim Biophys Acta Mol Basis Dis. 2018; 1864(11):3664-3671 [PubMed] Related Publications
Triple-negative breast cancer (TNBC) is often aggressive and metastatic. Transforming growth factor-β acts as a tumor-promoter in TNBC. Smad3, a major downstream effector protein in the TGF-β signaling pathway, is regulated by phosphorylation at several sites. The functional significance of the phosphorylation of the linker region in Smad3 is poorly understood for TNBC. Among the four sites in the Smad3 linker region, threonine-179 (T179) appears to be unique as it serves as the binding site for multiple WW-domain-containing proteins upon phosphorylation, suggesting that this phosphorylation is a key for Smad3 to engage other pathways. Using genome editing, we introduced for the first time a knock-in (KI) mutation in the endogenous Smad3 gene in IV2, a lung-tropic subline of the human MDA-MB-231 TNBC cell line. In the resulting cell line, the Smad3 T179 phosphorylation site is replaced by non-phosphorylatable valine (T179V) with the mutation in both alleles. The T179V KI reduced cell growth rate and mammosphere formation. These phenomena were accompanied by a significant upregulation of p21

Xu W, Zeng F, Li S, et al.
Crosstalk of protein kinase C ε with Smad2/3 promotes tumor cell proliferation in prostate cancer cells by enhancing aerobic glycolysis.
Cell Mol Life Sci. 2018; 75(24):4583-4598 [PubMed] Related Publications
Protein kinase C ε (PKCε) has emerged as an oncogenic protein kinase and plays important roles in cancer cell survival, proliferation, and invasion. It is, however, still unknown whether PKCε affects cell proliferation via glucose metabolism in cancer cells. Here we report a novel function of PKCε that provides growth advantages for cancer cells by enhancing tumor cells glycolysis. We found that either PKCε or Smad2/3 promoted aerobic glycolysis, expression of the glycolytic genes encoding HIF-1α, HKII, PFKP and MCT4, and tumor cell proliferation, while overexpression of PKCε or Smad3 enhanced aerobic glycolysis and cell proliferation in a protein kinase D- or TGF-β-independent manner in PC-3M and DU145 prostate cancer cells. The effects of PKCε silencing were reversed by ectopic expression of Smad3. PKCε or Smad3 ectopic expression-induced increase in cell growth was antagonized by inhibition of lactate transportation. Furthermore, interaction of endogenous PKCε with Smad2/3 was primarily responsible for phosphorylation of Ser213 in the Samd3 linker region, and resulted in Smad3 binding to the promoter of the glycolytic genes, thereby promoting cell proliferation. Forced expression of mutant Smad3 (S213A) attenuated PKCε-stimulated protein overexpression of the glycolytic genes. Thus, our results demonstrate a novel PKCε function that promotes cell growth in prostate cancer cells by increasing aerobic glycolysis through crosstalk between PKCε and Smad2/3.

Enzo MV, Cattelan P, Rastrelli M, et al.
Growth rate and myofibroblast differentiation of desmoid fibroblast-like cells are modulated by TGF-β signaling.
Histochem Cell Biol. 2019; 151(2):145-160 [PubMed] Related Publications
Desmoid-like fibromatosis (DF) is a rare myofibroblastic benign tumor, often associated with local and repeated injuries, spontaneous regression and stabilization of disease progression suggesting the involvement of altered Wnt/β-catenin signaling activation and/or aberrant response of the DF cells to external environmental stimuli. The aim of this study was to investigate the response of DF cells to microenvironmental factors such as inflammatory and growth factors or hormones. We observed that the inflammatory cytokine, transforming growth factor-β (TGF-β1) stimulated cell growth and myofibroblast differentiation of DF cells regardless of the presence of a β-catenin mutation. The role of TGF-β1 in cell growth and myogenic differentiation of in vitro cultures of primary DF cells and normal fibroblasts was investigated by gene and protein expression analyses. We demonstrated that TGF-β1 exerted its role via the canonical Smad pathway with the phosphorylation of Smad3 being crucial for TGF-β1 dependent DF cell growth and myofibroblastic differentiation. Furthermore we demonstrated that cell confluence is a critical determinant of TGF-β1 inducing the DF myofibroblast differentiation, implying that the intercellular communications have an important role on the DF myofibroblast behavior. We observed the formation of an increased stress-fiber pattern in DF cells with increased projected cell area and stronger cell-cell contacts in presence of TGF-β1. These results demonstrated that TGF-β1 plays a crucial role in the DF cells growth and, together with cell-cell interactions, in DF myofibroblast conversion; we also highlighted that the cellular sensitivity to this cytokine was an intrinsic feature of the DF cells.

Paul D, Dixit A, Srivastava A, et al.
Altered transforming growth factor beta/SMAD3 signalling in patients with hippocampal sclerosis.
Epilepsy Res. 2018; 146:144-150 [PubMed] Related Publications
Transforming growth factor beta (TGFβ) signalling cascade has been implicated in enhancing neuronal excitability and excitatory synaptogenesis following blood brain barrier (BBB) damage and inflammation. We aimed to study if TGFβ signalling expression is altered in patients with Hippocampal Sclerosis (HS). We probed into the protein expression level of the ligand transforming growth factor beta 1 (TGFβ1), transforming growth factor beta receptor II (TGFβRII) and downstream signalling molecule SMAD3 and phosphorylated SMAD3 (pSMAD3) on surgically resected hippocampal samples of thirty-four patients with HS through immuno-blotting. The increase in protein expression level of the ligand TGFβ1 was 285 ± 1.15% higher and its receptor TGFβRII was 170 ± 0.98% higher in hippocampus of patients with HS in comparison to the autopsy hippocampal control samples. The expression of the downstream signalling molecules, SMAD3 is 157 ± 0.13% and 106 ± 0.17% higher in patients with HS as compared to both types of non-seizure controls. The expression of active form of SMAD3, pSMAD3 (2.6010 ± 1.2735) was significantly upregulated in hippocampus of patients with HS compared to autopsy hippocampal controls (0.7899 ± 0.3688). While the expression of pSMAD3 (1.527 ± 0.9425) was significantly upregulated in hippocampus of patients with HS with another type of non-seizure control viz. tumour periphery tissue (0.5791 ± 0.2679), hence strongly supporting the altered expression of the pathway. This study provides the first evidence of alteration of TGFβ pathway in patients with HS which could be a potential therapeutic target.

Zhang RQ, Sun XF, Wu RY, et al.
Zearalenone exposure elevated the expression of tumorigenesis genes in mouse ovarian granulosa cells.
Toxicol Appl Pharmacol. 2018; 356:191-203 [PubMed] Related Publications
Zearalenone (ZEA) is one of mycotoxins which are from corn, sorghum and wheat. As an estrogenic compound, ZEA mainly affects animal growth and reproduction with causing abnormal reproduction capability. Previous studies have shown that ZEA poses adverse effects on follicular development, but the mechanism of genetic toxicity of ZEA is not understood. The purpose of this study was to explore the effects of ZEA exposure on granulosa cells which play vital roles during follicular development. Mouse granulosa cells were exposed to 10 μM or 30 μM ZEA for 72 h in vitro, and the differences in gene expression patterns between control and ZEA exposures were analyzed by RNA-seq. The data demonstrated that 30 μM ZEA had a significant effect on the gene expression, especially ZEA exposure increased the expression of many genes related to different kinds of cancers and cancer related pathways like Hippo signaling pathway and the related genes, such as Ccnd1, Smad3, Tead3, Yap1 and Wwtr1. Furthermore, immunohistochemistry confirmed the increase in the protein levels of YAP1, WWTR1 and CCND1 in 30 μM ZEA exposure group. Collectively, this investigation indicated that ZEA exposure promoted the expression of tumorigenesis genes in mouse granulosa cells to.

Vervoort SJ, Lourenço AR, Tufegdzic Vidakovic A, et al.
SOX4 can redirect TGF-β-mediated SMAD3-transcriptional output in a context-dependent manner to promote tumorigenesis.
Nucleic Acids Res. 2018; 46(18):9578-9590 [PubMed] Article available free on PMC after 30/10/2019 Related Publications
Expression of the transcription factor SOX4 is often elevated in human cancers, where it generally correlates with tumor-progression and poor-disease outcome. Reduction of SOX4 expression results in both diminished tumor-incidence and metastasis. In breast cancer, TGF-β-mediated induction of SOX4 has been shown to contribute to epithelial-to-mesenchymal transition (EMT), which controls pro-metastatic events. Here, we identify SMAD3 as a novel, functionally relevant SOX4 interaction partner. Genome-wide analysis showed that SOX4 and SMAD3 co-occupy a large number of genomic loci in a cell-type specific manner. Moreover, SOX4 expression was required for TGF-β-mediated induction of a subset of SMAD3/SOX4-co-bound genes regulating migration and extracellular matrix-associated processes, and correlating with poor-prognosis. These findings identify SOX4 as an important SMAD3 co-factor controlling transcription of pro-metastatic genes and context-dependent shaping of the cellular response to TGF-β. Targeted disruption of the interaction between these factors may have the potential to disrupt pro-oncogenic TGF-β signaling, thereby impairing tumorigenesis.

Sun L, Guo Z, Sun J, et al.
MiR-133a acts as an anti-oncogene in Hepatocellular carcinoma by inhibiting FOSL2 through TGF-β/Smad3 signaling pathway.
Biomed Pharmacother. 2018; 107:168-176 [PubMed] Related Publications
Hepatocellular carcinoma (HCC), one of the most common maligant cancers in the world, is difficult to diagnose in the early time. MicroRNAs (miRNAs), small non-coding RNAs, perform vital functions in cellular differentiation, metabolism and physiological processes. MiR-133a acts as a tumor suppressor in breast, lung and gastric cancer, while the molecular circadian mechanism has not been clear in HCC. In the present study, we certified that the expression of miR-133a decreased in HCC tissues and cell lines and that miR-133a inhibited proliferation, migration and invasion of hepatocellular carcinoma cells. Fos-related antigen 2 (FOSL2), also named FRA-2, was predicted to be a downstream target of miR-133a based on bioinformatic analysis and the prediction was verified by Western Blot, qRT-PCR and luciferase reporter assay. In addition, there was a negative correlation between miR-133a and FOSL2 expression in HCC samples. Furthermore, we verified that overexpression of miR-133a suppressed biological behaviour of HCC through TGF-β/Smad3 signaling pathway. In brief, miR-133a may be a potential prognostic biomarker and may thus be a new therapy in HCC.

Li P, Chen X, Qin G, et al.
Maelstrom Directs Myeloid-Derived Suppressor Cells to Promote Esophageal Squamous Cell Carcinoma Progression via Activation of the Akt1/RelA/IL8 Signaling Pathway.
Cancer Immunol Res. 2018; 6(10):1246-1259 [PubMed] Related Publications

Wang H, Wang G, Gao Y, et al.
Lnc-SNHG1 Activates the TGFBR2/SMAD3 and RAB11A/Wnt/β-Catenin Pathway by Sponging MiR-302/372/373/520 in Invasive Pituitary Tumors.
Cell Physiol Biochem. 2018; 48(3):1291-1303 [PubMed] Related Publications
BACKGROUND/AIMS: Long noncoding RNAs (lncRNAs) are critical regulators in various diseases including human cancer and could function as competing endogenous RNAs (ceRNAs) to regulate microRNAs (miRNAs).
METHODS: Quantitative real-time PCR (qRT-PCR) was used to analyze the expression of lnc-SNHG1 and miR-302/372/373/520 in pituitary tumor tissues and cell lines. Cell proliferation was investigated using MTT and cell count assays. The mechanisms by which lnc-SNHG1 affects pituitary tumor progression were investigated using Western blot assays, transwell migration assays, immunohistochemistry, immunofluorescence, luciferase reporter assays, tumor xenografts, and flow cytometry Results: We found that lnc-SNHG1 was overexpressed in invasive pituitary tumor tissues and cell lines. Ectopic expression of lnc-SNHG1 promoted cell proliferation, migration, and invasion, as well as the epithelial-mesenchymal transition (EMT), by affecting the cell cycle and cell apoptosis in vitro and tumor growth in vivo. Further study indicated that overexpression of lnc-SNHG1 markedly inhibited the expression of miR-302/372/373/520 (miRNA-pool) which is down-regulated in invasive pituitary tumor cells. Moreover, overexpression of lnc-SNHG1 significantly promoted the expression of TGFBR2 and RAB11A, the direct targets of miR-302/372/373/520. Finally, lnc-SNHG1 activates the TGFBR2/SMAD3 and RAB11A/Wnt/β-catenin pathways in pituitary tumor cells via sponging miR-302/372/373/520.
CONCLUSIONS: Our data suggest that lnc-SNHG1 promotes the progression of pituitary tumors and is a potential therapeutic target for invasive pituitary tumor.

Fu Q, Zhang Q, Lou Y, et al.
Primary tumor-derived exosomes facilitate metastasis by regulating adhesion of circulating tumor cells via SMAD3 in liver cancer.
Oncogene. 2018; 37(47):6105-6118 [PubMed] Article available free on PMC after 30/10/2019 Related Publications
Hepatocellular carcinoma (HCC) is a fatal disease and patients with HCC frequently die from metastasis. The mechanisms of HCC metastasis are not completely understood. In the present study, in vitro and in vivo data showed that HCC cells promoted cancer cell proliferation and lung metastases formation in a paracrinal/endocrinal way. We found that HCC-derived exosomes mediated this phenomenon and observed enhanced cell adhesion in the presence of these malignant exosomes. We further identified that reactive oxygen species (ROS) regulated the adhesive molecules. Intriguingly, attached HCC cells released exosomes containing both SMAD Family Member 3 (SMAD3) protein and mRNA, which were delivered to detached HCC cells and facilitated their adhesion. These exosomes induced enhanced SMAD3 signaling in the recipient HCC cells and increased their adhesive ability. In addition, we showed that SMAD3-abundant exosomes existed in the peripheral blood of patients with HCC, and their levels correlated with disease stage and the SMAD3 expression of primary tumors. Our study suggested a possible mechanism by which primary HCC supported metastases formation and revealed the role of SMAD3 in the exosomes-mediated crosstalk between primary and circulating HCC cells.

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