Gene Summary

Gene:SMAD2; SMAD family member 2
Aliases: JV18, MADH2, MADR2, JV18-1, hMAD-2, hSMAD2
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 mediates the signal of the transforming growth factor (TGF)-beta, and thus regulates multiple cellular processes, such as cell proliferation, apoptosis, and differentiation. This protein is recruited to the TGF-beta receptors through its interaction with the SMAD anchor for receptor activation (SARA) protein. In response to TGF-beta signal, this protein is phosphorylated by the TGF-beta receptors. The phosphorylation induces the dissociation of this protein with SARA and the association with the family member SMAD4. The association with SMAD4 is important for the translocation of this protein into the nucleus, where it binds to target promoters and forms a transcription repressor complex with other cofactors. This protein can also be phosphorylated by activin type 1 receptor kinase, and mediates the signal from the activin. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, May 2012]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:mothers against decapentaplegic homolog 2
Source:NCBIAccessed: 30 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 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 (7)

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: SMAD2 (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.

Kim YH, Lee SB, Shim S, et al.
Hyaluronic acid synthase 2 promotes malignant phenotypes of colorectal cancer cells through transforming growth factor beta signaling.
Cancer Sci. 2019; 110(7):2226-2236 [PubMed] Free Access to Full Article Related Publications
Hyaluronic acid synthase 2 (HAS2) is suggested to play a critical role in malignancy and is abnormally expressed in many carcinomas. However, its role in colorectal cancer (CRC) malignancy and specific signaling mechanisms remain obscure. Here, we report that HAS2 was markedly increased in both CRC tissue and malignant CRC cell lines. Depletion of HAS2 in HCT116 and DLD1 cells, which express high levels of HAS2, critically increased sensitivity of radiation/oxaliplatin-mediated apoptotic cell death. Moreover, downregulation of HAS2 suppressed migration, invasion and metastasis in nude mice. Conversely, ectopic overexpression of HAS2 in SW480 cells, which express low levels of HAS2, showed the opposite effect. Notably, HAS2 loss- and gain-of-function experiments revealed that it regulates CRC malignancy through TGF-β expression and SMAD2/Snail downstream components. Collectively, our findings suggest that HAS2 contributes to malignant phenotypes of CRC, at least partly, through activation of the TGF-β signaling pathway, and shed light on the novel mechanisms behind the constitutive activation of HAS2 signaling in CRC, thereby highlighting its potential as a therapeutic target.

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.

Moncho-Amor V, Pintado-Berninches L, Ibañez de Cáceres I, et al.
Role of Dusp6 Phosphatase as a Tumor Suppressor in Non-Small Cell Lung Cancer.
Int J Mol Sci. 2019; 20(8) [PubMed] Free Access to Full Article Related Publications
DUSP6/MKP3 is a dual-specific phosphatase that regulates extracellular regulated kinase ERK1/2 and ERK5 activity, with an increasingly recognized role as tumor suppressor. In silico studies from Gene expression Omnibus (GEO) and Cancer Genome atlas (TCGA) databases reveal poor prognosis in those Non-small cell lung cancer (NSCLC) patients with low expression levels of

Gao L, Hu Y, Tian Y, et al.
Lung cancer deficient in the tumor suppressor GATA4 is sensitive to TGFBR1 inhibition.
Nat Commun. 2019; 10(1):1665 [PubMed] Free Access to Full Article Related Publications
Lung cancer is the leading cause of cancer-related deaths worldwide. Tumor suppressor genes remain to be systemically identified for lung cancer. Through the genome-wide screening of tumor-suppressive transcription factors, we demonstrate here that GATA4 functions as an essential tumor suppressor in lung cancer in vitro and in vivo. Ectopic GATA4 expression results in lung cancer cell senescence. Mechanistically, GATA4 upregulates multiple miRNAs targeting TGFB2 mRNA and causes ensuing WNT7B downregulation and eventually triggers cell senescence. Decreased GATA4 level in clinical specimens negatively correlates with WNT7B or TGF-β2 level and is significantly associated with poor prognosis. TGFBR1 inhibitors show synergy with existing therapeutics in treating GATA4-deficient lung cancers in genetically engineered mouse model as well as patient-derived xenograft (PDX) mouse models. Collectively, our work demonstrates that GATA4 functions as a tumor suppressor in lung cancer and targeting the TGF-β signaling provides a potential way for the treatment of GATA4-deficient lung cancer.

Guo Y, Cui W, Pei Y, Xu D
Platelets promote invasion and induce epithelial to mesenchymal transition in ovarian cancer cells by TGF-β signaling pathway.
Gynecol Oncol. 2019; 153(3):639-650 [PubMed] Related Publications
OBJECTIVE: To test whether platelets could increase invasion potential and initiate EMT in ovarian cancer cells via a TGF-β signaling pathway.
METHODS: Blood samples were collected in 69 patients with ovarian cancer, 16 patients with benign ovarian tumor and 64 healthy donors. SK-OV-3 and OVCAR-3 ovarian cancer cells were treated with platelets. Transwell assays were used to analyze the invasive capacity, and EMT was assessed by microarray analysis, quantitative real-time PCR (qPCR) and Western blotting. Activation of TGF-β pathway was examined by ELISA and Western blotting. TGF-β type I receptor (TβR I) inhibitor A83-01 was used to confirm the role of TGF-β pathway in vitro and in vivo.
RESULTS: Clinical data showed ovarian cancer patients with elevated platelet counts had a higher incidence of advanced stages. Treatment with platelets increased the invasive properties of both cell lines. Mesenchymal markers (snail family transcriptional repressor-1, vimentin, neural cadherin, fibronectin-1 and matrix metalloproteinase-2) were up-regulated in platelet-treated cells, while the epithelial marker (epithelial cadherin) was down-regulated. Higher TGF-β level was observed in patients with elevated platelet counts when compared to the subjects. Higher levels of TGF-β were also found in culture medium treated with platelets, and cells treated with platelets also showed increased phosphorylation of Smad2. TβR I inhibitor A83-01 reversed the EMT-like alterations and inhibited platelet-induced invasion in vitro and in vivo.
CONCLUSION: Platelet increased invasion potential and induced EMT in ovarian cancer cells in a TGF-β dependent pathway. Platelet-derived TGF-β may be useful as a new target treatment for ovarian cancer.

Wang Y, Sun L, Luo Y, He S
Knockdown of KDM1B inhibits cell proliferation and induces apoptosis of pancreatic cancer cells.
Pathol Res Pract. 2019; 215(5):1054-1060 [PubMed] Related Publications
Pancreatic cancer (PC) is one of the common malignant tumors in digestive tract with a high fatality rate. The oncogenic role of lysine-specific demethylase1 (LSD1/KDM1 A) has been well recognized in PC. While, the role of its homolog LSD2 (KDM1B) in regulating PC progression is poorly understood. In this study, we attempted to evaluate the functional role of KDM1B in PC cells. The expression of KDM1B was detected by immunohistochemistry and immunoblotting in PC tissues and cells. Lentivirus-mediated shRNA was applied to silence KDM1B in PANC-1 and SW1990 cells. Cell proliferation was measured by MTT and Celigo assay. Cell apoptosis was determined by both Caspase-Glo

Xu B, Gong X, Zi L, et al.
Silencing of DLEU2 suppresses pancreatic cancer cell proliferation and invasion by upregulating microRNA-455.
Cancer Sci. 2019; 110(5):1676-1685 [PubMed] Free Access to Full Article Related Publications
Long noncoding RNA (lncRNA) DLEU2 has been shown to be dysregulated in several type of tumor. However, the potential biological roles and molecular mechanisms of DLEU2 in pancreatic cancer (PC) progression are poorly understood. In this study, we found that the DLEU2 level was substantially upregulated in PC tissues and PC cell lines, and significantly associated with poor clinical outcomes in PC patients. Overexpression of DLEU2 significantly induced PC cell proliferation and invasion, whereas knockdown of DLEU2 impaired cell proliferation and invasion in vitro. Furthermore, bioinformatics analysis, luciferase reporter assay, and RNA immunoprecipitation assay revealed that DLEU2 directly bond to microRNA-455 (miR-455) and functioned as an endogenous sponge for miR-455, which could remarkably suppress cell growth and invasion. We also determined that SMAD2 was a direct target of miR-455, and the restoration of SMAD2 rescued cell growth and invasion that were reduced by DLEU2 knockdown or miR-455 overexpression. In addition, low miR-455 expression and high SMAD2 expression was correlated with poor patient survival. These results indicate that DLEU2 is an important promoter of PC development, and targeting the DLEU2/miR-455/SMAD2 pathway could be a promising therapeutic approach in the treatment of PC.

Duan L, Pang HL, Chen WJ, et al.
The role of GDF15 in bone metastasis of lung adenocarcinoma cells.
Oncol Rep. 2019; 41(4):2379-2388 [PubMed] Related Publications
Lung cancer is the most common malignant tumor in China. It often metastasizes to bone, thereby significantly shortening the lives of patients, and reducing their quality of life. However, the efficacy of treatment for bone metastasis of lung cancer at this stage is very limited. The development and clinical application of molecular‑targeted drugs for the effective targeted therapy of bone metastasis of lung cancer are urgently required. The growth differentiation factor 15 (GDF15) gene which may be associated with bone metastasis of lung cancer, was screened out by whole‑genome sequencing. In the present study, we used a recombinant GDF15 lentivirus technique to upregulate the expression of GDF15 in lung adenocarcinoma A549 cells, and the results revealed that GDF15 could inhibit the proliferation, migration and invasion, while promoting apoptosis of A549 cells. In addition, GDF15 significantly decreased the number and sites of lung metastases and bone metastases in vivo compared to the control group. Finally, it was revealed that Smad2 and phospho‑Smad2 protein expression was lower in the GDF15‑overexpressing A549 cells. This result indicated that the tumor suppressive effect of GDF15 may be related to the TGF‑β/Smad signaling pathway, although more studies are still required for confirmation. In summary, GDF15 inhibited the growth and bone metastasis of lung adenocarcinoma A549 cells, and this effect may be achieved through the TGF‑β/Smad signaling pathway.

Zhou B, Guo H, Tang J
Long Non-Coding RNA TFAP2A-AS1 Inhibits Cell Proliferation and Invasion in Breast Cancer via miR-933/SMAD2.
Med Sci Monit. 2019; 25:1242-1253 [PubMed] Free Access to Full Article Related Publications
BACKGROUND It is well documented that long non-coding RNAs (lncRNAs) are involved in the progression of multiple human tumors by sponging microRNAs (miRNAs). However, whether lncRNA TFAP2A-AS1 plays a role in the tumorigenesis of breast cancer (BC) remains undetermined. MATERIAL AND METHODS Real-time PCR (qRT-PCR) assay was performed to detect the relative mRNA expression of TFAP2A-AS1 and miR-933. Flow cytometry analysis, CCK-8 assay, and Transwell assay were applied to detect the effects of TFAP2A-AS1 overexpression on cell cycle, apoptosis, viability, and invasion of BC cells. In vivo proliferation assay was performed to evaluate the effects of TFAP2A-AS1 overexpression on tumor growth. Bioinformatics methods, dual-luciferase reporter, RNA immunoprecipitation (RIP), and RNA pull-down assays were used to predict and validate the interaction between TFAP2A-AS1 and miR-933, as well as SMAD2 and miR-933. Western blot assay was performed to examine the protein expression of SMAD2 in treated BC cells. RESULTS TFAP2A-AS1 expression was significantly lower in BC tissues and cell lines, and patients with high TFAP2A-AS1 expression exhibited a better prognosis than those with low TFAP2A-AS1 expression. Overexpression of TFAP2A-AS1 in BC cells caused cell cycle arrest, promoted cell apoptosis, suppressed cell ability, and attenuated cell invasion in vitro, and inhibited tumor growth in vivo. TFAP2A-AS1 was revealed to act as a miRNA sponge for miR-933 and then regulated the expression of Smad2. CONCLUSIONS Results from the present study suggest that TFAP2A-AS1 acts as a tumor suppressor in BC via the miR-933/SMAD2 axis.

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

Araújo T, Khayat A, Quintana L, et al.
World J Gastroenterol. 2018; 24(47):5338-5350 [PubMed] Free Access to Full Article Related Publications
AIM: To establish a permanent
METHODS: CRISPR-Cas9 system used was purchased from Dharmacon GE Life Sciences (Lafayette, CO, United States) and permanent knockout was performed according to manufacturer's recommendations. Wound-healing assay was performed to investigate the effect of

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.

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.

Zhang Q, Wang C, Cliby WA
Cancer-associated stroma significantly contributes to the mesenchymal subtype signature of serous ovarian cancer.
Gynecol Oncol. 2019; 152(2):368-374 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
OBJECTIVE: Mesenchymal (MES) subtype of high-grade serous ovarian cancer (HGSOC) is associated with worse outcomes including survival and resectability compared with other molecular subtypes. Molecular subtypes have historically been derived from 'tumor', consisting of both cancer and stromal cells. We sought to determine the origins of multiple MES subtype gene signatures in HGSOC.
METHODS: Fifteen patients with MES subtype of HGSOC diagnosed between 2010 and 2013 were identified. Formalin-fixed paraffin-embedded (FFPE) blocks from primary surgery were sectioned for immunohistochemistry (IHC) staining of relevant proteins. Eight genes (ACTA2, COL5A1, COL11A1, FAP, POSTN, VCAN, ZEB1 and p-SMAD2) were selected for IHC staining based on their differential expression in MES vs. non-MES subtypes of HGSOC. Slides were scored for intensity and localization and simple statistics were used to compare expression results in cancer vs. stroma and between primary and metastatic sites.
RESULTS: COL5A1, VCAN, FAP, and ZEB1 proteins were almost exclusively expressed by stroma as opposed to cancer cells. In addition, stromal expression was dominant for ACTA2, COL11A1, POSTN and p-SMAD2. In general there were minimal differences in expression of proteins between primary and metastatic sites, exceptions being COL5A1 (reduced in metastases) and COL11A1 (increased in metastases). Nuclear p-SMAD2 expression was more common in metastatic stroma.
CONCLUSIONS: The existing molecular classification of HGSOC MES subtype reflects a significant stromal contribution, suggesting an important role in HGSOC behavior and thus stroma may be a relevant therapeutic target. Specific patterns of expression indicate that collagens and TGF-β signaling are involved in the metastatic process.

Zhang C, Wang B, Wu L
MicroRNA‑409 may function as a tumor suppressor in endometrial carcinoma cells by targeting Smad2.
Mol Med Rep. 2019; 19(1):622-628 [PubMed] Related Publications
MicroRNAs (miRNAs) are frequently dysregulated in human cancer and can act as either potent oncogenes or tumor suppressor genes. The aberrant expression of miRNA‑409 (miR‑409) has been found in certain types of cancer, however, its expression and potential biological role in endometrial cancer remain to be fully elucidated. In the present study, a total of 16 pairs of tissue samples from 16 patients with endometrial cancer were used in the present study, each of which consisted of human endometrial cancer tissue and matched adjacent normal tissue from the same patient. The expression of miR‑409 of the tissue were detected and its associations with Ishikawa and HEC‑1B human endometrial cancer cell lines were studied. The results of the present study demonstrated that miR‑409 was downregulated in human endometrial cancer, and it suppressed the growth of Ishikawa and HEC‑1B human endometrial cancer cell lines. Bioinformatics analysis indicated that small mothers against decapentaplegic 2 (Smad2) was a putative target of miR‑409. In a luciferase reporter system, it was confirmed that Smad2 was a direct target gene of miR‑409. It was also demonstrated that Smad2 was upregulated in human endometrial cancer tissues, and this was inversely correlated with the expression of miR‑409. These findings indicated that miR‑409 targeted the Smad2 transcript and suppressed endometrial cancer cell growth, suggesting that miR‑409 has a tumor suppressive role in the pathogenesis of human endometrial 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] Article available free on PMC after 01/02/2020 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.

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] Article available free on PMC after 01/02/2020 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.

Othman N, Nagoor NH
Overexpression of miR‑361‑5p plays an oncogenic role in human lung adenocarcinoma through the regulation of SMAD2.
Int J Oncol. 2019; 54(1):306-314 [PubMed] Related Publications
The silencing of Bcl‑xL in the non‑small cell lung cancer (NSCLC) cell line, A549, downregulates miR‑361‑5p expression. This study aimed to determine the biological effects of miR‑361‑5p on NSCLC, and to elucidate the molecular mechanisms through which apoptosis is regulated. MicroRNA (miRNA or miR) functional analyses were performed via transfection of miR‑361‑5p mimics and inhibitors, demonstrating that the inhibition of miR‑361‑5p induced the apoptosis of NSCLC cells. To elucidate the function of miR‑361‑5p in vivo, cells transfected with miR‑361‑5p inhibitors were microinjected into zebrafish embryos, and immunostained using antibodies to detect the active form of caspase‑3. Co-transfection with siBcl‑xL and miR‑361‑5p mimics illustrated the association between Bcl‑xL, miR‑361‑5p and apoptosis; miR‑361‑5p mimics blocked the apoptosis initiated by siBcl‑xL. Luciferase reporter assays identified mothers against decapentaplegic homolog 2 (SMAD2) as a novel target of miR‑361‑5p and the reduction of its protein level was validated by western blot analysis. To confirm the molecular mechanisms through which apoptosis is regulated, gene rescue experiments revealed that the ectopic expression of SMAD2 attenuated the inhibitory effects on apoptosis induced by miR‑361‑5p. In this study, to the best of our knowledge, we provide the first evidence that miR‑361‑5p functions as an oncomiR in A549 and SK‑LU‑1 cells through the regulation of SMAD2, suggesting that miR‑361‑5p may be employed as a potential therapeutic target for the miRNA-based therapy of NSCLC.

Harada M, Morikawa M, Ozawa T, et al.
Palbociclib enhances activin-SMAD-induced cytostasis in estrogen receptor-positive breast cancer.
Cancer Sci. 2019; 110(1):209-220 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Cyclin-dependent kinase (CDK) 4 and CDK6 inhibitors are effective therapeutic options for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Although CDK4/6 inhibitors mainly target the cyclin D-CDK4/6-retinoblastoma tumor suppressor protein (RB) axis, little is known about the clinical impact of inhibiting phosphorylation of other CDK4/6 target proteins. Here, we focused on other CDK4/6 targets, SMAD proteins. We showed that a CDK4/6 inhibitor palbociclib and activin-SMAD2 signaling cooperatively inhibited cell cycle progression of a luminal-type breast cancer cell line T47D. Palbociclib enhanced SMAD2 binding to the genome by inhibiting CDK4/6-mediated linker phosphorylation of the SMAD2 protein. We also showed that cyclin G2 plays essential roles in SMAD2-dependent cytostatic response. Moreover, comparison of the SMAD2 ChIP-seq data of T47D cells with those of Hs578T (triple-negative breast cancer cells) indicated that palbociclib augmented different SMAD2-mediated functions based on cell type, and enhanced SMAD2 binding to the target regions on the genome without affecting its binding pattern. In summary, palbociclib enhances the cytostatic effects of the activin-SMAD2 signaling pathway, whereas it possibly strengthens the tumor-promoting aspect in aggressive breast cancer.

Lupicki K, Elifio-Esposito S, Fonseca AS, et al.
Patterns of copy number alterations in primary breast tumors of South African patients and their impact on functional cellular pathways.
Int J Oncol. 2018; 53(6):2745-2757 [PubMed] Related Publications
Breast cancer is the most common and the leading cause of female mortality among South African (SA) women. Several non‑biological and biological risk factors may be attributed to their observed high mortality rate; however, the molecular profiles associated with their breast tumors are poorly characterized. The present study examined the patterns of genome-wide copy number alterations (CNAs) and their potential impact on functional cellular pathways targeted by cancer driver genes in patients with breast cancer from the Western Cape region of SA. Array-comparative genomic hybridization analysis, performed in 28 cases of invasive breast cancer, revealed a mean number of 8.68±6.18 CNAs per case, affecting primarily the Xp22.3 and 6p21-p25 cytobands (57.14% of the cases), followed by 19p13.3-p13.11 (35.7%), 2p25.3-p24.3, 4p16.3-p15.3, 8q11.1-q24.3 and 16 p13.3-p11.2 (32.14%). Functional enrichment analysis of genes and microRNA targets mapped in these affected cytobands revealed critical cancer-associated pathways, including fatty acid biosynthesis and metabolism, extracellular matrix-receptor interaction, hippo and tumor protein p53 signaling pathways, which are regulated by known cancer genes, including CCND1, CDKN1A, MAPK1, MDM2, TP53 and SMAD2. An inverse correlation was observed among the number of CNAs and tumor size and grade; CNAs on the 4p and 6p cytobands were also inversely correlated with tumor grade. No association was observed in the number of CNAs and/or the affected cytobands and the different ethnic groups of the SA patients, indicating that their tumor genome is affected by CNAs, irrespectively of their genetic descent. Additional genomic tumor profiling in SA and other Sub-Saharan African patients with breast cancer is required to determine the associations of the CNAs observed with prognosis and clinical outcome.

Yang C, Shao T, Zhang H, et al.
MiR-425 expression profiling in acute myeloid leukemia might guide the treatment choice between allogeneic transplantation and chemotherapy.
J Transl Med. 2018; 16(1):267 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
BACKGROUND: Acute myeloid leukemia (AML) is a highly heterogeneous disease. MicroRNAs function as important biomarkers in the clinical prognosis of AML.
METHODS: This study identified miR-425 as a prognostic factor in AML by screening the TCGA dataset. A total of 162 patients with AML were enrolled for the study and divided into chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT) groups.
RESULTS: In the chemotherapy group, patients with high miR-425 expression had significantly longer overall survival (OS) and event-free survival (EFS) compared with patients with low miR-425 expression. In multivariate analyses, high miR-425 expression remained independently predictive of a better OS (HR = 0.502, P = 0.005) and EFS (HR = 0.432, P = 0.001) compared with patients with low miR-425 expression. Then, all patients were divided into two groups based on the median expression levels of miR-425. Notably, the patients undergoing allo-HSCT had significantly better OS (HR = 0.302, P < 0.0001) and EFS (HR = 0.379, P < 0.0001) compared with patients treated with chemotherapy in the low-miR-425-expression group. Mechanistically, high miR-425 expression levels were associated with a profile significantly involved in regulating cellular metabolism. Among these genes, MAP3K5, SMAD2, and SMAD5 were predicted targets of miR-425.
CONCLUSIONS: The expression of miR-425 may be useful in identifying patients in need of strategies to select the optimal therapy between chemotherapy and allo-HSCT treatment regimens. Patients with low miR-425 expression may consider early allo-HSCT.

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 01/02/2020 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.

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.

Liu JX, Li W, Li JT, et al.
Screening key long non-coding RNAs in early-stage colon adenocarcinoma by RNA-sequencing.
Epigenomics. 2018; 10(9):1215-1228 [PubMed] Related Publications
AIM: We aim to identify the key long noncoding RNAs (lncRNAs) in early-stage colon adenocarcinoma (COAD).
PATIENTS & METHODS: Compared with colonic intraepithelial neoplasia, differentially expressed lncRNAs (DElncRNAs) in early-stage COAD were obtained by RNA-sequencing. Our previous work has obtained the differentially expressed mRNAs and miRNAs (DEmRNAs and DEmiRNAs) in early-stage COAD. DEmiRNA-DElncRNA-DEmRNA interaction analysis and functional annotation were performed. Validation of expression and receiver-operating characteristic analyses were performed based on The Cancer Genome Atlas.
RESULTS: Seventy-nine significantly DElncRNAs in early-stage COAD were obtained. MiR-153-3p-TUG1-DAPK1/ARNT2/KLK3/PLD1/SMAD2 and miR-153-3p-SNHG17-COL11A1/IGFBP3/KLF6 interactions were associated with early-stage COAD. Five DElncRNAs (ELFN1-AS1, LINC01234, SNHG17, UCA1 and LOC101929549) involved in early-stage COAD with potential diagnostic value.
CONCLUSION: LncRNAs involve in early-stage COAD by interaction with COAD-regulated genes and miRNAs.

Zhang MX, Gan W, Jing CY, et al.
S100A11 promotes cell proliferation via P38/MAPK signaling pathway in intrahepatic cholangiocarcinoma.
Mol Carcinog. 2019; 58(1):19-30 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
S100A11 is reported to associate with progression and poor prognosis in several tumors. We previously reported that S100A11 was highly expressed in intrahepatic cholangiocarcinoma (ICC) cells and promoted TGF-β1-induced EMT through SMAD2/3 signaling pathway. Here, we explored the prognostic role of S100A11 on ICC patients and preliminary molecular mechanisms how S100A11 regulated ICC cell proliferation. Our results showed that S100A11 was obviously increased in ICC tumor tissues. High expression of S100A11 was closely correlated with lymph node metastasis (LNM) and TNM stage and was an independent risk factor for patients' overall survival (OS) and recurrence-free survival (RFS). The nomograms comprising LNM and S100A11 achieved better predictive accuracy compared with TNM staging system for OS and RFS prediction. Silencing S100A11 significantly suppressed RBE cells and HCCC9810 cells proliferation, colony formation, and activation of P38/mitogen-activated protein kinase (MAPK) signaling pathway in vitro and inhibited tumor growth in vivo. In contrast, the overexpression of S100A11 in RBE cells and HCCC9810 cells achieved the opposite results. S100A11-induced proliferation was abolished after treatment with P38 inhibitor. Our findings suggest S100A11/P38/MAPK signaling pathway may be a potential therapeutic target for ICC patients.

Zou G, Ren B, Liu Y, et al.
Inhibin B suppresses anoikis resistance and migration through the transforming growth factor-β signaling pathway in nasopharyngeal carcinoma.
Cancer Sci. 2018; 109(11):3416-3427 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Inhibin B (INHBB), a heterodimer of a common α-subunit and a βB-subunit, is a glycoprotein belonging to the transforming growth factor-β (TGF-β) family. In this study, we observed INHBB expression was reduced in nasopharyngeal carcinoma (NPC) tissues compared to non-tumor nasopharyngeal epithelium tissues, and INHBB was associated with lymph node metastasis, stage of disease, and clinical progress. Positive expression of INHBB in NPC predicted a better prognosis (overall survival, P = 0.038). However, the molecular mechanisms of INHBB have not been addressed in NPC. We induced anoikis-resistant cells in NPC cell lines under anchorage-independent conditions, then found epithelial-mesenchymal transition markers changed, cell apoptosis decreased, cell cycle was modified, and invasion strengthened in anoikis-resistant NPC cells. These anoikis-resistant NPC cells showed decreased expression of INHBB compared with adhesion cells. Furthermore, INHBB was found to influence the above-mentioned changes. In the anoikis-resistant NPC cells with INHBB overexpression, apoptotic cells increased, S phase cells weakened, vimentin, matrix metallopeptidase-9, and vascular endothelial growth factor A expression were downregulated, and E-cadherin expression was upregulated, and vice versa in knockdown of INHBB (INHBB shRNA) anoikis-resistant NPC cells. Diminished INHBB expression could activate the TGF-β pathway to phosphorylate Smad2/3 and form complexes in the nucleus, which resulted in the above changes. Thus, our results revealed for the first time that INHBB could suppress anoikis resistance and migration of NPC cells by the TGF-β signaling pathway, decrease p53 overexpression, and could serve as a potential biomarker for NPC metastasis and prognosis as well as a therapeutic application.

Nakano M, Ito M, Tanaka R, et al.
Epithelial-mesenchymal transition is activated in CD44-positive malignant ascites tumor cells of gastrointestinal cancer.
Cancer Sci. 2018; 109(11):3461-3470 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Disseminated cancer cells in malignant ascites possess unique properties that differ from primary tumors. However, the biological features of ascites tumor cells (ATC) have not been fully investigated. By analyzing ascites fluid from 65 gastrointestinal cancer patients, the distinguishing characteristics of ATC were identified. High frequency of CD44

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