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Ding R, Liao L, Chen J, Zhang J, Cai S, Miao X, Li T, Zhao J, Chen Q, Cheng X, Deng J. Downregulation of ferroptosis-related Genes can regulate the invasion and migration of osteosarcoma cells. Sci Rep 2025; 15:17582. [PMID: 40399425 PMCID: PMC12095786 DOI: 10.1038/s41598-025-02319-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 05/13/2025] [Indexed: 05/23/2025] Open
Abstract
Osteosarcoma (OS) is a prevalent form of bone cancer among younger people, particularly children and adolescents. Ferroptosis is a non-apoptotic cell death identified by increased levels of iron-dependent lipid peroxidation. This study was designed to develop a prognostic model based on differentially expressed genes (DEGs) associated with ferroptosis and examined the functions of ferroptosis-related genes (FRGs) in OS cells. Gene expression profiles in OS were retrieved from TARGET and GEO databases, while GTEx provided data for healthy tissues. Prognostic genes were identified through bioinformatics analysis and data integration. In vitro experiments, cell cultures, qRT-PCR, immunohistochemistry (IHC), cell transfection, Edu assays, DHE assays, migration, and invasion assays validated the prognostic model and explored the functional role of FRGs in OS cells. Univariate Cox regression analysis demonstrated that 12 DEGs were differentially expressed. Based on four FRGs in OS constructed a risk-scoring model. The high-risk (HR) group showed a considerably lower OS rate than the low-risk (LR) group (p < 0.001 in the TARGET and p < 0.05 in the GSE21257 cohorts). A risk score was validated as an independent predictive factor for OS via multivariate Cox regression. Functional analysis shows that these FRGs affect the occurrence of ferroptosis by influencing the intracellular ROS levels and play a regulatory role in the proliferation, migration, and infiltration of OS cells. The findings suggested that four FRGs demonstrate significant prognostic value in OS, offering potential insights into novel therapeutic targets for OS treatment.
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Affiliation(s)
- Rui Ding
- Department of Orthopedics, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Jiangxi, 330006, China
| | - Le Liao
- Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Jiahui Chen
- Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Jian Zhang
- Department of Orthopedics, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Jiangxi, 330006, China
| | - Shenghao Cai
- Department of Orthopedics, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Jiangxi, 330006, China
| | - Xinxin Miao
- Department of Orthopedics, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Jiangxi, 330006, China
- Institute of Orthopedics of Jiangxi Province, Nanchang, 330006, Jiangxi, China
- Institute of Minimally Invasive Orthopedics, Nanchang University, Jiangxi, 330006, China
| | - Tao Li
- Department of Orthopedics, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Jiangxi, 330006, China
| | - Jiangminghao Zhao
- Department of Orthopedics, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Jiangxi, 330006, China
| | - Qi Chen
- Department of Orthopedics, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Jiangxi, 330006, China
| | - Xigao Cheng
- Department of Orthopedics, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Jiangxi, 330006, China.
- Institute of Orthopedics of Jiangxi Province, Nanchang, 330006, Jiangxi, China.
- Jiangxi Provincial Key Laboratory of Spine and Spinal Cord Disease, Jiangxi, 330006, China.
- Institute of Minimally Invasive Orthopedics, Nanchang University, Jiangxi, 330006, China.
| | - Jianjian Deng
- Department of Orthopedics, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Jiangxi, 330006, China.
- Institute of Orthopedics of Jiangxi Province, Nanchang, 330006, Jiangxi, China.
- Jiangxi Provincial Key Laboratory of Spine and Spinal Cord Disease, Jiangxi, 330006, China.
- Institute of Minimally Invasive Orthopedics, Nanchang University, Jiangxi, 330006, China.
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Večurkovská I, Stupák M, Kaťuchová J, Bohuš P, Hostačná L, Mareková M, Mašlanková J. Expression of individual members of the TGF-β/SMAD signalling pathway in the progression and survival of patients with colorectal carcinoma. Sci Rep 2024; 14:27442. [PMID: 39523401 PMCID: PMC11551139 DOI: 10.1038/s41598-024-79463-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Accepted: 11/08/2024] [Indexed: 11/16/2024] Open
Abstract
Current knowledge of tumor biology offers many "targets" for therapeutic intervention. The molecular basis of many processes that play a role in the pathogenesis of colorectal cancer has been identified. One part of colorectal cancer clinical trials is focused on testing substances in a group of patients with tumors in which the TGF-β signalling pathway is hyperactivated. The TGF-β/SMAD signalling pathway members are considered important markers; however, genetic, proteomic, or metabolomic analyses still yield controversial results. According to our results, TGF-βRII, and SMAD4 can be used in monitoring CRC progression. With increasing CRC stage, TGF-βRII expression decreases and SMAD4 expression increases. The patients with TGF-βRII expression lower than 700 pg/ml had a slightly lower survival time (28.103 months) than patients with higher TGF-βRII expression (31.620 months). Conversely, patients with SMAD4 expression lower than 200 pg/ml had a higher survival rate (30.979 months) than patients with higher expression (26.316 months). Regarding TGF-β1 expression, the patient´s survival assessment determined no significant difference between patients with high or low tissue TGF-β1 expression. A personalized approach and consideration of a wide range of factors are important when using these markers in treatment assessment.
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Grants
- VEGA 1/0435/23 Scientific Grant Agency of the Ministry of Education, Science, Research and Sport of the Slovak Republic and Slovak Academy of Sciences
- VEGA 1/0435/23 Scientific Grant Agency of the Ministry of Education, Science, Research and Sport of the Slovak Republic and Slovak Academy of Sciences
- VEGA 1/0435/23 Scientific Grant Agency of the Ministry of Education, Science, Research and Sport of the Slovak Republic and Slovak Academy of Sciences
- VEGA 1/0435/23 Scientific Grant Agency of the Ministry of Education, Science, Research and Sport of the Slovak Republic and Slovak Academy of Sciences
- VEGA 1/0435/23 Scientific Grant Agency of the Ministry of Education, Science, Research and Sport of the Slovak Republic and Slovak Academy of Sciences
- VEGA 1/0435/23 Scientific Grant Agency of the Ministry of Education, Science, Research and Sport of the Slovak Republic and Slovak Academy of Sciences
- VEGA 1/0435/23 Scientific Grant Agency of the Ministry of Education, Science, Research and Sport of the Slovak Republic and Slovak Academy of Sciences
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Affiliation(s)
- Ivana Večurkovská
- Department of Medical and Clinical Biochemistry, Faculty of Medicine, Pavol Jozef Šafárik University in Košice, Trieda SNP 1, 040 11, Košice, Slovakia
| | - Marek Stupák
- Department of Medical and Clinical Biochemistry, Faculty of Medicine, Pavol Jozef Šafárik University in Košice, Trieda SNP 1, 040 11, Košice, Slovakia
| | - Jana Kaťuchová
- Department of Surgery, Faculty of Medicine, Pavol Jozef Šafárik University in Košice, Trieda SNP 1, 040 11, Košice, Slovakia
| | - Peter Bohuš
- Department of Pathology, Louis Pasteur University Hospital, Rastislavová 43, 041 90, Košice, Slovakia
| | - Lenka Hostačná
- Department of Medical and Clinical Biochemistry, Faculty of Medicine, Pavol Jozef Šafárik University in Košice, Trieda SNP 1, 040 11, Košice, Slovakia
- Department of Clinical Biochemistry, Medirex, a.s., Magnezitárska 2/C, 040 13, Košice, Slovakia
| | - Mária Mareková
- Department of Medical and Clinical Biochemistry, Faculty of Medicine, Pavol Jozef Šafárik University in Košice, Trieda SNP 1, 040 11, Košice, Slovakia
| | - Jana Mašlanková
- Department of Medical and Clinical Biochemistry, Faculty of Medicine, Pavol Jozef Šafárik University in Košice, Trieda SNP 1, 040 11, Košice, Slovakia.
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Association of β-Catenin, APC, SMAD3/4, Tp53, and Cyclin D1 Genes in Colorectal Cancer: A Systematic Review and Meta-Analysis. Genet Res (Camb) 2022; 2022:5338956. [PMID: 36072013 PMCID: PMC9402361 DOI: 10.1155/2022/5338956] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 06/27/2022] [Indexed: 11/25/2022] Open
Abstract
Objectives Accumulating evidence indicates that the expression and/or variants of several genes play an essential role in the progress of colorectal cancer (CRC). The current study is a meta-analysis undertaken to estimate the prognosis and survival associated with CTNNB1/β-catenin, APC, Wnt, SMAD3/4, TP53, and Cyclin D1 genes among CRC patients. Methods The authors searched PubMed, EMBASE, and Science Direct for relevant reports published between 2000 and 2020 and analyzed them to determine any relationship between the (immunohistochemically/sequencing-detected) gene expression and variants of the selected genes and the survival of CRC patients. Results The analysis included 34,074 patients from 64 studies. To evaluate association, hazard ratios (HRs) were estimated for overall survival (OS) or disease-free survival (DFS), with a 95% confidence interval (CIs). Pooled results showed that β-catenin overexpression, APC mutation, SMAD-3 or 4 loss of expression, TP53 mutations, and Cyclin D1 expression were associated with shorter OS. β-Catenin overexpression (HR: 0.137 (95% CI: 0.131–0.406)), loss of expression of SMAD3 or 4 (HR: 0.449 (95% CI: 0.146–0.753)), the mutations of TP53 (HR: 0.179 (95% CI: 0.126–0.485)), and Cyclin D1 expression (HR: 0.485 (95% CI: 0.772–0.198)) also presented risk for shorter DFS. Conclusions The present meta-analysis indicates that overexpression or underexpression and variants of CTNNB1/β-catenin, APC, SMAD3/4, TP53, and Cyclin D1 genes potentially acted as unfavorable biomarkers for the prognosis of CRC. The Wnt gene was not associated with prognosis.
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Chang K, Jiang L, Sun Y, Li H. Effect of E-cadherin on Prognosis of Colorectal Cancer: A Meta-Analysis Update. Mol Diagn Ther 2022; 26:397-409. [PMID: 35732878 DOI: 10.1007/s40291-022-00593-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/25/2022] [Indexed: 12/15/2022]
Abstract
PURPOSE The effect of E-cadherin on colorectal cancer is still controversial. In order to clarify the effect of E-cadherin on the prognosis and clinicopathological features of colorectal cancer, a meta-analysis was conducted. METHODS PubMed, Embase and Cochrane Library were used to collect all relevant literature published before November 2021, and the corresponding data was extracted to analyze the correlation between the expression of E-cadherin and the prognosis and clinicopathological features of colorectal cancer. In addition, the Gene Expression Profiling Interactive Analysis (GEPIA) was used to validate our results. RESULTS Fifty-two studies, including 9591 patients, were included in this meta-analysis. According to the meta-analysis, low expression of E-cadherin was significantly associated with shorter overall survival (OS) (hazard ratio [HR] 2.09, 95% confidence interval [CI]1.67-2.62; Z = 6.42, p = 0.000) and disease-free survival (DFS) (HR 2.03, 95% CI 1.71-2.42; Z = 7.95, p = 0.000). In addition, low expression of E-cadherin resulted in higher risk of low differentiation (odds ratio [OR] 0.35, 95% CI 0.25-0.50; p = 0.000), high risk of distant metastasis (OR 0.45, 95% CI 0.35-0.58; p = 0.000), high risk of vascular invasion (OR 0.61, 95% CI 0.45-0.83; p = 0.002), higher risk of lymph node metastasis (OR 0.54, 95% CI 0.42-0.69; p = 0.000), high risk of lymphatic invasion (OR 0.56, 95% CI 0.40-0.80; p = 0.001), high risk of deep infiltration (OR 0.63, 95% CI 0.50-0.80; p = 0.000), later TNM stage (OR 0.60, 95% CI 0.46-0.78; p = 0.000) and late Dukes' stage (OR 0.35,95% CI 0.25-0.49; p = 0.000), but wasn't associated with tumor size (OR 0.90, 95% CI 0.71-1.15; p = 0.406).The results of GEPIA showed that E-cadherin mRNA expression in colorectal cancer tumor tissues and normal tissues had no difference, and had no effect on OS and DFS. CONCLUSION Although not supported by GEPIA, our meta-analysis provided abundant data to suggest that low expression of E-cadherin is associated with poor prognosis in colorectal cancer patients and is an important factor influencing adverse clinicopathological features. Therefore, E-cadherin may be used to predict the prognosis of colorectal cancer and provide guidance for clinical treatment.
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Affiliation(s)
- Kaibin Chang
- Department of Stomach and Intestine, Yantai Affiliated Hospital of Binzhou Medical University, 717 Jinbu Street, Yantai, 264100, Shandong Province, China
| | - Lei Jiang
- Department of Stomach and Intestine, Yantai Affiliated Hospital of Binzhou Medical University, 717 Jinbu Street, Yantai, 264100, Shandong Province, China
| | - Yifeng Sun
- Department of Stomach and Intestine, Yantai Affiliated Hospital of Binzhou Medical University, 717 Jinbu Street, Yantai, 264100, Shandong Province, China
| | - He Li
- Department of Stomach and Intestine, Yantai Affiliated Hospital of Binzhou Medical University, 717 Jinbu Street, Yantai, 264100, Shandong Province, China.
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Oncogenic Role of Connective Tissue Growth Factor Is Associated with Canonical TGF-β Cascade in Colorectal Cancer. Genes (Basel) 2022; 13:genes13040689. [PMID: 35456495 PMCID: PMC9031605 DOI: 10.3390/genes13040689] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 03/28/2022] [Accepted: 04/05/2022] [Indexed: 01/27/2023] Open
Abstract
TGF-β signaling pathways promote tumour development and control several downstream genes such as CTGF and MMPs. This study aimed to investigate the association between CTGF and MMP-1 mRNA expressions with clinicopathological status and survival rate in colorectal cancer patients. We investigated expression levels of CTGF and MMP-1 genes in paraffin-embedded tumours and adjacent normal tissue blocks (ADJ) by Real Time-PCR. Then, the expression of Smad2 and Smad4 proteins in the TGF-β canonical pathway was evaluated by immunohistochemistry. Finally, the correlation between CTGF, MMP-1, and the canonical TGF-β-signalling pathway with the clinicopathological features was investigated. Expression levels of MMP-1and CTGF were higher in tumours compared with adjacent normal tissues. Overexpression levels of MMP-1 and CTGF were associated with lymph node metastasis, distant metastasis, tumour histopathological grading, advanced stage, and poor survival (p < 0.05). Additionally, a significant association between the upregulation of MMP-1 and tumour location was noted. Upregulation of Smad2 and Smad4 proteins were also significantly correlated with lymph node metastasis, distant metastasis, advanced stage, and poor survival (p < 0.0001). This study showed that canonical TGF-β signalling regulates both CTGF and MMP-1 expression and CRC progression. Moreover, TGF-β signalling and its downstream genes could be used as novel biomarkers and novel approaches for targeted therapy in CRC.
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Stanilov N, Grigorova A, Velikova T, Stanilova SA. Genetic variation of TGF-ΒR2 as a protective genotype for the development of colorectal cancer in men. World J Gastrointest Oncol 2021; 13:1766-1780. [PMID: 34853649 PMCID: PMC8603459 DOI: 10.4251/wjgo.v13.i11.1766] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 05/19/2021] [Accepted: 09/22/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The role of transforming growth factor beta (TGF-β) signaling, including both the cytokine and their receptors, in the etiology of colorectal cancer (CRC) has been of particular interest lately. AIM To investigate the association between promoter polymorphism in TGF-β receptor 2 TGF-ΒR2G[-875]A with a CRC risk in a cohort of Bulgarian patients using a case-control gene association study approach, as well as the protein levels of TGF-β1 in the peripheral blood. METHODS A cohort of 184 CRC patients and 307 sex and age-matched healthy subjects were recruited in the study. A genotyping of the TGF-ΒR2G[-875]A (rs3087465) polymorphism was performed by primer-introduced restriction analyses-polymerase chain reaction approaches. RESULTS The frequency of TGF-ΒR2G[-875]A genotype was decreased in male patients with CRC than in healthy men (31.3% vs 44.8%; P = 0.058). Among males, the TGF-ΒR2G[-509]G genotype was related to a significantly increased risk of CRC development (OR = 1.820, 95%CI: 0.985-3.362, P = 0.055) than the GA + AA genotype. Also, TGF-ΒR2[-875]*A-allele itself was rarer in men with CRC than healthy men (19.1% vs 26.9%, P = 0.086) and was associated with a protective effect (OR = 0.644; 95%CI: 0.389-1.066; P = 0.086). Regarding the genotypes, we found that TGF-β1 serum levels were higher in GG genotype in healthy persons above 50 years than the CRC patients [36.3 ng/mL interquartile range (IQR) 19.9-56.5 vs 22.4 ng/mL IQR 14.8-29.7, P = 0.014]. We found significant differences between higher levels of TGF-β1 serum levels in healthy controls above 50 years (GG genotype) and CRC patients (GG genotype) at the early stage (36.3 ng/mL IQR 19.9-56.5 vs 22.8 ng/mL IQR 14.6-28.6, P = 0.037) and advanced CRC (36.3 ng/mL IQR 19.9-56.5 vs 21.6 ng/mL IQR 15.9-33.9, P = 0.039). CONCLUSION In summary, our results demonstrated that TGF-ΒR2 AG and AA genotypes were associated with a reduced risk of CRC, as well as circulating levels of TGF-β could prevent CRC development in a gender-specific manner. Notably, male carriers of TGF-ΒR2 -875A allele genotypes had a lower risk of CRC development and progression, suggesting that TGF-ΒR2 -875A/G polymorphism significantly affects the protective biological factors that also impact the risk of colon and rectal carcinogenesis.
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Affiliation(s)
- Noyko Stanilov
- Oncoplastic Unit, University College London Hospital, London NW1 2BU, United Kingdom
| | - Antonia Grigorova
- Department of Molecular Biology, Immunology and Medical Genetics, Medical Faculty, Trakia University, Stara Zagora 6000, Bulgaria
| | - Tsvetelina Velikova
- Department of Clinical Immunology, University Hospital Lozenetz, Sofia 1407, Bulgaria
- Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
| | - Spaska Angelova Stanilova
- Department of Molecular Biology, Immunology and Medical Genetics, Medical Faculty, Trakia University, Stara Zagora 6000, Bulgaria
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Pulido T, Velarde MC, Alimirah F. The senescence-associated secretory phenotype: Fueling a wound that never heals. Mech Ageing Dev 2021; 199:111561. [PMID: 34411604 DOI: 10.1016/j.mad.2021.111561] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 07/29/2021] [Accepted: 08/12/2021] [Indexed: 12/15/2022]
Abstract
Wound healing is impaired with advanced age and certain chronic conditions, such as diabetes and obesity. Moreover, common cancer treatments, including chemotherapy and radiation, can cause unintended tissue damage and impair wound healing. Available wound care treatments are not always effective, as some wounds fail to heal or recur after treatment. Hence, a more thorough understanding of the pathophysiology of chronic, nonhealing wounds may offer new ideas for the development of effective wound care treatments. Cancers are sometimes referred to as wounds that never heal, sharing mechanisms similar to wound healing. We describe in this review how cellular senescence and the senescence-associated secretory phenotype (SASP) contribute to chronic wounds versus cancer.
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Affiliation(s)
- Tanya Pulido
- Buck Institute for Research on Aging, Novato, CA, 94945, USA
| | - Michael C Velarde
- Institute of Biology, College of Science, University of the Philippines Diliman, Quezon City, 1101, Philippines.
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Par-4 mediated Smad4 induction in PDAC cells restores canonical TGF-β/ Smad4 axis driving the cells towards lethal EMT. Eur J Cell Biol 2020; 99:151076. [PMID: 32439219 DOI: 10.1016/j.ejcb.2020.151076] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Revised: 03/20/2020] [Accepted: 03/20/2020] [Indexed: 12/22/2022] Open
Abstract
Deregulation of TGF-β signaling is intricately engrossed in the pathophysiology of pancreatic adenocarcinomas (PDACs). The role of TGF-β all through pancreatic cancer initiation and progression is multifarious and somewhat paradoxical. TGF-β plays a tumor suppressive role in early-stage pancreatic cancer by promoting apoptosis and inhibiting epithelial cell cycle progression, but incites tumor promotion in late-stage by modulating genomic instability, neo-angiogenesis, immune evasion, cell motility, and metastasis. Here, we provide evidences that Par-4 acts as one of the vital mediators to regulate TGF-β/Smad4 pathway, wherein, Par-4 induction/over-expression induced EMT which was later culminated in to apoptosis in presence of TGF-β via positive regulation of Smad4. Intriguingly, Par-4-/- cells were devoid of significant Smad4 induction compared to Par-4+/+ cells in presence of TGF-β and ectopic Par-4 steadily augmented Smad4 expression by restoring TGF-β/Smad4 axis in Panc-1 cells. Further, our FACS and western blotting results unveiled that Par-4 dragged the PDAC cells to G1 arrest in presence of TGF-β byelevating p21 and p27 levels while attenuating Cyclin E and A levels and augmenting caspase 3 cleavage triggering lethal EMT. Through restoration of Smad4, we further establish that in BxPC3 cell line (Smad4-/-), Smad4 is essential for Par-4 to indulge TGF-β dependent lethal EMT program. The mechanistic relevance of Par-4 mediated Smad4 activation was additionally validated by co-immunoprecipitation wherein disruption of NM23H1-STRAP interaction by Par-4 rescues TGF-β/Smad4 pathway in PDAC and mediates the tumor suppressive role of TGF-β, therefore serving as a vital cog to restore the apoptotic functions of TGF-β pathway.
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Zhou J, Jiang W, Huang W, Ye M, Zhu X. Prognostic Values of Transforming Growth Factor-Beta Subtypes in Ovarian Cancer. BIOMED RESEARCH INTERNATIONAL 2020; 2020:2170606. [PMID: 32351985 PMCID: PMC7174935 DOI: 10.1155/2020/2170606] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 03/05/2020] [Accepted: 03/18/2020] [Indexed: 12/27/2022]
Abstract
PURPOSE To explore the potential role of the transforming growth factor-beta (TGF-β) subtypes in the prognosis of ovarian cancer patients. Materials and Methods. The prognostic roles of individual TGF-β subtypes in women with ovarian cancer were retrieved from the Kaplan-Meier plotter (KM plotter) database. In addition, the Oncomine database and immunohistochemistry were used to observe the mRNA and protein expression of TGF-β subtypes between human ovarian carcinoma and normal ovarian samples, respectively. RESULTS TGF-β1 and TGF-β4 were totally uncorrelated with survival outcomes in women with ovarian cancer. Increased TGF-β2 and TGF-β3 mRNA expression was markedly related to unfavorable prognosis, especially in women with serous, poorly differentiated, and late-stage ovarian carcinoma. High expression levels of TGF-β2 were related to worse progression-free survival (PFS) while TGF-β3 was linked to unfavorable overall survival (OS) and PFS in women with TP53-mutated ovarian cancer. TGF-β2 was associated with poor OS and PFS from treatment with chemotherapy with platins, Taxol, or a platin+Taxol. However, overexpression of TGF-β3 was associated with poor OS from the use of platins and poor PFS of Taxol or a platin+Taxol in women with ovarian carcinoma. Furthermore, the expression of TGF-β2 mRNA and protein was higher but only TGF-β3 mRNA expression was higher in cancerous tissues than in normal ovarian samples. CONCLUSION Higher expression of TGF-β2 functioned as a significant predictor of poor prognosis in women with ovarian cancer, especially those with TP53 mutations or who were undergoing chemotherapy with platins, Taxol, or a platin+Taxol.
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Affiliation(s)
- Junhan Zhou
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
| | - Wenxiao Jiang
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
| | - Wenbin Huang
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
| | - Miaomiao Ye
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
| | - Xueqiong Zhu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
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Zhang S, Song G, Yuan J, Qiao S, Xu S, Si Z, Yang Y, Xu X, Wang A. Circular RNA circ_0003204 inhibits proliferation, migration and tube formation of endothelial cell in atherosclerosis via miR-370-3p/TGFβR2/phosph-SMAD3 axis. J Biomed Sci 2020; 27:11. [PMID: 31900142 PMCID: PMC6941276 DOI: 10.1186/s12929-019-0595-9] [Citation(s) in RCA: 93] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Accepted: 11/18/2019] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Circular RNAs (circRNAs) represent a class of non-coding RNAs (ncRNAs) which are widely expressed in mammals and tissue-specific, of which some could act as critical regulators in the atherogenesis of cerebrovascular disease. However, the underlying mechanisms by which circRNA regulates the ectopic phenotype of endothelial cells (ECs) in atherosclerosis remain largely elusive. METHODS CCK-8, transwell, wound healing and Matrigel assays were used to assess cell viability, migration and tube formation. QRT-qPCR and Immunoblotting were used to examine targeted gene expression in different groups. The binding sites of miR-370-3p (miR-370) with TGFβR2 or hsa_circ_0003204 (circ_0003204) were predicted using a series of bioinformatic tools, and validated using dual luciferase assay and RNA immunoprecipitation (RIP) assay. The localization of circ_0003204 and miR-370 in ECs were investigated by fluorescence in situ hybridization (FISH). Gene function and pathways were enriched through Metascape and gene set enrichment analysis (GSEA). The association of circ_0003204 and miR-370 in extracellular vesicles (EVs) with clinical characteristics of patients were investigated using multiple statistical analysis. RESULTS Circ_0003204, mainly located in the cytoplasm of human aorta endothelial cells (HAECs), was upregulated in the ox-LDL-induced HAECs. Functionally, the ectopic expression of circ_0003204 inhibited proliferation, migration and tube formation of HAECs exposed to ox-LDL. Mechanically, circ_0003204 could promote protein expression of TGFβR2 and its downstream phosph-SMAD3 through sponging miR-370, and miR-370 targeted the 3' untranslated region (UTR) of TGFβR2. Furthermore, the expression of circ_0003204 in plasma EVs was upregulated in the patients with cerebral atherosclerosis, and represented a potential biomarker for diangnosis and prognosis of cerebrovascular atherogenesis. CONCLUSIONS Circ_0003204 could act as a novel stimulator for ectopic endothelial inactivation in atherosclerosis and a potential biomarker for cerebral atherosclerosis.
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Affiliation(s)
- Shanchao Zhang
- Department of Neurology, the First Affiliated Hospital of Shandong, First Medical University, NO.16766 JingShi Road, Jinan, 250014, Shandong, China.
| | - Guixiang Song
- Department of Neurology, the First Affiliated Hospital of Shandong, First Medical University, NO.16766 JingShi Road, Jinan, 250014, Shandong, China
| | - Jing Yuan
- Department of Neurology, the First Affiliated Hospital of Shandong, First Medical University, NO.16766 JingShi Road, Jinan, 250014, Shandong, China
| | - Shan Qiao
- Department of Neurology, the First Affiliated Hospital of Shandong, First Medical University, NO.16766 JingShi Road, Jinan, 250014, Shandong, China
| | - Shan Xu
- Department of Neurology, the First Affiliated Hospital of Shandong, First Medical University, NO.16766 JingShi Road, Jinan, 250014, Shandong, China
| | - Zhihua Si
- Department of Neurology, the First Affiliated Hospital of Shandong, First Medical University, NO.16766 JingShi Road, Jinan, 250014, Shandong, China
| | - Yang Yang
- Department of Neurology, the First Affiliated Hospital of Shandong, First Medical University, NO.16766 JingShi Road, Jinan, 250014, Shandong, China
| | - Xuxu Xu
- Department of Neurology, the First Affiliated Hospital of Shandong, First Medical University, NO.16766 JingShi Road, Jinan, 250014, Shandong, China
| | - Aihua Wang
- Department of Neurology, the First Affiliated Hospital of Shandong, First Medical University, NO.16766 JingShi Road, Jinan, 250014, Shandong, China
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11
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Girolami I, Veronese N, Smith L, Caruso MG, Reddavide R, Leandro G, Demurtas J, Nottegar A. The Activation Status of the TGF-β Transducer Smad2 Is Associated with a Reduced Survival in Gastrointestinal Cancers: A Systematic Review and Meta-Analysis. Int J Mol Sci 2019; 20:ijms20153831. [PMID: 31387321 PMCID: PMC6695973 DOI: 10.3390/ijms20153831] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 07/31/2019] [Accepted: 08/01/2019] [Indexed: 12/12/2022] Open
Abstract
Aberrant function of Smad2, a crucial member of transforming growth factor beta (TGF-β) signaling, is associated with the development of malignancies, particularly in the gastrointestinal district. However, little is known about its possible prognostic role in such tumor types. With the first meta-analysis on this topic, we demonstrated that the lack of the activated form of Smad2 (phosphor-Smad2 or pSmad2), which was meant to be the C-terminally phosphorylated form, showed a statistically significant association with an increased risk of all-cause mortality in patients with gastrointestinal cancers (RR, 1.58; 95% CI, 1.05–2.37, p = 0.029, I2 = 84%), also after having adjusted for potential confounders (RR, 1.65; 95% CI, 1.24–2.18; p < 0.001; I2 = 4%). This finding highlights the importance of the TGF-β signaling in this type of cancer. In this line, further studies are needed to explore more in depth this important molecular pathway, focusing also on potential therapeutic strategies based on its effectors or molecular targets.
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Affiliation(s)
- Ilaria Girolami
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134 Verona, Italy
| | - Nicola Veronese
- National Institute of Gastroenterology "S. de Bellis", Research Hospital, Castellana Grotte, 70013 Bari, Italy
| | - Lee Smith
- The Cambridge Centre for Sport and Exercise Sciences, Anglia Ruskin University, Cambridge CB1 1PT, UK
| | - Maria G Caruso
- National Institute of Gastroenterology "S. de Bellis", Research Hospital, Castellana Grotte, 70013 Bari, Italy
| | - Rosa Reddavide
- National Institute of Gastroenterology "S. de Bellis", Research Hospital, Castellana Grotte, 70013 Bari, Italy
| | - Gioacchino Leandro
- National Institute of Gastroenterology "S. de Bellis", Research Hospital, Castellana Grotte, 70013 Bari, Italy
| | - Jacopo Demurtas
- Primary Care Department, Azienda USL Toscana Sud Est, 58100 Grosseto, Italy
| | - Alessia Nottegar
- Department of Diagnostics, Section of Pathology, San Bortolo Hospital, 36100 Vicenza, Italy.
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12
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Yang L, Liu Z, Wen T. Multiplex fluorescent immunohistochemistry quantitatively analyses microvascular density (MVD) and the roles of TGF-β signalling in orchestrating angiogenesis in colorectal cancer. Transl Cancer Res 2019; 8:429-438. [PMID: 35116775 PMCID: PMC8797362 DOI: 10.21037/tcr.2019.02.09] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Accepted: 12/07/2018] [Indexed: 12/28/2022]
Abstract
Background Advances in multiplex fluorescent immunohistochemistry (mfIHC) techniques and digital pathology platforms allow the quantification of multiple proteins in the same tissue section and produce continuous data. Previously, we used mfIHC to establish the expressed profiles of proteins involved in TGF-β signalling in colorectal cancer (CRC). Methods We used mfIHC to show microvascular density (MVD) by staining CD31 in the tissues from CRC patients. We further investigated the relationship between MVD and TGF-β signalling. Results We found that the levels of MVD were significantly higher in cancer tissues than in paired normal tissues. Prognostic analysis revealed that the survival time for CRC patients with high levels of MVD was significantly shorter than that for those with low levels of MVD. Systematic analysis of the levels of MVD and TGF-β signalling proteins revealed that TGF-β signalling showed contradictory roles in sustained tumour angiogenesis. In CRC cells, the expression of VEGFA was increased by low concentrations of TGFB1 but decreased by high concentrations of TGFB1. Vessel-forming assays demonstrated that low-dose TGFB1 stimulated but high-dose TGFB1 inhibited HUVECs to form vessel tubes. Conclusions Our analysis based on mfIHC staining in CRC tissues supports the concept that TGF-β signalling either promotes or inhibits tumour angiogenesis.
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Affiliation(s)
- Lei Yang
- Medical Research Center, Beijing Chao-yang Hospital, Capital Medical University, Beijing 100020, China
| | - Zheng Liu
- Medical Research Center, Beijing Chao-yang Hospital, Capital Medical University, Beijing 100020, China
| | - Tao Wen
- Medical Research Center, Beijing Chao-yang Hospital, Capital Medical University, Beijing 100020, China
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13
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Stanilova S, Stanilov N, Julianov A, Manolova I, Miteva L. Transforming growth factor-β1 gene promoter -509C/T polymorphism in association with expression affects colorectal cancer development and depends on gender. PLoS One 2018; 13:e0201775. [PMID: 30071009 PMCID: PMC6072135 DOI: 10.1371/journal.pone.0201775] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Accepted: 07/20/2018] [Indexed: 12/12/2022] Open
Abstract
It is widely known that sporadic colorectal cancer (CRC) is age-related diseases with higher incidence rate among men. Transforming growth factor-β1 (TGF-β1) is a major immune regulatory cytokine with a great impact and dual role in gastrointestinal carcinogenesis. In this context, the aim of the study was to explore the role of circulating TGF-β1 and the -509C/T functional promoter polymorphism (rs1800469) within the TGF-β1 gene (TGFB1) in the susceptibility, progression, and prognosis of CRC among Bulgarian male and female patients. Patients with sporadic CRC and healthy controls were genotyped by polymerase-chain reaction–restriction fragment length polymorphism. Serum TGF-β1 levels before and after curative surgery were determined by ELISA. Total RNA was extracted from paired tumor, normal mucosa and distant metastasis samples and was used for quantitative detection of TGFB1 mRNA by TaqMan qPCR.We observed that TGF-β1 serum levels depend on the -509C/T genotype in combination with gender. TGF-β1 serum levels in CRC patients were decreased compared to controls, but statistical significance was reached only for men. In the stratified analysis by gender and genotype, a significant association was found for the CC genotype. Overall, our results indicate that the -509C allele increased the cancer risk, particularly for advanced stages (OR = 1.477; p = 0.029). The results from the relative mRNA quantification showed a significant upregulation of TGFB1 in distant metastases compared to primary tumor tissues and higher TGFB1 mRNA levels in men (RQ = 4.959; p = 0.022). In conclusion, we present data that diminished circulating TGF-β1 due to the CC genotype could be a possible risk factor for tumor susceptibility and progression. This association is more pronounced in males than in females. Colorectal cancer tissue expression of TGFB1 gene mRNA correlates with tumor progression and metastasis.
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Affiliation(s)
- Spaska Stanilova
- Department of Molecular Biology, Immunology and Medical Genetics, Medical Faculty, Trakia University, Stara Zagora, Bulgaria
- * E-mail:
| | - Noyko Stanilov
- Breast Oncoplastic Unit, University College London Hospital, London, United Kingdom
| | - Alexander Julianov
- Trakia Hospital, Stara Zagora, Bulgaria
- Department of Surgery, Medical Faculty, Trakia University, Stara Zagora, Bulgaria
| | - Irena Manolova
- Department of Molecular Biology, Immunology and Medical Genetics, Medical Faculty, Trakia University, Stara Zagora, Bulgaria
| | - Lyuba Miteva
- Department of Molecular Biology, Immunology and Medical Genetics, Medical Faculty, Trakia University, Stara Zagora, Bulgaria
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14
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Yang L, Liu Z, Tan J, Dong H, Zhang X. Multispectral imaging reveals hyper active TGF-β signaling in colorectal cancer. Cancer Biol Ther 2017; 19:105-112. [PMID: 29219668 DOI: 10.1080/15384047.2017.1395116] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Advances in multiplex immunohistochemistry (IHC) techniques and digital pathology platforms allow quantification of multiple proteins at same tissue section and produce continuous data. TGF-β signaling plays crucial and complex roles in colorectal cancer (CRC). We here aimed to investigate clinical pathological relevant of proteins involved in TGF-β signaling at CRC tissues. Multiplex fluorescent IHC was used to quantitative analysis. The levels of eight proteins (TGF-β1, TGFBRI, TGFBRII, SMAD4, SMAD2/3, p-SMAD2/3, SMAD1/5/9, and p-SMAD1/5/9) were determined in TMA sections. Quantitative analysis was carried out by a scoring system by InForm software. It revealed that TGF-β signaling was hyper active. The levels of TGF-β1, TGFBRI, TGFBRII, SMAD4, SMAD1/5/9 and p-SMAD2/3 were significantly increased in cancer tissues when compared their levels in normal tissues. Furthermore, the levels of eight proteins in stroma were significantly lower than the levels that in cancer tissues. Clinical pathological relevant analysis exhibited that TGF-β signaling inclined to suppress the progression of tumor. SMAD1/5/9, TGFBRII, SMAD2/3 were confirmed as significant predictors for overall survival. In conclusion, we established a method based on multispectral imaging to extensively explore the clinical relevant of TGF-β signaling proteins. These results provided an opportunity to consider the novel application for proteins involving TGF-β signaling that used as diagnostic or prognostic biomarkers to conduct tumor therapy.
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Affiliation(s)
- Lei Yang
- a Medical Research Center, Beijing Chaoyang Hospital , Capital Medical University , Beijing , P.R. China
| | - Zheng Liu
- a Medical Research Center, Beijing Chaoyang Hospital , Capital Medical University , Beijing , P.R. China
| | - Jinjing Tan
- b Department of Cellular and Molecular Biology, Beijing Chest Hospital , Capital Medical University , Beijing , P.R. China
| | - Hongwei Dong
- c Oncology Department, Beijing Chaoyang Hospital , Capital Medical University , Beijing , P.R. China
| | - Xiaojing Zhang
- c Oncology Department, Beijing Chaoyang Hospital , Capital Medical University , Beijing , P.R. China
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15
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Shen Y, Cao R, Liu W, Zhou Y, Wu Y, Tan J, Jin M, Zhong J, Zhang Q, Liu J, Zu X. Negative feedback loop between ZBTB7A and TGF-β in breast cancer. Oncol Lett 2017; 14:1403-1410. [PMID: 28789356 PMCID: PMC5529933 DOI: 10.3892/ol.2017.6291] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Accepted: 04/04/2017] [Indexed: 01/05/2023] Open
Abstract
Zinc finger and BTB domain containing 7A (ZBTB7A) is aberrantly expressed in breast cancer, but the involvement of ZBTB7A in breast cancer remains controversial. Transforming growth factor-β (TGF-β) is a pleiotropic cytokine which promotes breast cancer metastasis. ZBTB7A and TGF-β are important factors in tumor development. However, the association between ZBTB7A and TGF-β in breast cancer remains unknown. The results of the present study revealed that TGF-β1 induced the expression of ZBTB7A via the phosphoinositide 3-kinase-protein kinase B signaling pathway in human breast cancer cells, and ZBTB7A inhibited the expression of TGF-β1 through indirectly suppressing the promoter activity of TGF-β1. Furthermore, no significant correlation between the expression of ZBTB7A and TGF-β1 were identified in breast cancer tissues using tissue microarray assay and human cancer genomics analysis. These results have identified a negative feedback loop between ZBTB7A and TGF-β signaling, suggesting ZBTB7A as a potential modulator of breast cancer metastasis. Thus, the results of the present study suggested that ZBTB7A is a potential prognostic biomarker for breast cancer.
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Affiliation(s)
- Yingying Shen
- Institute of Clinical Medicine, The First Affiliated Hospital of The University of South China, Hengyang, Hunan 421001, P.R. China
| | - Renxian Cao
- Institute of Clinical Medicine, The First Affiliated Hospital of The University of South China, Hengyang, Hunan 421001, P.R. China.,Department of Metabolism and Endocrinology, The First Affiliated Hospital of The University of South China, Hengyang, Hunan 421001, P.R. China
| | - Wen Liu
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of The University of South China, Hengyang, Hunan 421001, P.R. China
| | - Yuqing Zhou
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of The University of South China, Hengyang, Hunan 421001, P.R. China
| | - Ying Wu
- Institute of Clinical Medicine, The First Affiliated Hospital of The University of South China, Hengyang, Hunan 421001, P.R. China
| | - Jingjing Tan
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of The University of South China, Hengyang, Hunan 421001, P.R. China
| | - Min Jin
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of The University of South China, Hengyang, Hunan 421001, P.R. China
| | - Jing Zhong
- Institute of Clinical Medicine, The First Affiliated Hospital of The University of South China, Hengyang, Hunan 421001, P.R. China
| | - Qinghai Zhang
- Institute of Clinical Medicine, The First Affiliated Hospital of The University of South China, Hengyang, Hunan 421001, P.R. China
| | - Jianghua Liu
- Institute of Clinical Medicine, The First Affiliated Hospital of The University of South China, Hengyang, Hunan 421001, P.R. China.,Department of Metabolism and Endocrinology, The First Affiliated Hospital of The University of South China, Hengyang, Hunan 421001, P.R. China
| | - Xuyu Zu
- Institute of Clinical Medicine, The First Affiliated Hospital of The University of South China, Hengyang, Hunan 421001, P.R. China
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16
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Bailey KL, Agarwal E, Chowdhury S, Luo J, Brattain MG, Black JD, Wang J. TGFβ/Smad3 regulates proliferation and apoptosis through IRS-1 inhibition in colon cancer cells. PLoS One 2017; 12:e0176096. [PMID: 28414818 PMCID: PMC5393866 DOI: 10.1371/journal.pone.0176096] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Accepted: 04/05/2017] [Indexed: 01/15/2023] Open
Abstract
In this study, we have uncovered a novel crosstalk between TGFβ and IGF-1R signaling pathways. We show for the first time that expression and activation of IRS-1, an IGF-1R adaptor protein, is decreased by TGFβ/Smad3 signaling. Loss or attenuation of TGFβ activation leads to elevated expression and phosphorylation of IRS-1 in colon cancer cells, resulting in enhanced cell proliferation, decreased apoptosis and increased tumor growth in vitro and in vivo. Downregulation of IRS-1 expression reversed Smad3 knockdown-mediated oncogenic phenotypes, indicating that TGFβ/Smad3 signaling inhibits cell proliferation and increases apoptosis at least partially through the inhibition of IRS-1 expression and activation. Additionally, the TGFβ/Smad3/IRS-1 signaling axis regulates expression of cyclin D1 and XIAP, which may contribute to TGFβ/Smad3/IRS-1-mediated cell cycle progression and survival. Given that loss of TGFβ signaling occurs frequently in colon cancer, an important implication of our study is that IRS-1 could be a potential therapeutic target for colon cancer treatment.
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Affiliation(s)
- Katie L. Bailey
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - Ekta Agarwal
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Nebraska, United States of America
- Wistar Institute, Philadelphia, Pennsylvania
| | - Sanjib Chowdhury
- Section of Gastroenterology, Department of Medicine, Boston University Medical Center, Boston, Massachusetts, United States of America
| | - Jiangtao Luo
- Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - Michael G. Brattain
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Nebraska, United States of America
| | - Jennifer D. Black
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - Jing Wang
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Nebraska, United States of America
- Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
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17
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Chen XL, Chen ZQ, Zhu SL, Liu TW, Wen Y, Su YS, Xi XJ, Hu Y, Lian L, Liu FB. Prognostic value of transforming growth factor-beta in patients with colorectal cancer who undergo surgery: a meta-analysis. BMC Cancer 2017; 17:240. [PMID: 28376764 PMCID: PMC5379512 DOI: 10.1186/s12885-017-3215-7] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Accepted: 03/22/2017] [Indexed: 02/07/2023] Open
Abstract
Background Transforming growth factor-beta (TGF-β) is associated with a higher incidence of distant metastasis and decreased survival. Whether TGF-β can be used as a prognostic indicator of colorectal cancer (CRC) remains controversial. Methods The Medline, EMBASE and Cochrane databases were searched from their inception to March 2016. The studies that focused on TGF-β as a prognostic factor in patients with CRC were included in this analysis. Overall survival (OS) and disease-free survival (DFS) were analysed separately. A meta-analysis was performed, and hazard ratios (HR) with 95% confidence intervals (CI) were calculated. Results Twelve studies were included in the analysis, of which 8 were used for OS and 7 for DFS. In all, 1622 patients with CRC undergoing surgery were included. Combined HRs suggested that high expression of TGF-β had a favourable impact on OS (HR = 1.68, 95% CI: 1.10–2.59) and DFS (HR = 1.11, 95% CI: 1.03–1.19) in CRC patients. For OS, the combined HRs of Asian studies and Western studies were 1.50 (95% CI: 0.61–3.68) and 1.80 (95% CI: 1.33–2.45), respectively. For DFS, the combined HRs of Asian studies and Western studies were 1.42 (95% CI: 0.61–3.31) and 1.11 (95% CI: 1.03–1.20), respectively. Conclusions This meta-analysis demonstrates that TGF-β can be used as a prognostic biomarker for CRC patients undergoing surgery, especially for CRC patients from Western countries. Electronic supplementary material The online version of this article (doi:10.1186/s12885-017-3215-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Xin-Lin Chen
- School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhuo-Qun Chen
- The First Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Shui-Lian Zhu
- The First Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Tian-Wen Liu
- Guangdong Province Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yi Wen
- The First Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yi-Sheng Su
- Guangdong Province Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xu-Jie Xi
- Guangdong Province Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yue Hu
- School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Lei Lian
- Department of Colorectal Surgery, Sun Yat-sen University, Guangzhou, China.
| | - Feng-Bin Liu
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China.
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18
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Refaat B, El-Shemi AG, Mohamed AM, Kensara OA, Ahmad J, Idris S. Activins and their related proteins in colon carcinogenesis: insights from early and advanced azoxymethane rat models of colon cancer. BMC Cancer 2016; 16:879. [PMID: 27835986 PMCID: PMC5106801 DOI: 10.1186/s12885-016-2914-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Accepted: 10/27/2016] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Activin-A may exert pro- or anti-tumorigenic activities depending on cellular context. However, little is known about its role, or the other mature activin proteins, in colorectal carcinoma (CRC). This study measured the expression of activin βA- & βB-subunits, activin type IIA & IIB receptors, smads 2/3/4/6/7 and follistatin in CRC induced by azoxymethane (AOM) in rats. The results were compared with controls and disseminated according to the characteristics of histopathological lesions. METHODS Eighty male Wistar rats were allocated into 20 controls and the remaining were equally divided between short 'S-AOM' (15 weeks) and long 'L-AOM' (35 weeks) groups following injecting AOM for 2 weeks. Subsequent to gross and histopathological examinations and digital image analysis, the expression of all molecules was measured by immunohistochemistry and quantitative RT-PCR. Activin-A, activin-B, activin-AB and follistatin were measured by ELISA in serum and colon tissue homogenates. RESULTS Colonic pre-neoplastic and cancerous lesions were identified in both AOM groups and their numbers and sizes were significantly (P < 0.05) greater in the L-AOM group. All the molecules were expressed in normal colonic epithelial cells. There was a significantly (P < 0.05) greater expression of βA-subunit, IIB receptor and follistatin in both pre-neoplastic and cancerous tissues. Oppositely, a significant (P < 0.05) decrease in the remaining molecules was detected in both AOM groups. Metastatic lesions were only observed within the L-AOM group and were associated with the most significant alterations of all molecules. Significantly higher concentrations of activin-A and follistatin and lower activin-AB were also detected in both groups of AOM. Tissue and serum concentrations of activin-A and follistatin correlated positively, while tissue activin-AB inversely, and significantly with the numbers and sizes of colonic lesions. CONCLUSIONS Normal rat colon epithelial cells are capable of synthesising, controlling as well as responding to activins in a paracrine/autocrine manner. Colonic activin systems are pathologically altered during tumorigenesis and appear to be time and lesion-dependent. Activins could also be potential sensitive markers and/or molecular targets for the diagnosis and/or treatment of CRC. Further studies are required to illustrate the clinical value of activins and their related proteins in colon cancer.
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Affiliation(s)
- Bassem Refaat
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al-Abdeyah, PO Box 7607, Makkah, Kingdom of Saudi Arabia
| | - Adel Galal El-Shemi
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al-Abdeyah, PO Box 7607, Makkah, Kingdom of Saudi Arabia
- Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Amr Mohamed Mohamed
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al-Abdeyah, PO Box 7607, Makkah, Kingdom of Saudi Arabia
- Clinical Laboratory Diagnosis, Department of Animal Medicine, Faculty of Veterinary Medicine, Assiut University, 71526 Assiut, Egypt
| | - Osama Adnan Kensara
- Clinical Nutrition Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al-Abdeyah, PO Box 7607, Makkah, Kingdom of Saudi Arabia
| | - Jawwad Ahmad
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al-Abdeyah, PO Box 7607, Makkah, Kingdom of Saudi Arabia
| | - Shakir Idris
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al-Abdeyah, PO Box 7607, Makkah, Kingdom of Saudi Arabia
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19
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McCubrey JA, Rakus D, Gizak A, Steelman LS, Abrams SL, Lertpiriyapong K, Fitzgerald TL, Yang LV, Montalto G, Cervello M, Libra M, Nicoletti F, Scalisi A, Torino F, Fenga C, Neri LM, Marmiroli S, Cocco L, Martelli AM. Effects of mutations in Wnt/β-catenin, hedgehog, Notch and PI3K pathways on GSK-3 activity-Diverse effects on cell growth, metabolism and cancer. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2016; 1863:2942-2976. [PMID: 27612668 DOI: 10.1016/j.bbamcr.2016.09.004] [Citation(s) in RCA: 116] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Revised: 08/14/2016] [Accepted: 09/02/2016] [Indexed: 02/07/2023]
Abstract
Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that participates in an array of critical cellular processes. GSK-3 was first characterized as an enzyme that phosphorylated and inactivated glycogen synthase. However, subsequent studies have revealed that this moon-lighting protein is involved in numerous signaling pathways that regulate not only metabolism but also have roles in: apoptosis, cell cycle progression, cell renewal, differentiation, embryogenesis, migration, regulation of gene transcription, stem cell biology and survival. In this review, we will discuss the roles that GSK-3 plays in various diseases as well as how this pivotal kinase interacts with multiple signaling pathways such as: PI3K/PTEN/Akt/mTOR, Ras/Raf/MEK/ERK, Wnt/beta-catenin, hedgehog, Notch and TP53. Mutations that occur in these and other pathways can alter the effects that natural GSK-3 activity has on regulating these signaling circuits that can lead to cancer as well as other diseases. The novel roles that microRNAs play in regulation of the effects of GSK-3 will also be evaluated. Targeting GSK-3 and these other pathways may improve therapy and overcome therapeutic resistance.
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Affiliation(s)
- James A McCubrey
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University Greenville, NC 27858, USA.
| | - Dariusz Rakus
- Department of Animal Molecular Physiology, Institute of Experimental Biology, Wroclaw University, Wroclaw, Poland
| | - Agnieszka Gizak
- Department of Animal Molecular Physiology, Institute of Experimental Biology, Wroclaw University, Wroclaw, Poland
| | - Linda S Steelman
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University Greenville, NC 27858, USA
| | - Steve L Abrams
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University Greenville, NC 27858, USA
| | - Kvin Lertpiriyapong
- Department of Comparative Medicine, Brody School of Medicine at East Carolina University, USA
| | - Timothy L Fitzgerald
- Department of Surgery, Brody School of Medicine at East Carolina University, USA
| | - Li V Yang
- Department of Internal Medicine, Hematology/Oncology Section, Brody School of Medicine at East Carolina University, USA
| | - Giuseppe Montalto
- Biomedical Department of Internal Medicine and Specialties, University of Palermo, Palermo, Italy; Consiglio Nazionale delle Ricerche, Istituto di Biomedicina e Immunologia Molecolare "Alberto Monroy", Palermo, Italy
| | - Melchiorre Cervello
- Consiglio Nazionale delle Ricerche, Istituto di Biomedicina e Immunologia Molecolare "Alberto Monroy", Palermo, Italy
| | - Massimo Libra
- Department of Bio-medical Sciences, University of Catania, Catania, Italy
| | | | - Aurora Scalisi
- Unit of Oncologic Diseases, ASP-Catania, Catania 95100, Italy
| | - Francesco Torino
- Department of Systems Medicine, Chair of Medical Oncology, Tor Vergata University of Rome, Rome, Italy
| | - Concettina Fenga
- Department of Biomedical, Odontoiatric, Morphological and Functional Images, Occupational Medicine Section - Policlinico "G. Martino" - University of Messina, Messina 98125, Italy
| | - Luca M Neri
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Sandra Marmiroli
- Department of Surgery, Medicine, Dentistry and Morphology, University of Modena and Reggio Emilia, Modena, Italy
| | - Lucio Cocco
- Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy
| | - Alberto M Martelli
- Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy
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20
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Huang MY, Lin CH, Huang CM, Tsai HL, Huang CW, Yeh YS, Chai CY, Wang JY. Relationships between SMAD3 expression and preoperative fluoropyrimidine-based chemoradiotherapy response in locally advanced rectal cancer patients. World J Surg 2015; 39:1257-1267. [PMID: 25561186 DOI: 10.1007/s00268-014-2917-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND SMAD3, which is accumulated in the nucleus, transcriptionally regulates TGF-β target genes, playing a significant role in mediating the activities of TGF-β. In this study, we assessed the roles of TGF-β1, SMAD3, and phosphorylated SMAD3 expressions in patients with locally advanced rectal cancer following preoperative fluoropyrimidine-based chemoradiotherapy. METHODS Using immunohistochemistry, we examined TGF-β1, SMAD3, and phosphorylated SMAD3 expressions in pre-chemoradiotherapy cancer tissues from 86 locally advanced rectal cancer patients. After chemoradiotherapy, 64 of 86 (74.4 %) locally advanced rectal cancer patients were classified as responders (pathological tumor regression grades of 2-4). RESULTS A multivariate analysis showed that phosphorylated SMAD3 overexpression correlated to poor preoperative chemoradiotherapy responses (P = 0.015; OR 7.218; 95 % CI 1.479-35.229). Furthermore, a poor response (pathological tumor regression grades of 0-1) was an independent predictor of postoperative relapse (P = 0.021; OR 5.452; 95 % CI 1.286-23.113). Additionally, patients with phosphorylated SMAD3 overexpression were found to have a worse disease-free survival (P = 0.023). CONCLUSIONS Our data suggested that analyzing pre-chemoradiotherapy tumors for phosphorylated SMAD3 overexpression would assist physicians in identifying locally advanced rectal cancer patients who may have a poor response risk to preoperative fluoropyrimidine-based chemoradiotherapy.
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Affiliation(s)
- Ming-Yii Huang
- Department of Radiation Oncology, Cancer Center, Kaohsiung Medical University Hospital, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
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Gargalionis AN, Korkolopoulou P, Farmaki E, Piperi C, Dalagiorgou G, Adamopoulos C, Levidou G, Saetta A, Fragkou P, Tsioli P, Kiaris H, Zizi-Serbetzoglou A, Karavokyros I, Papavassiliou KA, Tsavaris N, Patsouris E, Basdra EK, Papavassiliou AG. Polycystin-1 and polycystin-2 are involved in the acquisition of aggressive phenotypes in colorectal cancer. Int J Cancer 2015; 136:1515-1527. [PMID: 25123959 DOI: 10.1002/ijc.29140] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2014] [Revised: 08/01/2014] [Accepted: 08/07/2014] [Indexed: 01/01/2023]
Abstract
The polycystins PC1 and PC2 are emerging as major players in mechanotransduction, a process that influences all steps of the invasion/metastasis cascade. We hypothesized that PC1 and PC2 facilitate cancer aggressiveness. Immunoblotting, RT-PCR, semi-quantitative and quantitative real-time PCR and FACS analyses were employed to investigate the effect of polycystin overexpression in colorectal cancer (CRC) cells. The impact of PC1 inhibition on cancer-cell proliferation was evaluated through an MTT assay. In vitro data were analyzed by Student's t-test. HT29 human xenografts were treated with anti-PC1 (extracellular domain) inhibitory antibody and analyzed via immunohistochemistry to determine the in vivo role of PC1 in CRC. Clinical significance was assessed by examining PC1 and PC2 protein expression in CRC patients (immunohistochemistry). In vivo and clinical data were analyzed by non-parametric tests, Kaplan-Meier curves, log-rank test and Cox model. All statistical tests were two-sided. PC1 overexpression promotes epithelial-to-mesenchymal transition (EMT) in HCT116 cells, while PC2 overexpression results in upregulation of the mTOR pathway in SW480 cells. PC1 inhibition causes reduced cell proliferation in CRC cells inducing tumor necrosis and suppressing EMT in HT29 tumor xenografts. In clinical study, PC1 and PC2 overexpression associates with adverse pathological parameters, including invasiveness and mucinous carcinomas. Moreover, PC1 overexpression appears as an independent prognostic factor of reduced recurrence-free survival (HR = 1.016, p = 0.03) and lowers overall survival probability, while aberrant PC2 expression predicts poor overall survival (p = 0.0468). These results support, for the first time, a direct link between mechanosensing polycystins (PC1 and PC2) and CRC progression.
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22
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Voorneveld PW, Jacobs RJ, Kodach LL, Hardwick JCH. A Meta-Analysis of SMAD4 Immunohistochemistry as a Prognostic Marker in Colorectal Cancer. Transl Oncol 2015; 8:18-24. [PMID: 25749173 PMCID: PMC4350636 DOI: 10.1016/j.tranon.2014.11.003] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2014] [Revised: 11/02/2014] [Accepted: 11/05/2014] [Indexed: 01/17/2023] Open
Abstract
AIM: SMAD4 immunohistochemistry is considered a valuable prognostic marker in colorectal cancer, but individual studies have often been small and the results variable. A meta-analysis could potentially clarify these findings. METHODS: In September 2014, a Pubmed and Google Scholar search was conducted to find publications that reported the prognostic value of SMAD4 expression. A meta-analysis was performed to clarify the association between SMAD4 expression and survival outcomes. RESULTS: 137 studies were found, of which 13 were considered eligible. The studies consisted of a total of 3800 patients. Three different endpoints were taken into account, namely, overall survival (OS), disease-free survival (DFS), and cancer-specific survival (CSS). In addition, the studies were divided into univariate and multivariate analyses. The pooled hazard ratios were given as follows: univariate CSS = 1.75 [95% confidence interval (CI): 0.93-3.32; z= 1.69; P= .09]; multivariate CSS = 2.17 (95% CI: 1.56-3.01; z= 4.65; P= .000); univariate DFS = 2.11 (95% CI: 1.36-3.28; z= 3.32; P= .001); multivariate DFS = 2.15 (95% CI: 1.56-3.01; z= 4.65; P= .000); univariate OS and DFS = 2.30 (95% CI: 1.41-3.73; z= 3.36; P= .001); univariate OS = 2.28 (95% CI: 1.30-4.00; z= 2.89; P= .004). CONCLUSION: The results of the presented meta-analyses indicate that SMAD4 expression status using immunohistochemistry is a prognostic marker for patient survival.
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Affiliation(s)
- Philip W Voorneveld
- Department of Gastroenterology, Leiden University Medical Center, Leiden, The Netherlands.
| | - Rutger J Jacobs
- Department of Gastroenterology, Leiden University Medical Center, Leiden, The Netherlands
| | - Liudmila L Kodach
- Department of Gastroenterology, Leiden University Medical Center, Leiden, The Netherlands
| | - James C H Hardwick
- Department of Gastroenterology, Leiden University Medical Center, Leiden, The Netherlands
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23
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Evaluation of transforming growth factor-β1 suppress Pokemon/epithelial-mesenchymal transition expression in human bladder cancer cells. Tumour Biol 2014; 36:1155-62. [PMID: 25722217 DOI: 10.1007/s13277-014-2625-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2014] [Accepted: 09/10/2014] [Indexed: 01/08/2023] Open
Abstract
Transforming growth factor-β1 (TGF-β1) plays a dual role in apoptosis and in proapoptotic responses in the support of survival in a variety of cells. The aim of this study was to determine the function of TGF-β1 in bladder cancer cells and the relationship with POK erythroid myeloid ontogenic factor (Pokemon). TGF-β1 and its receptors mediate several tumorigenic cascades that regulate cell proliferation, migration, and survival of bladder cancer cells. Bladder cancer cells T24 were treated with different levels of TGF-β1. Levels of Pokemon, E-cadherin, Snail, MMP2, MMP9, Twist, VEGF, and β-catenin messenger RNA (mRNA) and protein were examined by real-time quantitative fluorescent PCR and Western blot analysis, respectively. The effects of TGF-β1 on epithelial-mesenchymal transition of T24 cells were evaluated with wound-healing assay, proliferation of T24 was evaluated with reference to growth curves with MTT assay, and cell invasive ability was investigated by Transwell assay. Data show that Pokemon was inhibited by TGF-β1 treatment; the gene and protein of E-cadherin and β-catenin expression level showed decreased markedly after TGF-β1 treatment (P < 0.05). While the bladder cancer cell after TGF-β1 treatment showed a significantly reduced wound-closing efficiency at 6, 12, and 24 h, mechanistic analyses demonstrated that different levels of TGF-β1 promotes tumor cell growth, migration, and invasion in bladder cancer cells (P < 0.01, P < 0.05, respectively). In summary, our findings suggest that TGF-β1 may inhibit the expression of Pokemon, β-catenin, and E-cadherin. The high expression of TGF-β1 leads to an increase in the phenotype and apical-base polarity of epithelial cells. These changes of cells may result in the recurrence and progression of bladder cancer at last. Related mechanism is worthy of further investigation.
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24
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Du Y, Zhou X, Huang Z, Qiu T, Wang J, Zhu W, Wang T, Liu P. Meta-analysis of the prognostic value of smad4 immunohistochemistry in various cancers. PLoS One 2014; 9:e110182. [PMID: 25333693 PMCID: PMC4198206 DOI: 10.1371/journal.pone.0110182] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Accepted: 09/07/2014] [Indexed: 12/17/2022] Open
Abstract
Background Accumulating evidence indicates that Smad4 (DPC4) plays a fundamental role in the development and prognosis of several types of cancer. The objective of this study was to conduct a meta-analysis to evaluate whether the loss of Smad4 staining could serve as a prognostic marker. Methods A comprehensive meta-analysis was conducted using major useful databases to determine the relationship between the immunohistochemical detection of Smad4 and the survival of patients with various cancers. We used hazard ratios (HRs) with 95% confidence interval (CIs) as the effect estimation to evaluate the association of Smad4 with overall survival (OS), cancer-specific survival (CSS) or recurrence-free survival (RFS). The relationship between the clinical characteristics of patients and Smad4 was also evaluated using the odds ratio (OR). Results A total of 7570 patients from 26 studies were included in the analysis. The pooled results showed that loss of Smad4 staining was a negative predictor of OS with an HR of 1.97 (95% CI: 1.55–2.51; Pheterogeneity<0.001) and CSS/RFS (HR = 1.81; 95% CI: 1.30–2.54; Pheterogeneity<0.001). In addition, loss of Smad4 staining was more likely to be found in older (OR = 1.69, 95% CI: 1.09–2.61; Pheterogeneity = 0.648) colorectal cancer patients with a late tumor stage (OR = 2.31, 95% CI: 1.71–3.10; Pheterogeneity = 0.218) and in gastric cancer patients with lymph node metastasis (OR = 2.11, 95% CI: 1.03–4.34; Pheterogeneity = 0.038). Conclusion Based on these results, our meta-analysis provided evidence that loss of Smad4 staining could act as an unfavorable biomarker in the prognosis of various cancers and should be used as a powerful tool in future clinical trials.
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Affiliation(s)
- Yiping Du
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xin Zhou
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zebo Huang
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Tianzhu Qiu
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jian Wang
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Wei Zhu
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Tongshan Wang
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- * E-mail: (TSW); (PL)
| | - Ping Liu
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Cancer Center of Nanjing Medical University, Nanjing, China
- * E-mail: (TSW); (PL)
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25
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Gao ZH, Lu C, Wang ZN, Song YX, Zhu JL, Gao P, Sun JX, Chen XW, Wang MX, Dong YL, Xu HM. ILEI: a novel marker for epithelial-mesenchymal transition and poor prognosis in colorectal cancer. Histopathology 2014; 65:527-38. [PMID: 24738665 DOI: 10.1111/his.12435] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2013] [Accepted: 04/11/2014] [Indexed: 01/09/2023]
Affiliation(s)
- Zhao-Hua Gao
- Department of Surgical Oncology and General Surgery; First Hospital of China Medical University; Shenyang China
| | - Chong Lu
- Department of Surgical Oncology and General Surgery; First Hospital of China Medical University; Shenyang China
| | - Zhen-Ning Wang
- Department of Surgical Oncology and General Surgery; First Hospital of China Medical University; Shenyang China
| | - Yong-Xi Song
- Department of Surgical Oncology and General Surgery; First Hospital of China Medical University; Shenyang China
| | - Jin-Liang Zhu
- Department of Surgical Oncology and General Surgery; First Hospital of China Medical University; Shenyang China
| | - Peng Gao
- Department of Surgical Oncology and General Surgery; First Hospital of China Medical University; Shenyang China
| | - Jing-Xu Sun
- Department of Surgical Oncology and General Surgery; First Hospital of China Medical University; Shenyang China
| | - Xiao-Wan Chen
- Department of Surgical Oncology and General Surgery; First Hospital of China Medical University; Shenyang China
| | - Mei-Xian Wang
- Department of Tumour Pathology and Surgical Oncology; First Hospital of China Medical University; Shenyang China
| | - Yu-Lan Dong
- Department of Tumour Pathology and Surgical Oncology; First Hospital of China Medical University; Shenyang China
| | - Hui-Mian Xu
- Department of Surgical Oncology and General Surgery; First Hospital of China Medical University; Shenyang China
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26
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Chun HK, Jung KU, Choi YL, Hong HK, Kim SH, Yun SH, Kim HC, Lee WY, Cho YB. Low expression of transforming growth factor beta-1 in cancer tissue predicts a poor prognosis for patients with stage III rectal cancers. Oncology 2014; 86:159-69. [PMID: 24643220 DOI: 10.1159/000358064] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2013] [Accepted: 12/13/2013] [Indexed: 11/19/2022]
Abstract
OBJECTIVE Transforming growth factor beta (TGF-β) plays an important role in tumorigenesis and metastasis. It works as a tumor suppressor in the normal colon, but acts as a cancer promoter during the late stages of colorectal carcinogenesis. High expression of TGF-β is known to be associated with advanced stages, tumor recurrence and decreased survival of patients. We investigated the expression of TGF-β and its signaling axis molecules and evaluated their prognostic significance in patients with stage III rectal cancers. METHODS Tissues from 201 cases of stage III rectal cancer were subjected to immunohistochemistry for TGF-β1, type II TGF-β receptor, Smad3, Smad4 and Smad7 proteins. The immunoactivities of these molecules were evaluated and the results were compared with clinicopathological variables including patient survival. RESULTS Low expression of TGF-β1 protein was correlated with a decreased disease-free survival in univariate Kaplan-Meier (p = 0.003) and multivariate Cox regression (HR 9.188 and 95% CI 1.256-67.198, p = 0.029) analyses. The loss of Smad4 protein expression was associated with a reduction in disease-free survival in the univariate analysis, but this finding was not significant after the multivariate analysis. CONCLUSION Low expression of TGF-β1 protein is associated with a poor prognosis for patients with stage III rectal cancers.
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Affiliation(s)
- Ho-Kyung Chun
- Department of Surgery, Kangbuk Samsung Hospital, Seoul, Republic of Korea
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He X, Chen Z, Jia M, Zhao X. Downregulated E-cadherin expression indicates worse prognosis in Asian patients with colorectal cancer: evidence from meta-analysis. PLoS One 2013; 8:e70858. [PMID: 23923027 PMCID: PMC3726621 DOI: 10.1371/journal.pone.0070858] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2013] [Accepted: 06/24/2013] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Epithelial-mesenchymal transition (EMT) plays a crucial role in the progression and aggressiveness of colorectal carcinoma. E-cadherin is the best-characterized molecular marker of EMT, but its prognostic significance for patients with CRC remains inconclusive. METHODOLOGY Eligible studies were searched from the PubMed, Embase and Web of Science databases. Correlation between E-cadherin expression and clinicopathological features and prognosis was analyzed. Subgroup analysis was also performed according to study location, number of patients, quality score of studies and cut-off value. PRINCIPAL FINDINGS A total of 27 studies comprising 4244 cases met the inclusion criteria. Meta-analysis suggested that downregulated E-cadherin expression had an unfavorable impact on overall survival (OS) of CRC (n = 2730 in 14 studies; HR = 2.27, 95%CI: 1.63-3.17; Z = 4.83; P = 0.000). Subgroup analysis indicated that low E-cadherin expression was significantly associated with worse OS in Asian patients (n = 1054 in 9 studies; HR = 2.86, 95%CI: 2.13-3.7, Z = 7.11; P = 0.000) but not in European patients (n = 1552 in 4 studies; HR = 1.14, 95%CI: 0.95-1.35, Z = 1.39; P = 0.165). In addition, reduced E-cadherin expression indicated an unfavorable OS only when the cut off value of low E-cadherin expression was >50% (n = 512 in 4 studies; HR = 2.08, 95%CI 1.45-2.94, Z = 4.05; P = 0.000). Downregulated E-cadherin expression was greatly related with differentiation grade, Dukes' stages, lymphnode status and metastasis. The pooled OR was 0.36(95%CI: 0.19-0.7, Z = 3.03, P = 0.002), 0.34(95%CI: 0.21-0.55, Z = 6.61, P = 0.000), 0.49(95%CI: 0.32-0.74, Z = 3.02, P = 0.002) and 0.45(95%CI: 0.22-0.91, Z = 3.43, P = 0.001), respectively. CONCLUSIONS This study showed that low or absent E-cadherin expression detected by immunohistochemistry served as a valuable prognostic factor of CRC. However, downregulated E-cadherin expression seemed to be associated with worse prognosis in Asian CRC patients but not in European CRC patients. Additionally, this meta-analysis suggested that the negative threshold of E-cadherin should be >50% when we detected its expression in the immunohistochemistry stain.
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Affiliation(s)
- Xin He
- Department of Hematology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhigang Chen
- Department of Oncology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Minyue Jia
- Department of Endocrinology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaoying Zhao
- Department of Hematology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Abstract
The transforming growth factor-β (TGF-β) system signals via protein kinase receptors and SMAD mediators to regulate a large number of biological processes. Alterations of the TGF-β signalling pathway are implicated in human cancer. Prior to tumour initiation and early during progression, TGF-β acts as a tumour suppressor; however, at later stages, it is often a tumour promoter. Knowledge about the mechanisms involved in TGF-β signal transduction has allowed a better understanding of cancer progression, invasion, metastasis and epithelial-to-mesenchymal transition. Furthermore, several molecular targets with great potential in therapeutic interventions have been identified. This review discusses the TGF-β signalling pathway, its involvement in cancer and current therapeutic approaches.
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Quantitative analysis of the association between interleukin-10 1082A/G polymorphism and susceptibility to sepsis. Mol Biol Rep 2013; 40:4327-32. [DOI: 10.1007/s11033-013-2520-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2012] [Accepted: 04/27/2013] [Indexed: 01/09/2023]
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Matrix metalloproteinase 9 expression and prognosis in colorectal cancer: a meta-analysis. Tumour Biol 2012; 34:735-41. [PMID: 23269605 DOI: 10.1007/s13277-012-0601-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2012] [Accepted: 11/19/2012] [Indexed: 01/29/2023] Open
Abstract
Matrix metalloproteinase-9 (MMP-9) is an important member of the matrix metalloproteinase family and is considered to be involved in the invasion and metastasis of cancer cells. Many studies were published to assess the prognostic role of MMP-9 overexpression in patients with colorectal cancer, but the findings from those studies were inconsistent. We searched eligible studies in Pubmed, Embase, and Web of Science databases. Thirteen studies with a total of 2, 390 CRC patients were finally included into the meta-analysis. The pooled hazard ratios (HRs) with the corresponding 95 % confidence interval (95 % CIs) for overall and progression-free survival were calculated by using meta-analysis. There were nine studies with a total of 1,674 colorectal cancer patients relating the progression-free survival, and eight studies with a total of 1,379 colorectal cancer patients relating the overall survival. Overall, MMP-9 overexpression was associated with poorer progression-free survival in patients with colorectal cancer (fixed-effects HR 1.81, 95 % CI 1.48-2.20, P < 0.001; random-effects HR 1.92, 95 % CI 1.46-2.53, P < 0.001). In addition, MMP-9 overexpression was also associated with poorer overall survival in patients with colorectal cancer (fixed-effects HR 1.74, 95 % CI 1.39-2.19, P < 0.001; random-effects HR 1.78, 95 % CI 1.31-2.41, P < 0.001). MMP-9 expression is associated with the prognosis of patients with colorectal cancer, and patients with higher MMP-9 expression have poorer survival.
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