Structural and functional analysis of SMAD4 gene promoter in malignant pancreatic and colorectal tissues: Detection of two novel polymorphic nucleotide repeats

Nikolić, Aleksandra; Kojić, Snežana; Knežević, S; Krivokapić, Zoran; Ristanovic, Momcilo; Radojković, Dragica

doi:10.1016/j.canep.2010.10.002

Cited by 20 publications

(21 citation statements)

References 15 publications

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“…We found SMAD4 loss to be strongly associated with poor survival in RFS and OS in stage III patients. Other authors have also reported that the incidence of SMAD4 loss increases from adenoma to carcinoma stage II to carcinoma stage III to liver metastasis, providing strong support for the notion that SMAD4 loss is involved in tumor progression (21,29,44).…”

Section: Discussionmentioning

confidence: 70%

“…Furthermore, SMAD4 has been found deleted or mutated in approximately 5% of adenomas and 20% of sporadic colorectal cancer, consistent with its role in colorectal cancer progression (29,37). In addition, retrospective trial data suggest that tumors expressing high SMAD4 levels show significantly better overall and diseasefree survival (38,39).…”

Section: Introductionmentioning

confidence: 64%

“…As previously noted, one of the most important and frequently encountered events is allelic loss on chromosome 18q (20,21), where SMAD4 (also called deleted in pancreatic carcinoma 4, DPC4) gene is located (22)(23)(24). The SMAD4 tumor-suppressor gene (TSG) codes for the common intracellular mediator of the TGFb superfamily signaling pathway, one of the most commonly altered cellular signaling pathways in human cancers (25)(26)(27) and involved in the regulation of cell proliferation, differentiation, apoptosis, and cell migration (27)(28)(29)(30).…”

Section: Introductionmentioning

confidence: 99%

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Reduced Expression of SMAD4 Is Associated with Poor Survival in Colon Cancer

Yan

Klingbiel

Saridaki

et al. 2016

Clinical Cancer Research

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Purpose: SMAD4 loss is associated with the development of metastases and poor prognosis. We evaluated expression of SMAD4 protein and its association with tumor characteristics, including biomarkers and outcome in terms of relapse-free survival and overall survival.Experimental design: We used 1,564 stage II/III colon cancer samples from PETACC-3 to evaluate SMAD4 expression by immunohistochemistry. SMAD4 protein expression was validated by assessing mRNA expression using available expression array data. SMAD4 expression was also studied on 34 adenomas and 10 colon cancer liver metastases with their primaries. Loss of SMAD4 immunoreactivity was defined as focal or diffuse. Cases without SMAD4 loss were subdivided into those with strong and weak expression.Results: SMAD4 protein expression was informative in 1,381/1,564 cases. SMAD4 loss was found in 293/1,381 (21%) cases. Of 1,088 cases without SMAD4 loss (79%), 530 showed weak and 558 strong expression. SMAD4 loss occurred also in adenomas, but less extensively than in carcinomas. Liver metastases followed mostly the expression pattern of the primary tumor. SMAD4 loss, including weak expression, identified patients with poor survival in stage II as well as III and in both treatment arms. SMAD4 loss was less frequent in tumors with microsatellite instability and more frequent in those with loss of heterozygosity of 18q.Conclusions: We conclude that clonal loss of SMAD4 expression in adenomas, carcinomas, and liver metastases increases with disease progression. SMAD4 loss, and to a lesser extent weak expression, is strongly associated with poor survival regardless of stage.

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Section: Discussionmentioning

confidence: 70%

Section: Introductionmentioning

confidence: 64%

Section: Introductionmentioning

confidence: 99%

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Reduced Expression of SMAD4 Is Associated with Poor Survival in Colon Cancer

Yan

Klingbiel

Saridaki

et al. 2016

Clinical Cancer Research

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“…Two somatic mutations were found to disturb transcription in endometrial carcinoma, − 154T/C and GG to AA transversion at + 5-6 (Zhou et al, 1999). Also, two mononucleotide repeats in the SMAD4 gene promoter, −462T(15) and −4T(12), were found to be altered in some types of tumors (Nikolic et al, 2011(Nikolic et al, , 2012. Somatic alterations of both variants were found in patients with pancreatic, colorectal and endometrial cancer and some of them were shown to alter SMAD4 promoter activity (Nikolic et al, 2011).…”

Section: Introductionmentioning

confidence: 97%

Mononucleotide repeats in the SMAD4 gene promoter in colon carcinoma tissue of Croatian patients

Nikolić

Čačev

Aralica

et al. 2015

Experimental and Molecular Pathology

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“…Therefore, their role in asthma should also be investigated since they may act as potential risk factors and/or phenotype modulators. In addition, recent findings indicate that the regulatory region of the SMAD4 gene may also harbor genetic variants associated with haploinsufficiency [14]. For this reason, future research should be directed at the analysis of the complete gene, including regulatory elements, in order to resolve the exact role of SMAD4 in asthma.…”

Section: Communicationmentioning

confidence: 99%

Analysis of the SMAD4 gene in asthma

Miletić

Petrovic-Stanojevic²,

Radojković

et al. 2014

Open Medicine

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AbstractConsidering the importance of the TGF-β signaling pathway for normal lung function and especially its roles in inflammation and tissue remodeling, key features of asthma pathology, it can be assumed that these molecules may harbor mutations in asthmatics. The aim of this study was to analyze the SMAD4 gene in patients with asthma. Analysis has encompassed exons 10, 11, 12 and 13 encoding the carboxy-terminal (MH2) domain of the SMAD4 protein, where mutations most frequently occur. The study included 50 patients (20 men and 30 women) with asthma aged between 17 and 73 years (average age 45.2±15.6 years). Polymerase chain reaction (PCR) was used to amplify exons 10, 11, 12 and 13 of the SMAD4 gene and the obtained PCR products were subjected to direct DNA sequencing. No nucleotide changes were found in any of the analyzed exons in either of the subjects. Based on the results of this study, it seems that mutations in the carboxy-terminal (MH2) domain of the SMAD4 are not present in asthmatic patients. Future research should be directed at the analysis of the complete gene, including regulatory elements, in order to resolve the exact role of SMAD4 in asthma.

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Structural and functional analysis of SMAD4 gene promoter in malignant pancreatic and colorectal tissues: Detection of two novel polymorphic nucleotide repeats

Cited by 20 publications

References 15 publications

Reduced Expression of SMAD4 Is Associated with Poor Survival in Colon Cancer

Reduced Expression of SMAD4 Is Associated with Poor Survival in Colon Cancer

Mononucleotide repeats in the SMAD4 gene promoter in colon carcinoma tissue of Croatian patients

Analysis of the SMAD4 gene in asthma

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