Journal of Pathology and Translational Medicine

Original Articles

Clinicopathological Characterization and Prognostic Implication of SMAD4 Expression in Colorectal Carcinoma: Seung-Yeon Yoo, Ji-Ae Lee, Yunjoo Shin, Nam-Yun Cho, Jeong Mo Bae, Gyeong Hoon Kang; J Pathol Transl Med. 2019;53(5):289-297. Published online June 24, 2019; DOI: https://doi.org/10.4132/jptm.2019.06.07

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Background
SMAD family member 4 (SMAD4) has gained attention as a promising prognostic factor of colorectal cancer (CRC) as well as a key molecule to understand the tumorigenesis and progression of CRC.
Methods
We retrospectively analyzed 1,281 CRC cases immunohistochemically for their expression status of SMAD4, and correlated this status with clinicopathologic and molecular features of CRCs.
Results
A loss of nuclear SMAD4 was significantly associated with frequent lymphovascular and perineural invasion, tumor budding, fewer tumor-infiltrating lymphocytes, higher pT and pN category, and frequent distant metastasis. In contrast, tumors overexpressing SMAD4 showed a significant association with sporadic microsatellite instability. After adjustment for TNM stage, tumor differentiation, adjuvant chemotherapy, and lymphovascular invasion, the loss of SMAD4 was found to be an independent prognostic factor for worse 5-year progression-free survival (hazard ratio [HR], 1.27; 95% confidence interval [CI], 1.01 to 1.60; p=.042) and 7-year cancerspecific survival (HR, 1.45; 95% CI, 1.06 to 1.99; p=.022).
Conclusions
We confirmed the value of determining the loss of SMAD4 immunohistochemically as an independent prognostic factor for CRC in general. In addition, we identified some histologic and molecular features that might be clues to elucidate the role of SMAD4 in colorectal tumorigenesis and progression.

Citations

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Association between the expression of epithelial–mesenchymal transition (EMT)-related markers and oncologic outcomes of colorectal cancer
Mona Hany Emile, Sameh Hany Emile, Amr Awad El-Karef, Mohamed Awad Ebrahim, Ibrahim Eldosoky Mohammed, Dina Abdallah Ibrahim
Updates in Surgery.2024; 76(6): 2181. CrossRef
TGF-β and SMAD2/4 Expression in Nonmetastatic and Metastatic Colorectal Cancer Patients
Ainul Mardiah, Hendra Susanto, Sri Rahayu Lestari, A. Taufiq, H. Susanto, H. Nur, M. Diantoro, M. Aziz, N.A.N.N. Malek
BIO Web of Conferences.2024; 117: 01001. CrossRef
Unraveling Resistance to Immunotherapy in MSI-High Colorectal Cancer
Ronald Heregger, Florian Huemer, Markus Steiner, Alejandra Gonzalez-Martinez, Richard Greil, Lukas Weiss
Cancers.2023; 15(20): 5090. CrossRef
Association of β-Catenin, APC, SMAD3/4, Tp53, and Cyclin D1 Genes in Colorectal Cancer: A Systematic Review and Meta-Analysis
Hongfeng Yan, Fuquan Jiang, Jianwu Yang, Ying-Kun Xu
Genetics Research.2022; 2022: 1. CrossRef
Comprehensive genetic features of gastric mixed adenoneuroendocrine carcinomas and pure neuroendocrine carcinomas
Jiwon Koh, Soo Kyung Nam, Yoonjin Kwak, Gilhyang Kim, Ka‐Kyung Kim, Byung‐Chul Lee, Sang‐Hoon Ahn, Do Joong Park, Hyung‐Ho Kim, Kyoung Un Park, Woo Ho Kim, Hye Seung Lee
The Journal of Pathology.2021; 253(1): 94. CrossRef
Alterations of PTEN and SMAD4 methylation in diagnosis of breast cancer: implications of methyl II PCR assay
Menha Swellam, Entsar A. Saad, Shimaa Sabry, Adel Denewer, Camelia Abdel Malak, Amr Abouzid
Journal of Genetic Engineering and Biotechnology.2021; 19(1): 54. CrossRef
Molecular Characterization and Functional Analysis of Two Steroidogenic Genes TSPO and SMAD4 in Yellow Catfish
Fang Chen, Chong-Chao Zhong, Chang-Chun Song, Shu-Wei Chen, Yang He, Xiao-Ying Tan
International Journal of Molecular Sciences.2021; 22(9): 4505. CrossRef
SMAD7 and SMAD4 expression in colorectal cancer progression and therapy response
Jovana Rosic, Sandra Dragicevic, Marko Miladinov, Jovana Despotovic, Aleksandar Bogdanovic, Zoran Krivokapic, Aleksandra Nikolic
Experimental and Molecular Pathology.2021; 123: 104714. CrossRef
Actionable Potentials of Less Frequently Mutated Genes in Colorectal Cancer and Their Roles in Precision Medicine
Ryia Illani Mohd Yunos, Nurul Syakima Ab Mutalib, Francis Yew Fu Tieng, Nadiah Abu, Rahman Jamal
Biomolecules.2020; 10(3): 476. CrossRef

The Smad4/PTEN Expression Pattern Predicts Clinical Outcomes in Colorectal Adenocarcinoma: Yumin Chung, Young Chan Wi, Yeseul Kim, Seong Sik Bang, Jung-Ho Yang, Kiseok Jang, Kyueng-Whan Min, Seung Sam Paik; J Pathol Transl Med. 2018;52(1):37-44. Published online October 23, 2017; DOI: https://doi.org/10.4132/jptm.2017.10.20

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Abstract PDF Supplementary Material

Background
Smad4 and PTEN are prognostic indicators for various tumor types. Smad4 regulates tumor suppression, whereas PTEN inhibits cell proliferation. We analyzed and compared the performance of Smad4 and PTEN for predicting the prognosis of patients with colorectal adenocarcinoma.
Methods
Combined expression patterns based on Smad4+/– and PTEN+/– status were evaluated by immunostaining using a tissue microarray of colorectal adenocarcinoma. The relationships between the protein expression and clinicopathological variables were analyzed.
Results
Smad4–/PTEN– status was most frequently observed in metastatic adenocarcinoma, followed by primary adenocarcinoma and tubular adenoma (p<.001). When Smad4–/PTEN– and Smad4+/PTEN+ groups were compared, Smad4–/PTEN– status was associated with high N stage (p=.018) and defective mismatch repair proteins (p=.006). Significant differences in diseasefree survival and overall survival were observed among the three groups (Smad4+/PTEN+, Smad4–/PTEN+ or Smad4+/PTEN–, and Smad4–/PTEN–) (all p<.05).
Conclusions
Concurrent loss of Smad4 and PTEN may lead to more aggressive disease and poor prognosis in patients with colorectal adenocarcinoma compared to the loss of Smad4 or PTEN alone.

Citations

Citations to this article as recorded by

Association between the expression of epithelial–mesenchymal transition (EMT)-related markers and oncologic outcomes of colorectal cancer
Mona Hany Emile, Sameh Hany Emile, Amr Awad El-Karef, Mohamed Awad Ebrahim, Ibrahim Eldosoky Mohammed, Dina Abdallah Ibrahim
Updates in Surgery.2024; 76(6): 2181. CrossRef
The Potential Role of Genomic Signature in Stage II Relapsed Colorectal Cancer (CRC) Patients: A Mono-Institutional Study
Michela Roberto, Giulia Arrivi, Emanuela Pilozzi, Andrea Montori, Genoveffa Balducci, Paolo Mercantini, Andrea Laghi, Debora Ierinò, Martina Panebianco, Daniele Marinelli, Silverio Tomao, Paolo Marchetti, Federica Mazzuca
Cancer Management and Research.2022; Volume 14: 1353. CrossRef
Alterations of PTEN and SMAD4 methylation in diagnosis of breast cancer: implications of methyl II PCR assay
Menha Swellam, Entsar A. Saad, Shimaa Sabry, Adel Denewer, Camelia Abdel Malak, Amr Abouzid
Journal of Genetic Engineering and Biotechnology.2021; 19(1): 54. CrossRef
E3 ubiquitin ligase HECW1 promotes the metastasis of non-small cell lung cancer cells through mediating the ubiquitination of Smad4
Chen Lu, Guangyao Ning, Panpan Si, Chunsheng Zhang, Wenjian Liu, Wei Ge, Kai Cui, Renquan Zhang, Shenglin Ge
Biochemistry and Cell Biology.2021; 99(5): 675. CrossRef
Computational quantification of global effects induced by mutations and drugs in signaling networks of colorectal cancer cells
Sara Sommariva, Giacomo Caviglia, Silvia Ravera, Francesco Frassoni, Federico Benvenuto, Lorenzo Tortolina, Nicoletta Castagnino, Silvio Parodi, Michele Piana
Scientific Reports.2021;[Epub] CrossRef
Clinicopathological characterization of SMAD4-mutated intestinal adenocarcinomas: A case-control study
Xiaoyan Liao, Yansheng Hao, Xiaofei Zhang, Stephen Ward, Jane Houldsworth, Alexandros D. Polydorides, Noam Harpaz, Aldo Scarpa
PLOS ONE.2019; 14(2): e0212142. CrossRef
Clinicopathological Characterization and Prognostic Implication of SMAD4 Expression in Colorectal Carcinoma
Seung-Yeon Yoo, Ji-Ae Lee, Yunjoo Shin, Nam-Yun Cho, Jeong Mo Bae, Gyeong Hoon Kang
Journal of Pathology and Translational Medicine.2019; 53(5): 289. CrossRef
Dissecting the therapeutic implications of the complex SMAD4 regulatory network in metastatic colorectal cancer
Ion Cristóbal, Blanca Torrejón, Andrea Santos, Melani Luque, Marta Sanz-Alvarez, Federico Rojo, Jesús García-Foncillas
European Journal of Surgical Oncology.2018; 44(8): 1283. CrossRef
Reply to: Dissecting the therapeutic implications of the complex SMAD4 regulatory network in metastatic colorectal cancer
Jordan M. Cloyd, Takashi Mizuno, Jean-Nicolas Vauthey
European Journal of Surgical Oncology.2018; 44(8): 1285. CrossRef

Smad1 Expression in Follicular Lymphoma: Jai Hyang Go; J Pathol Transl Med. 2015;49(3):243-248. Published online May 15, 2015; DOI: https://doi.org/10.4132/jptm.2015.03.30

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Abstract PDF: Background
Follicular lymphomas present with various immunohistologic patterns. The immunohistochemical markers used in the diagnosis of follicular lymphoma show variable degrees of sensitivity and specificity, and thus, additional germinal center markers are required. Smad1 has been reported to be overexpressed in follicular lymphoma, but little is known regarding the expression patterns of Smad proteins in human lymphoid tissue. Methods: In the present study, we performed immunohistochemistry for traditional germinal center markers and for Smad1 in human reactive lymphoid and follicular lymphoma tissues to investigate Smad1’s usefulness in the diagnosis of follicular lymphoma. Results: In the reactive germinal centers, most cells were positive for Smad1. Among the 27 follicular lymphoma cases, 17 of 21 (80%) were Smad1 positive, 17 of 27 (63%) were positive for CD10, and 23 of 27 (85%) were positive for Bcl6. Notably, three cases expressed CD10 only, and one only expressed Bcl6. All these cases were grade 3 tumors and showed follicular and diffuse growth patterns. Conclusions: These results indicate that Smad1 is a candidate as a germinal center marker. Furthermore, they suggest that the Smad signaling pathway might be involved in follicular lymphoma.

DPC4 Expression in the Small Intestinal Adenocarcinomas: Sun Jae Lee, Eunsil Yu, Young Kyung Bae, Kee-Taek Jang, Joon Mee Kim, Han-Ik Bae, Seung-Mo Hong, Ghil Suk Yoon; Korean J Pathol. 2012;46(5):415-422. Published online October 25, 2012; DOI: https://doi.org/10.4132/KoreanJPathol.2012.46.5.415

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Abstract PDF

Background

Small intestinal adenocarcinomas (SACs) are rare malignancies of the alimentary tract with uncertain carcinogenesis.

Methods

We investigated the expression of deleted in pancreatic cancer 4 (DPC4) in 188 cases of surgically resected SACs, using tissue microarray technology.

Results

Twenty-four of the 188 tumors showed complete loss of Smad4/DPC4 expression in cytoplasm (score, 0; 12.8%). Eighty-four and 31 cases were moderately and strongly positive, respectively (score, 2 and 3; 44.7% and 16.5%, respectively) and 49 cases were focally or weakly stained (score, 1; 29.1%). Immunohistochemistry analysis showed that the expression of Smad4/DPC4 was related to an increased risk of lymphatic invasion but not to other clinicopathological features of the tumors (tumor location, differentiation, growth pattern, T stage, direct invasion, vascular invasion, and nodal metastasis). There was no significant association between Smad4/DPC4 expression and patient survival.

Conclusions

The present research is the first study to evaluate Smad4/DPC4 expression in a large sample of SACs with clinicopathologic correlation. Future studies should focus on the immunohistochemical and molecular characteristics of SACs to clarify their tumorigenesis.

Citations

Citations to this article as recorded by

American Registry of Pathology Expert Opinions: Evaluation of poorly differentiated malignant neoplasms on limited samples - Gastrointestinal mucosal biopsies
Andrew M. Bellizzi, Elizabeth A. Montgomery, Jason L. Hornick
Annals of Diagnostic Pathology.2020; 44: 151419. CrossRef

Expression of Minichromosome Maintenance Protein 7 and Smad 4 in Squamous Cell Carcinoma of the Esophagus.: Ji Hyun Ahn, Hee Kyung Chang; Korean J Pathol. 2010;44(4):346-353.; DOI: https://doi.org/10.4132/KoreanJPathol.2010.44.4.346

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Abstract PDF

BACKGROUND
Minichromosome maintenance protein 7 (MCM 7) performs a direct role in the initiation of DNA replication, which suggests that it may prove useful as a marker of cell proliferation. Smad 4 is a tumor suppressor gene that mediates the transforming growth factor beta pathway. The principal objective of this study was to characterize the expression of MCM 7 and Smad 4 and to analyze their relationship to clinicopathological parameters in patients with esophageal squamous cell carcinoma.
METHODS
Expression levels of MCM 7 and Smad 4 were evaluated via immunohistochemistry on formalin-fixed and paraffin-embedded tissues from 67 cases of esophageal squamous cell carcinoma.
RESULTS
High levels of MCM 7 expression were detected in 53 cases (74.6%), and were associated with higher T stages (p = 0.030). Kaplan-Meier survival curves demonstrated that patients with higher levels of MCM 7 expression had poorer prognoses, although this association was not significant (p = 0.086). Loss of Smad 4 expression was noted in 18 cases (23.4%), and was not associated with clinicopathological characteristics, including MCM 7 expression, or prognosis.
CONCLUSIONS
MCM 7 expression is associated with the invasiveness of esophageal squamous cell carcinoma. Altered expression of Smad 4 does not appear to have pathobiological significance in esophageal carcinoma.

Citations

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scDiffCoAM: A complete framework to identify potential biomarkers for esophageal squamous cell carcinoma using scRNA-Seq data analysis
Manaswita Saikia, Dhruba K Bhattacharyya, Jugal K Kalita
Journal of Biosciences.2024;[Epub] CrossRef
Immunohistochemical analysis of proliferating cell nuclear antigen and minichromosome maintenance complex component 7 in benign and malignant salivary gland tumors
Nafiseh Shamloo, Nasim Taghavi, Samane Ahmadi, Soudeh Shalpoush
Dental Research Journal.2022; 19(1): 17. CrossRef
Expression of Minichromosome Maintenance Proteins in Actinic Keratosis and Squamous Cell Carcinoma
Jelena Stojkovic-Filipovic, Dimitrije Brasanac, Martina Bosic, Novica Boricic, Branislav Lekic
Applied Immunohistochemistry & Molecular Morphology.2018; 26(3): 165. CrossRef
Ki-67 protein predicts survival in oral squamous carcinoma cells: an immunohistochemical study
Verena Karla Monteiro LOPES, Adriana Souza de JESUS, Lucas Lacerda de SOUZA, Ligia Akiko Ninokata MIYAHARA, Douglas Magno GUIMARÃES, Helder Antônio Rebelo PONTES, Flavia Sirotheau Correa PONTES, Pedro Luiz de CARVALHO
Brazilian Oral Research.2017;[Epub] CrossRef
Immunohistochemical Expression of MCM2 in Nonmelanoma Epithelial Skin Cancers
Asmaa Gaber Abdou, Mohammed Gaber Abd Elwahed, Marwa Mohammed Serag El-dien, Dina Sharaf Eldien
The American Journal of Dermatopathology.2014; 36(12): 959. CrossRef

Expression Pattern of Smad Proteins in Diffuse Large B-cell Lymphomas.: Jai Hyang Go; Korean J Pathol. 2004;38(5):301-305.

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Abstract PDF: BACKGROUND
Smad proteins mediate the cellular signaling from members of transforming growth factor-beta family (TGF-beta s). Smads 2 and 3 transmit signals from TGF-beta and activin, and Smads 1, 5, and 8 transmit signals from the bone morphogenetic protein. Smad4 is known to be a common mediator of both pathways, yet little is known about the expression pattern of Smad proteins in normal lymphoid tissue and malignant lymphoma.
METHODS
Immunohistochemistry was performed for Smad3 and Smad4 on the paraffin-embedded tissue sections from 32 cases of diffuse large B-cell lymphomas.
RESULTS
In reactive lymphoid tissue, nearly all cells of the germinal centers were positive for Smad3 and more than 50% of paracortical cells were positive for Smad3. For Smad4 immunostaining, nearly all cells of the germinal centers showed diffuse cytoplasmic staining, and most of them revealed nuclear positivity as well. Most of the cells in the paracortex regions were positive for Smad4. For the malignant lymphomas, all the cases were positive for Smad3, but 26 cases were positive for Smad4 and 6 cases (19%) were negative for Smad4.
CONCLUSIONS
These results suggest that TGF-beta-specific Smads may be actively involved for signal transduction in lymphoid organs, and the TGF-beta signaling pathway through Smads is operative in malignant lymphoma. The loss of Smad4 expression might be associated with development of some diffuse large B-cell lymphomas.

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