SMAD4 Expression in Renal Cell Carcinomas Correlates With a Stem-Cell Phenotype and Poor Clinical Outcomes
Renal cell carcinoma (RCC) is the most lethal neoplasm of common urologic cancers with poor prognoses. SMAD4 has a principal role in TGF-β (Transformis growth factorβ)-induced epithelial to mesenchymal transition (EMT) as a key factor in gaining cancer stem cell (CSC) features and tumor aggressivene...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-05-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2021.581172/full |
| _version_ | 1818430136404410368 |
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| author | Arezoo Rasti Arezoo Rasti Arezoo Rasti Zahra Madjd Zahra Madjd Leili Saeednejad Zanjani Sadegh Babashah Maryam Abolhasani Maryam Abolhasani Mojgan Asgari Mojgan Asgari Mitra Mehrazma Mitra Mehrazma |
| author_facet | Arezoo Rasti Arezoo Rasti Arezoo Rasti Zahra Madjd Zahra Madjd Leili Saeednejad Zanjani Sadegh Babashah Maryam Abolhasani Maryam Abolhasani Mojgan Asgari Mojgan Asgari Mitra Mehrazma Mitra Mehrazma |
| author_sort | Arezoo Rasti |
| collection | DOAJ |
| description | Renal cell carcinoma (RCC) is the most lethal neoplasm of common urologic cancers with poor prognoses. SMAD4 has a principal role in TGF-β (Transformis growth factorβ)-induced epithelial to mesenchymal transition (EMT) as a key factor in gaining cancer stem cell (CSC) features and tumor aggressiveness. This study aimed to evaluate the expression patterns and clinical significance of SMAD4 in RCC and the impact of its targeting on stem cell/mesenchymal cells and EMT characteristics in renal spheroid derived cells (SDCs) compared to parental cells (PCs) in RCC. The expression pattern and clinical significance of SMAD4 was evaluated in RCC. SDCs were enriched using a sphere culture system. Then SDCs and their PCs were compared with respect to their sphere and colony formation, expression of putative CSC markers, invasiveness as well as expression of genes, including stemness/mesenchymal, SMAD4 and TGFβ1genes. Finally, the effect of SMAD4 knockdown on SDCs was analyzed. We demonstrated that SMAD4 is positively correlated with decreased disease specific survival (DSS) in RCC patients and clear cell RCC (ccRCC) subtype and associates with poor DSS in patients with RCC, especially in ccRCC as the most metastatic RCC subtype. SDCs exhibited higher stem cell/mesenchymal properties. Inhibition of SMAD4 in PCs accelerated the dissociation of SDCs and decreased their clonogenicity, invasiveness, expression of mesenchymal markers and expression of SMAD4 and TGFβ1 genes compared to SDCs before transfection. We suggest that targeting SMAD4 may be useful against renal CSCs and may improve RCC prognosis. |
| first_indexed | 2024-12-14T15:28:37Z |
| format | Article |
| id | doaj.art-e12ba8ff795744cf8feb93937346ea6a |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-14T15:28:37Z |
| publishDate | 2021-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-e12ba8ff795744cf8feb93937346ea6a2022-12-21T22:55:58ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2021-05-011110.3389/fonc.2021.581172581172SMAD4 Expression in Renal Cell Carcinomas Correlates With a Stem-Cell Phenotype and Poor Clinical OutcomesArezoo Rasti0Arezoo Rasti1Arezoo Rasti2Zahra Madjd3Zahra Madjd4Leili Saeednejad Zanjani5Sadegh Babashah6Maryam Abolhasani7Maryam Abolhasani8Mojgan Asgari9Mojgan Asgari10Mitra Mehrazma11Mitra Mehrazma12Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Tehran, IranCellular and Molecular Research Center, Iran University of Medical Sciences (IUMS), Tehran, IranDepartment of Basic Sciences/Medical Surgical Nursing, Faculty of Nursing and Midwifery, Tehran University of Medical Sciences (TUMS), Tehran, IranOncopathology Research Center, Iran University of Medical Sciences (IUMS), Tehran, IranDepartment of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences (IUMS), Tehran, IranOncopathology Research Center, Iran University of Medical Sciences (IUMS), Tehran, IranDepartment of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University (TMU), Tehran, IranOncopathology Research Center, Iran University of Medical Sciences (IUMS), Tehran, IranHasheminejad Kidney Center, Iran University of Medical Sciences (IUMS), Tehran, IranOncopathology Research Center, Iran University of Medical Sciences (IUMS), Tehran, IranHasheminejad Kidney Center, Iran University of Medical Sciences (IUMS), Tehran, IranOncopathology Research Center, Iran University of Medical Sciences (IUMS), Tehran, IranHasheminejad Kidney Center, Iran University of Medical Sciences (IUMS), Tehran, IranRenal cell carcinoma (RCC) is the most lethal neoplasm of common urologic cancers with poor prognoses. SMAD4 has a principal role in TGF-β (Transformis growth factorβ)-induced epithelial to mesenchymal transition (EMT) as a key factor in gaining cancer stem cell (CSC) features and tumor aggressiveness. This study aimed to evaluate the expression patterns and clinical significance of SMAD4 in RCC and the impact of its targeting on stem cell/mesenchymal cells and EMT characteristics in renal spheroid derived cells (SDCs) compared to parental cells (PCs) in RCC. The expression pattern and clinical significance of SMAD4 was evaluated in RCC. SDCs were enriched using a sphere culture system. Then SDCs and their PCs were compared with respect to their sphere and colony formation, expression of putative CSC markers, invasiveness as well as expression of genes, including stemness/mesenchymal, SMAD4 and TGFβ1genes. Finally, the effect of SMAD4 knockdown on SDCs was analyzed. We demonstrated that SMAD4 is positively correlated with decreased disease specific survival (DSS) in RCC patients and clear cell RCC (ccRCC) subtype and associates with poor DSS in patients with RCC, especially in ccRCC as the most metastatic RCC subtype. SDCs exhibited higher stem cell/mesenchymal properties. Inhibition of SMAD4 in PCs accelerated the dissociation of SDCs and decreased their clonogenicity, invasiveness, expression of mesenchymal markers and expression of SMAD4 and TGFβ1 genes compared to SDCs before transfection. We suggest that targeting SMAD4 may be useful against renal CSCs and may improve RCC prognosis.https://www.frontiersin.org/articles/10.3389/fonc.2021.581172/fullrenal cancercancer stem cellstargetingTGFβ signaling pathwayepithelial to mesenchymal transition |
| spellingShingle | Arezoo Rasti Arezoo Rasti Arezoo Rasti Zahra Madjd Zahra Madjd Leili Saeednejad Zanjani Sadegh Babashah Maryam Abolhasani Maryam Abolhasani Mojgan Asgari Mojgan Asgari Mitra Mehrazma Mitra Mehrazma SMAD4 Expression in Renal Cell Carcinomas Correlates With a Stem-Cell Phenotype and Poor Clinical Outcomes Frontiers in Oncology renal cancer cancer stem cells targeting TGFβ signaling pathway epithelial to mesenchymal transition |
| title | SMAD4 Expression in Renal Cell Carcinomas Correlates With a Stem-Cell Phenotype and Poor Clinical Outcomes |
| title_full | SMAD4 Expression in Renal Cell Carcinomas Correlates With a Stem-Cell Phenotype and Poor Clinical Outcomes |
| title_fullStr | SMAD4 Expression in Renal Cell Carcinomas Correlates With a Stem-Cell Phenotype and Poor Clinical Outcomes |
| title_full_unstemmed | SMAD4 Expression in Renal Cell Carcinomas Correlates With a Stem-Cell Phenotype and Poor Clinical Outcomes |
| title_short | SMAD4 Expression in Renal Cell Carcinomas Correlates With a Stem-Cell Phenotype and Poor Clinical Outcomes |
| title_sort | smad4 expression in renal cell carcinomas correlates with a stem cell phenotype and poor clinical outcomes |
| topic | renal cancer cancer stem cells targeting TGFβ signaling pathway epithelial to mesenchymal transition |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2021.581172/full |
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