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SMAD4 Expression in Renal Cell Carcinomas Correlates With a Stem-Cell Phenotype and Poor Clinical Outcomes
Arezoo Rasti1,2,3, Zahra Madjd1,4, Leili Saeednejad Zanjani1
1Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iran.
Abstract:
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.
Insights
Targeting SMAD4 may improve renal cell carcinoma (RCC) prognosis. Inhibiting SMAD4 in renal cancer stem cells (CSCs) reduces their invasiveness and stemness, offering a potential therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Renal cell carcinoma (RCC) is a lethal urologic cancer with poor outcomes.
- SMAD4 plays a key role in TGF-β-induced epithelial-to-mesenchymal transition (EMT), cancer stem cell (CSC) features, and tumor aggressiveness.
Purpose of the Study:
- To investigate SMAD4 expression patterns and clinical significance in RCC.
- To assess the impact of SMAD4 targeting on CSCs, mesenchymal characteristics, and EMT in RCC.
Main Methods:
- Evaluation of SMAD4 expression and clinical significance in RCC patient data.
- Enrichment of renal spheroid-derived cells (SDCs) and comparison with parental cells (PCs).
- Analysis of sphere formation, stemness markers, invasiveness, and gene expression (SMAD4, TGFβ1).
- SMAD4 knockdown experiments in SDCs.
Main Results:
- SMAD4 expression correlates with decreased disease-specific survival (DSS) in RCC, particularly in clear cell RCC (ccRCC).
- SDCs displayed enhanced stem cell and mesenchymal properties compared to PCs.
- SMAD4 inhibition in SDCs reduced spheroid dissociation, clonogenicity, invasiveness, and mesenchymal marker expression.
Conclusions:
- SMAD4 is a prognostic marker for poor survival in RCC patients, especially ccRCC.
- Targeting SMAD4 may be a viable strategy against renal CSCs.
- Inhibition of SMAD4 could potentially improve RCC prognosis.
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