Digestive diseases and sciences · 2026
Suppression of TRIM33 and SMAD4 Indicates a Possible Tumor-Suppressive Role in Esophageal Squamous Cell Carcinoma.
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Kumar Arun, Nimisha, Sharma Abhay Kumar, Apurva, Bera Pinki, Harsh Niket, Ahmad Ejaj, Kaushik Amit, Mandal Dibyakanti, Saluja Sundeep Singh
Аннотация
PURPOSE: TRIM33, a transcriptional regulator, and SMAD4, a central mediator of TGF-β signaling, have been implicated in Esophageal Squamous Cell Carcinoma (ESCC), but their combined role remains unclear. We evaluated the expression and methylation status of TRIM33 and SMAD4 and their interaction with clinico-pathological parameters in ESCC.
METHODS: We assessed the expression and promoter methylation patterns of TRIM33 and SMAD4 in 75 ESCC tumor and paired adjacent normal tissue samples using quantitative real-time PCR, Western blotting, and methylation-specific PCR, respectively. Clinico-pathological correlation and in silico validation using the GSE26886, GSE161533, and GSE29001 datasets were also performed.
RESULTS: TRIM33 and SMAD4 were frequently downregulated at mRNA (70.7% and 64.0%) and protein levels (64.3% and 59.5%) in ESCC, with protein expression concordant with mRNA (p < 0.05). TRIM33 promoter methylation occurred in 33.3-36.1% of tumors while SMAD4 in 16.7-22.7%. Both TRIM33 and SMAD4 showed increased monoallelic and biallelic methylation in tumors (p < 0.05). SMAD4 methylation showed a significant association with advanced disease (p < 0.05). Methylated cases of TRIM33 and SMAD4 exhibited reduced mRNA (80% and 58%) and protein expression (56% and 76%). TRIM33 downregulation was significantly associated with advanced TNM stage (metastatic vs non‑metastatic; p < 0.05); SMAD4 also showed a similar trend (p > 0.05). TRIM33 and SMAD4 expression were positively correlated (p < 0.05). In silico analysis confirmed downregulation and positive correlation of both genes.
CONCLUSION: Concurrent downregulation and positive correlation between TRIM33 and SMAD4 in ESCC may contribute to disease progression. TRIM33 and SMAD4 methylation were observed in ESCC, with SMAD4 methylation showing an association with advanced disease. However, further functional studies are warranted to confirm the clinical utility of our findings.
METHODS: We assessed the expression and promoter methylation patterns of TRIM33 and SMAD4 in 75 ESCC tumor and paired adjacent normal tissue samples using quantitative real-time PCR, Western blotting, and methylation-specific PCR, respectively. Clinico-pathological correlation and in silico validation using the GSE26886, GSE161533, and GSE29001 datasets were also performed.
RESULTS: TRIM33 and SMAD4 were frequently downregulated at mRNA (70.7% and 64.0%) and protein levels (64.3% and 59.5%) in ESCC, with protein expression concordant with mRNA (p < 0.05). TRIM33 promoter methylation occurred in 33.3-36.1% of tumors while SMAD4 in 16.7-22.7%. Both TRIM33 and SMAD4 showed increased monoallelic and biallelic methylation in tumors (p < 0.05). SMAD4 methylation showed a significant association with advanced disease (p < 0.05). Methylated cases of TRIM33 and SMAD4 exhibited reduced mRNA (80% and 58%) and protein expression (56% and 76%). TRIM33 downregulation was significantly associated with advanced TNM stage (metastatic vs non‑metastatic; p < 0.05); SMAD4 also showed a similar trend (p > 0.05). TRIM33 and SMAD4 expression were positively correlated (p < 0.05). In silico analysis confirmed downregulation and positive correlation of both genes.
CONCLUSION: Concurrent downregulation and positive correlation between TRIM33 and SMAD4 in ESCC may contribute to disease progression. TRIM33 and SMAD4 methylation were observed in ESCC, with SMAD4 methylation showing an association with advanced disease. However, further functional studies are warranted to confirm the clinical utility of our findings.