UC Davis

Background

The small mother against decapentaplegic proteins (SMADs) are a family of transforming growth factor (TGF)-β signal transduction molecules, playing a vital role in the initiation and development of tumors. This research aimed to determine SMADs' prognostic values and their involvement in immune infiltration.

Methods

Expression patterns and prognostic values of SMADs were evaluated by pan-cancer analysis in multiple cancer cohorts based on The Cancer Genome Atlas data. cBioPortal database was used for genetic mutation analyses. UALCAN and LinkedOmics databases were applied for the analysis of the methylation level and its correlation with gene expression, respectively. The correlation of gene expression was analyzed by Gene Expression Profiling Interactive Analysis platform. Additionally, we utilized the Tumor Immune Estimation Resource database to explore the correlation between SMAD expressions and the number of tumor-infiltrating immune cells. Functional prediction was performed by Gene Set Enrichment Analysis (GSEA) method.

Results

We found that the expressions of SMAD1, 2, 3, 4, 6 were significantly decreased whereas the expression of SMAD9 was significantly increased in kidney renal clear cell carcinoma (KIRC) tissues than in normal control tissues. And aberrant DNA methylation in the promoter regions may cause the dysregulation of these differentially expressed SMADs. Also, we found that the expressions of SMAD1, 2, 3, 4, 6 decreased significantly with the progression of KIRC tumors, and their high expression level was significantly associated with favorable prognoses of KIRC patients. Genetic mutations analysis using the cBioPortal database found that there were missense mutations in SMAD2 and 4, and truncation mutations in SMAD2 and 3. Further, SMAD1, 2, 3, 4, 6 expressions showed correlations with diverse immune infiltrating cells and immune markers. In particular, SMAD1, 2, 4 expressions were strongly correlated with monocyte, tumor-associated macrophage, M1/M2 macrophage, revealing their potential to regulate the polarity of macrophages. Finally, function prediction by GSEA indicated that SMAD1, 2, 3, 4, 6 were closely involved in immune-related signaling pathways.

Conclusions

Our findings indicate that SMAD1, 2, 3, 4 and 6 were potent biomarkers for predicting the prognosis and immune cell infiltration of KIRC patients.