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. 2021 Jun;10(6):2678-2693.
doi: 10.21037/tcr-21-178.

The prognostic value and immunological role of the small mother against decapentaplegic proteins in kidney renal clear cell carcinoma

Siyue Zhang #  1   2   3   4 , Zhuang Liu #  3   4 , Mingming Xiao #  3   4 , Hong Liu  1   2
Affiliations

The prognostic value and immunological role of the small mother against decapentaplegic proteins in kidney renal clear cell carcinoma

Siyue Zhang et al. Transl Cancer Res. 2021 Jun.

Abstract

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.

Keywords: Small mother against decapentaplegic protein (SMAD); expression patterns; immune infiltration; kidney renal clear cell carcinoma (KIRC); prognosis.

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Conflict of interest statement

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/tcr-21-178). The authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
The expression pattern and methylation level of SMAD family genes in KIRC patients. (A,B) The expression patterns of SMAD1, 2, 3, 4, 5, 6, 7 and 9 in 530 KIRC patient tissues and 72 normal tissues as well as 72 paired KIRC tissues and corresponding adjacent normal tissues (TCGA). The expression patterns of SMAD1 (C), SMAD2 (D), SMAD3 (E), SMAD4 (F), SMAD6 (G), SMAD9 (H). Promoter methylation status of SMAD1 (I), SMAD2 (J), SMAD3 (K), SMAD4 (L), SMAD6 (M), SMAD9 (N) in 324 KIRC patient tissues and 160 normal tissues (UALCAN). The correlation between the expressions of SMAD1 (O), SMAD2 (P), SMAD3 (Q), SMAD4 (R), SMAD6 (S), SMAD9 (T) with their promoter methylation status (LinkedOmics). P<0.05 was considered significant (*, P<0.05; ***, P<0.001; **** P<0.001). SMAD, small mother against decapentaplegic protein; KIRC, kidney renal clear cell carcinoma.
Figure 2
Figure 2
The expression pattern of SMAD genes in the main pathological stages of KIRC patients. The expression patterns of SMAD1 (A), SMAD2 (B), SMAD3 (C), SMAD4 (D), SMAD6 (E), SMAD9 (F) in the main pathological stages of KIRC patients. P<0.05 was considered significant. SMAD, small mother against decapentaplegic protein; KIRC, kidney renal clear cell carcinoma.
Figure 3
Figure 3
Prognostic value of differential expression SMAD genes in KIRC patients. (A,B) Survival significant maps of differentially expressed SMADs showed the overall survival (OS) and disease-free survival (DFS) analysis results based on the Cox proportional hazard ratio (HR) through GEPIA. The OS curve of SMAD1 (C), SMAD2 (D), SMAD3 (E), SMAD4 (F), SMAD6 (G), and the DFS curve of SMAD2 (H), SMAD3 (I), SMAD4 (J), SMAD6 (K) in KIRC. The group cutoff choice for OS was the median. A log-rank test was used to estimate the difference in OS and DFS, and a value of P<0.05 was considered statistically significant. SMAD, small mother against decapentaplegic protein; KIRC, kidney renal clear cell carcinoma.
Figure 4
Figure 4
Genetic mutations, expression correlation, and interaction network analyses of SMAD family genes in KIRC patients. (A) Gene mutation information of SMAD genes in KIRC (cBioPortal). (B) Correlation heat map of SMAD genes in KIRC (GEPIA). (C) Protein-protein interaction network of SMAD genes (STRING). (D) The interaction network and function prediction of SMAD genes (GeneMANIA). SMAD, small mother against decapentaplegic protein; KIRC, kidney renal clear cell carcinoma.
Figure 5
Figure 5
The expression of SMAD 1/2/3/4/6 was correlated with immune infiltration levels in patients with KIRC (TIMER). The correlation between the abundance of immune cells and the expression of SMAD1 (A), SMAD2 (B), SMAD3 (C), SMAD4 (D), SMAD6 (E) in KIRC. P<0.05 was considered significant. SMAD, small mother against decapentaplegic protein; KIRC, kidney renal clear cell carcinoma.
Figure 6
Figure 6
Expressions of SMAD1/2/4 correlated with macrophage polarization in KIRC (TIMER). The correlation between the expression of SMAD1/2/4 and monocytes (gene markers: CD86 and CD115), TAM (gene markers: IL10, VSIG4 and FCGR2A), M1 macrophage (gene markers: INOS and PTGS2) and M2 macrophage (gene markers: CD163, MS4A4A and MRC1) infiltration levels was assessed. Scatterplots of correlations between SMAD1 expression and monocytes (A), TAM (B), M1 macrophage (C) and M2 macrophage (D) in KIRC. Scatterplots of correlations between SMAD2 expression and monocytes (E), TAM (F), M1 macrophage (G) and M2 macrophage (H) in KIRC. Scatterplots of correlations between SMAD4 expression and monocytes (I), TAM (J), M1 macrophage (K) and M2 macrophage (L) in KIRC. P<0.05 was considered significant. SMAD, small mother against decapentaplegic protein; KIRC, kidney renal clear cell carcinoma.
Figure 7
Figure 7
Functional enrichment analysis of SMAD1/2/3/4/6 in patients with KIRC. The bubble diagram displayed the GSEA results in phenotype low group of SMAD1 (A), SMAD2 (B), SMAD3 (C), SMAD4 (D), SMAD6 (E). The nominal P value <0.05 and false discovery rate q<0.25 were used to screen significantly enriched gene sets. SMAD, small mother against decapentaplegic protein; KIRC, kidney renal clear cell carcinoma; GSEA, Gene Set Enrichment Analysis.
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