Correlation between SMADs and Colorectal Cancer Expression, Prognosis, and Immune Infiltrates

Abstract

Background. In recent years, the incidence and mortality of colorectal cancer (CRC) are increasing, and the 5-year survival rate of advanced metastatic CRC is poor. Small mothers against decapentaplegic (SMAD) superfamily are intracellular signal transduction proteins associated with the development and prognosis of a variety of tumors. At present, no study has systematically analysed the relationship between SMADs and CRC. Methods. Here, R3.6.3 was used to analyse the expression of SMADs in pan-cancer and CRC. Protein expression of SMADs were analysed by Human Protein Atlas (HPA). Gene expression profiling interactive analysis (GEPIA) was used to evaluate the correlation between SMADs and tumor stage in CRC. The effect of R language and GEPIA on prognosis was analysed. Mutation rates of SMADs in CRC were determined by cBioPortal, and potentially related genes were predicted using GeneMANIA. R analysis was used to correlate immune cell infiltration in CRC. Results. Both SMAD1 and SMAD2 were found to be weakly expressed in CRC and correlated with the immune invasion level. SMAD1 was correlated with patient prognosis, and SMAD2 was correlated with tumor stage. SMAD3, SMAD4, and SMAD7 were all expressed at low levels in CRC and associated with a variety of immune cells. SMAD3 and SMAD4 proteins were also expressed at low levels, and SMAD4 had the highest mutation rate. SMAD5 and SMAD6 were overexpressed in CRC, and SMAD6 was also associated with patient overall survival (OS) and CD8+ T cells, macrophages, and neutrophils. Conclusions. Our results reveal innovative and strong evidence that SMADs can be used as biomarkers for the treatment and prognosis of CRC.

The Role of the Transforming Growth Factor-β Signaling Pathway in Gastrointestinal Cancers

“…Carcinoembryonic antigen-associated cell adhesion molecule 5 (CEACAM5), a highly glycosylated protein of the CEACAM family, reduces the expression of TGF-β pathway members (TGFBR2, SMAD4, and SPTBN1), which alters the colonic microbiome to promote CRC [40]. By contrast, SMAD2 mutations have been reported in hepatocellular carcinoma (HCC) [41]. For SMAD4, about 70% of esophageal adenocarcinoma (EAC) associated with Barrett's esophagus (BE) revealed loss of heterozygosity in a region involving SMAD2 and SMAD4 on chromosome 18q [42,43].…”

Therapeutic targeting of ARID1A-deficient cancer cells with RITA (Reactivating p53 and inducing tumor apoptosis)

“…The earliest trigger is APC inactivation [ 2 ]. Mutations in other suppressor genes ( SMAD2 , SMAD4 [ 3 ], DCC [ 4 ], and TP53 [ 5 ]), oncogenes ( KRAS [ 6 ] and BRAF [ 7 ]), and other genes contribute to neoplastic transformation in foci of the altered colon mucosa, which in turn leads to further degeneration toward malignancy. Next-generation sequencing revealed that ARID1A (AT-rich interactive domain 1A) is one of the most frequently mutated genes in CRC [ 8 ].…”