Multiple roles of mothers against decapentaplegic homolog 4 in tumorigenesis, stem cells, drug resistance, and cancer therapy

Abstract

The transforming growth factor (TGF)-β signaling pathway controls many cellular processes, including proliferation, differentiation, and apoptosis. Abnormalities in the TGF-β signaling pathway and its components are closely related to the occurrence of many human diseases, including cancer. Mothers against decapentaplegic homolog 4 (Smad4), also known as deleted in pancreatic cancer locus 4, is a typical tumor suppressor candidate gene locating at q21.1 of human chromosome 18 and the common mediator of the TGF-β/Smad and bone morphogenetic protein/Smad signaling pathways. It is believed that Smad4 inactivation correlates with the development of tumors and stem cell fate decisions. Smad4 also interacts with cytokines, miRNAs, and other signaling pathways, jointly regulating cell behavior. However, the regulatory function of Smad4 in tumorigenesis, stem cells, and drug resistance is currently controversial. In addition, Smad4 represents an attractive therapeutic target for cancer. Elucidating the specific role of Smad4 is important for understanding the mechanism of tumorigenesis and cancer treatment. Here, we review the identification and characterization of Smad4, the canonical TGF-β/Smad pathway, as well as the multiple roles of Smad4 in tumorigenesis, stem cells, and drug resistance. Furthermore, we provide novel insights into the prospects of Smad4-targeted cancer therapy and the challenges that it will face in the future.

Functional filter for whole-genome sequencing data identifies HHT and stress-associated non-coding SMAD4 polyadenylation site variants >5 kb from coding DNA

“…SMAD4 is ubiquitously expressed and encodes the common partner SMAD which regulates signaling by transforming growth factor (TGF)-β, bone morphogenetic protein (BMP), and activin ligands. 8 As indicated by its function and earlier gene names ( DPC4 [deleted in pancreatic cancer]; MADH4 [mothers against decapentaplegic]), the SMAD4 protein has major pathological and developmental roles. 8 , 9 SMAD4 is a target of cancer genetic diagnostics because it is a driver gene for major cancers due to somatic loss 8 , 9 and because germline heterozygous loss causes gastrointestinal polyposis (juvenile polyposis syndrome/JPS [MIM: 174900 ]) where untreated hamartomatous polyps can undergo malignant transformation leading to colon, gastric, and other cancers.…”

“… 8 As indicated by its function and earlier gene names ( DPC4 [deleted in pancreatic cancer]; MADH4 [mothers against decapentaplegic]), the SMAD4 protein has major pathological and developmental roles. 8 , 9 SMAD4 is a target of cancer genetic diagnostics because it is a driver gene for major cancers due to somatic loss 8 , 9 and because germline heterozygous loss causes gastrointestinal polyposis (juvenile polyposis syndrome/JPS [MIM: 174900 ]) where untreated hamartomatous polyps can undergo malignant transformation leading to colon, gastric, and other cancers. 9 , 10 Heterozygous loss also causes TGF-β/BMP-related vasculopathies including hereditary hemorrhagic telangiectasia (HHT) which usually results from a loss-of-function variant in ACVRL1 (MIM: 600376 ) or ENG (MIM: 187300 ).…”

“…10 Scientifically, SMAD4 is of great interest because despite its wide-ranging roles in development and disease, little is known of its regulation. 8 , 9 …”

Development of Molecular Mechanisms and Their Application on Oncolytic Newcastle Disease Virus in Cancer Therapy

“…Based on these, a single type of viral therapy may not be effective against all types of cancer ( Kwan et al, 2021 ). Therefore, we believe that the combination of OV therapy and other cancer therapies will be significant for cancer patients ( Dai et al, 2022 ).…”

Puerarin inhibits EMT induced by oxaliplatin via targeting carbonic anhydrase XII

“…Chemotherapy is used to treat cancer, prolong the life of cancer patients, and even cure cancer, however, sometimes it can stimulate cancer cells and cause metastasis ( Wills et al, 2021 ; Dai et al, 2022 ). Therefore, continuous efforts have been made to find and develop new strategies for cancer therapy with lower side effects and better efficacy.…”