Dai CJ, Cao YT, Huang F, Wang YG. Multiple roles of mothers against decapentaplegic homolog 4 in tumorigenesis, stem cells, drug resistance, and cancer therapy. World J Stem Cells 2022; 14(1): 41-53 [PMID: 35126827 DOI: 10.4252/wjsc.v14.i1.41]
Corresponding Author of This Article
Yi-Gang Wang, PhD, Professor, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, No. 2 Street of Xiasha District, Hangzhou 310018, Zhejiang Province, China. wangyigang43@163.com
Research Domain of This Article
Oncology
Article-Type of This Article
Review
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Stem Cells. Jan 26, 2022; 14(1): 41-53 Published online Jan 26, 2022. doi: 10.4252/wjsc.v14.i1.41
Multiple roles of mothers against decapentaplegic homolog 4 in tumorigenesis, stem cells, drug resistance, and cancer therapy
Chuan-Jing Dai, Yu-Ting Cao, Fang Huang, Yi-Gang Wang
Chuan-Jing Dai, Yu-Ting Cao, Yi-Gang Wang, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang Province, China
Fang Huang, Department of Pathology, Zhejiang Provincial People’s Hospital of Hangzhou Medical University, Hangzhou 310014, Zhejiang Province, China
Author contributions: Dai CJ wrote the paper; Cao YT and Huang F wrote the partial manuscript, and contributed equally to this work; Wang YG designed the layout of the review and edited the manuscript.
Supported bythe National Natural Science Foundation of China, No. 8180306; the Natural Science Foundation of Zhejiang Province, No. LY18C070002; and the 521 Talent Project of Zhejiang Sci-Tech University, No. 2021437620 and No. 2019337459.
Conflict-of-interest statement: The authors do not have any possible conflicts of interest to disclose.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Yi-Gang Wang, PhD, Professor, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, No. 2 Street of Xiasha District, Hangzhou 310018, Zhejiang Province, China. wangyigang43@163.com
Received: March 16, 2021 Peer-review started: March 16, 2021 First decision: May 5, 2021 Revised: May 13, 2021 Accepted: December 21, 2021 Article in press: December 21, 2021 Published online: January 26, 2022 Processing time: 309 Days and 19.6 Hours
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.
Core Tip: Mothers against decapentaplegic homolog 4 (Smad4) is regarded as a tumor suppressor. Recent studies have shown that Smad4 plays a tumor-promoting role in specific types of cancer, rather than a tumor-suppressing role. Smad4 also correlates with the stem cells fate and drug resistance of cancer cells. Elucidating the specific role of Smad4 is of positive guiding significance for understanding the mechanism of tumorigenesis and cancer treatment. In this review, we focus on the multiple roles of Smad4 in tumorigenesis, stem cells, and drug resistance, and provide novel insights into the prospect of Smad4 in combination therapy.
