The Activation Status of the TGF-β Transducer Smad2 Is Associated with a Reduced Survival in Gastrointestinal Cancers: A Systematic Review and Meta-Analysis.

Ilaria Girolami,Jacopo Demurtas,Nicola Veronese,Maria G Caruso,Rosa Reddavide,Alessia Nottegar,Gioacchino Leandro,Lee Smith

doi:10.3390/ijms20153831

Abstract

Aberrant function of Smad2, a crucial member of transforming growth factor beta (TGF-β) signaling, is associated with the development of malignancies, particularly in the gastrointestinal district. However, little is known about its possible prognostic role in such tumor types. With the first meta-analysis on this topic, we demonstrated that the lack of the activated form of Smad2 (phosphor-Smad2 or pSmad2), which was meant to be the C-terminally phosphorylated form, showed a statistically significant association with an increased risk of all-cause mortality in patients with gastrointestinal cancers (RR, 1.58; 95% CI, 1.05–2.37, p = 0.029, I2 = 84%), also after having adjusted for potential confounders (RR, 1.65; 95% CI, 1.24–2.18; p < 0.001; I2 = 4%). This finding highlights the importance of the TGF-β signaling in this type of cancer. In this line, further studies are needed to explore more in depth this important molecular pathway, focusing also on potential therapeutic strategies based on its effectors or molecular targets.

Highlights

Transforming growth factor beta (TGF-β) signaling plays an essential role throughout development and later in adult homeostasis, interacting and coordinating different cell mechanisms
1197 non-duplicated articles were identified through the literature search
A seminal paper in this field pointed out that the level of pSmad2 is inversely associated to histological differentiation in head and neck tumors [24], Smad2 is a specific intracellular mediator of TGF-β signaling and plays a pivotal role in the antiproliferative effects of this pathway [18]

Summary

Introduction

Transforming growth factor beta (TGF-β) signaling plays an essential role throughout development and later in adult homeostasis, interacting and coordinating different cell mechanisms. Biological activities of TGF-β initiate with its binding to a heteromeric complex of two types of transmembrane receptors, namely type I and type II receptors; TGF-β occupancy induces an association between the type I and II receptors, causing the phosphorylation of the type I receptor by the constitutively active type II receptor [1,2,3,4,5,6]. The phosphorylated type I receptor triggers activation of important cofactors, namely Smad and Smad, by phosphorylating their C-terminal serine residues. Activated Smad and Smad form heteromeric complexes with Smad and other mediators, and translocate into the nucleus, forming a transcription complex with other cofactors, as well as participating in the expression of target genes [1,2,3,4,5,6] (Figure 1). Aberrant function of members of the TGF-β superfamily is associated with a wide range of human diseases, including cancer. Sci. 2019, 20, x FOR PEER REVIEW chr18:47,808,957-47,931,193; www.genecards.org, last access 07/22/2019), appear very important in tulomcaotriiogne:necshirs1[87:–4172,8].08,957-47,931,193; www.genecards.org, last access 07/22/2019), appear very important in tumorigenesis [7,8,9,10,11,12]

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