The TGF-β/Smad4 Signaling Pathway in Pancreatic Carcinogenesis and Its Clinical Significance

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal human cancers due to its complicated genomic instability. PDAC frequently presents at an advanced stage with extensive metastasis, which portends a poor prognosis. The known risk factors associated with PDAC include advanced age, smoking, long-standing chronic pancreatitis, obesity, and diabetes. Its association with genomic and somatic mutations is the most important factor for its aggressiveness. The most common gene mutations associated with PDAC include KRas2, p16, TP53, and Smad4. Among these, Smad4 mutation is relatively specific and its inactivation is found in more than 50% of invasive pancreatic adenocarcinomas. Smad4 is a member of the Smad family of signal transducers and acts as a central mediator of transforming growth factor beta (TGF-β) signaling pathways. The TGF-β signaling pathway promotes many physiological processes, including cell growth, differentiation, proliferation, fibrosis, and scar formation. It also plays a major role in the development of tumors through induction of angiogenesis and immune suppression. In this review, we will discuss the molecular mechanism of TGF-β/Smad4 signaling in the pathogenesis of pancreatic adenocarcinoma and its clinical implication, particularly potential as a prognostic factor and a therapeutic target.

Keywords: Smad4; TGF-β; pancreatic ductal adenocarcinoma; prognosis; therapy.

Figure 1

The TGF-β/Smad4 signaling pathway. The Ligand TGF-β binds a complex of transmembrane receptor serine/threonine kinases (Types I and II) in the cell surface and induces transphosphorylation of the receptors. The consequently activated receptors phosphorylate selected Smads at C-terminal serines, and these receptor-activated Smads (R-Smads) then form a complex with a common Smad4. Activated Smad complexes translocate into the nucleus, where they regulate transcription of target genes, through physical interaction and functional cooperation with DNA-binding transcription factors. Besides the Smad4-mediated signaling, Smad2/3 form a complex with Tiflγ and Smad complexes then translocate into nucleus, thus regulating the transcription of target genes. Activation of R-Smads by Type-I receptor kinases is inhibited by Smad6 or Smad7. Phosphorylated TGF-β receptors also activate Ras and ERK in a Smad-independent manner and induced tumorigenesis.