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.

Tumour‐derived transforming growth factor‐β signalling contributes to fibrosis in patients with cancer cachexia

“…10,58,59 Recent studies suggest TGF-β signalling may lead to muscle atrophy by a mechanism which is ROS dependent 25 and plays a central role in fibrosis. 60 TGF-β signals can activate SMADdependent canonical pathway, 61 as well as induce the JNK/p38 MAPK signalling pathway (non-canonical). 62 However, the signalling pathway underlying TGF-β effect upon ECM expression in the tumour of cachectic patients has not been previously identified.…”

Microarray screening of differentially expressed genes after up-regulating miR-205 or down-regulating miR-141 in cervical cancer cells

“…It also induces programmed cell death (PCD) or apoptosis of pancreatic cells by regulating the TIEG, a zinc-finger gene transducted by TGF-β/Smad4 signaling, and takes part in tumor inhibition. (24) Smad proteins regulate the TGF-β signaling pathway, and the absence of the tumor suppressor. Smad4 is one of the molecular mechanisms leading to TGF-β resistance.…”

An overview of polyamine metabolism in pancreatic ductal adenocarcinoma

“…Beyond KRAS mutations, the mutation or loss of key tumor suppressor genes like CDKN2a (a.k.a. p16), p53 and SMAD4 are also common in PDAC . Their loss increases cell cycle rates (thru CDKN2a loss) and increases resistance to apoptosis and KRAS G12D induced senescence ( via p53 loss) .…”

“…p16), p53 and SMAD4 are also common in PDAC. 57 Their loss increases cell cycle rates (thru CDKN2a loss) and increases resistance to apoptosis and KRAS G12D induced senescence (via p53 loss). 58 These genes also have connections to polyamine metabolism.…”