NOTCH receptors in gastric and other gastrointestinal cancers: oncogenes or tumor suppressors?

Abstract

Gastric cancer (GC) ranks the most common cancer types and is one of the leading causes of cancer-related death. Due to delayed diagnosis and high metastatic frequency, 5-year survival rate of GC is rather low. It is a complex disease resulting from the interaction between environmental factors and host genetic alterations that deregulate multiple signaling pathways. The Notch signaling pathway, a highly conserved system in the regulation of the fate in several cell types, plays a pivotal role in cell differentiation, survival and proliferation. Notch is also one of the most commonly activated signaling pathways in tumors and its aberrant activation plays a key role in cancer advancement. Whether Notch cascade exerts oncogenic or tumor suppressive function in different cancer types depends on the cellular context. Mammals have four NOTCH receptors that modulate Notch pathway activity. In this review, we provide a comprehensive summary on the functional role of NOTCH receptors in gastric and other gastrointestinal cancers. Increasing knowledge of NOTCH receptors in gastrointestinal cancers will help us recognize the underlying mechanisms of Notch signaling and develop novel therapeutic strategies for GC.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-016-0566-7) contains supplementary material, which is available to authorized users.

Notch4 and mhc class II polymorphisms are associated with hcv-related benign and malignant lymphoproliferative diseases

“…The medium LD between NOTCH4 rs2071286 and HLA-II rs9461776 polymorphisms suggested that a functional sequence included in the NOTCH4 and HLA-II region, could have a role in HCV-related LPDs. A potential role of NOTCH4 in the pathogenesis of HCV-related LPDs and members of the NOTCH family in several malignancies such as leukemia, gastric breast, bladder, ovarian and colon cancer were consistent with a role of NOTCH protein alteration, in the onset of some autoimmune disorders including NHL-HCV malignancies [ 31 – 34 ]. Moreover, Arcaini and co-workers observed that NOTCH pathway somatic mutations are associated with 25% of HCV-positive diffuse large B-cells lymphoma cases [ 35 ].…”

Decreased NOTCH1 Activation Correlates with Response to Ibrutinib in Chronic Lymphocytic Leukemia

“…In addition, ibrutinib reduced phosphorylated HER2 and AKT in breast cancer (43), while sensitivity to inhibition of BTK has been demonstrated in MYC-amplified esophageal tumor lines (44). Interestingly, aberrant NOTCH signaling activation has been implicated in many of the abovementioned solid tumors (45). Therefore, our finding of the anti-NOTCH effects of ibrutinib might open new potential avenues for expanding the clinical utility of BTK inhibitors by repurposing this drug to other NOTCH-related tumors, beside CLL.…”

DNA Methyltransferases and Gastric Cancer: Insight Into Targeted Therapy

“…Moreover, it has been reported that notch signaling is a conserved pathway that plays a critical role in cellular functions vital for cell survival. Notch may act as both an oncogene and a suppressor in gastric cancer [40]. Epigenetic alterations of this pathway may lead to gastric cancer progression.…”

“…Conversely, other investigations show that NOTCH1 can promote tumorigenesis by cyclooxygenase-2 activation [43]. It seems that the function of notch pathway components is ambiguous as they were reported either as suppressor or activator of gastric carcinoma, and their exact effect on different steps of gastric cancer pathogenesis still remains unclear [40,42,[44][45]. Iroquois homeobox 1 (IRX1) is a member of Iroquois homeobox factors family that is required for embryonic development [46].…”