Pituitary Tumor-Transforming Gene 1/Delta like Non-Canonical Notch Ligand 1 Signaling in Chronic Liver Diseases

Abstract

The management of chronic liver diseases (CLDs) remains a challenge, and identifying effective treatments is a major unmet medical need. In the current review we focus on the pituitary tumor transforming gene (PTTG1)/delta like non-canonical notch ligand 1 (DLK1) axis as a potential therapeutic target to attenuate the progression of these pathological conditions. PTTG1 is a proto-oncogene involved in proliferation and metabolism. PTTG1 expression has been related to inflammation, angiogenesis, and fibrogenesis in cancer and experimental fibrosis. On the other hand, DLK1 has been identified as one of the most abundantly expressed PTTG1 targets in adipose tissue and has shown to contribute to hepatic fibrosis by promoting the activation of hepatic stellate cells. Here, we extensively analyze the increasing amount of information pointing to the PTTG1/DLK1 signaling pathway as an important player in the regulation of these disturbances. These data prompted us to hypothesize that activation of the PTTG1/DLK1 axis is a key factor upregulating the tissue remodeling mechanisms characteristic of CLDs. Therefore, disruption of this signaling pathway could be useful in the therapeutic management of CLDs.

Deletion of Meg8-DMR Enhances Migration and Invasion of MLTC-1 Depending on the CTCF Binding Sites

“…We then tested some proteins that may have contributed to this process in order to thoroughly examine its molecular underpinnings. According to many studies, Dlk1 is identified as a Notch family protein and the best studied noncanonical Notch ligand [ 25 , 26 ], so we first tested Notch1, one of the four Notch receptors, which has been verified to directly interact with Dlk1 in both yeast and mammalian two-hybrid systems [ 27 , 28 ]. Then, we looked at Rhoc, which is a protein that plays a key role in cell migration [ 29 ].…”

Identification of tumor antigens and immune subtypes of hepatocellular carcinoma for mRNA vaccine development

“…Its abnormal expression can promote tumor progression[ 58 ]. PTTG1 is a proto-oncogene involved in proliferation, metabolism, cell cycle progression, DNA damage/repair, and apoptosis[ 59 ]. Previous studies have shown that PTTG1 is overexpressed in HCC cell lines and HCC tissues[ 60 ].…”

Cancer Stem Cell and Hepatic Stellate Cells in Hepatocellular Carcinoma

“…42 The activation is mediated by focal adhesion kinase (FAK)-MMP9 signaling, p53/21, phosphatidylinositol 3-kinase/protein kinase B (MAPK/ERK), IL-6/ signal transducer and activator of transcription 3 (IL-6/STAT3) signaling pathways, and tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN), peroxisome proliferator-activated receptor gamma (PPARγ), nuclear factor kappa-light-chain-enhancer of activated B cells, and toll-like receptors, and recently was associated with the pituitary tumor transforming gene 1 (PTTG1)/delta like non-canonical notch ligand 1 (DLK1) signaling pathway. [43][44][45][46][47][48] When activated, HSCs promote migration, proliferation, and resistance of HCC cells though modulation of TGF-β signaling and MMP9 upregulation. 35,49 Autophagy, an intracellular degradation system and protective mechanism, has recently been shown to be involved in the activation of HSCs.…”

“…Moreover, DLK1 suppresses PPARγ, which inhibits tumor growth, invasion, and EMT. 46 Multidrug resistance can also be mediated by overexpression of ATP-binding cassette transporters (ABC transporters), which extrude a variety of toxic substances, thus increasing cancer stemness, EMT, and chemoresistance. [108][109][110][111] As a result, ABC transports could be used in research as CSC and chemotherapy markers.…”