Molecular and proteomic insight into Notch1 characterization in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) ranks fifth in frequency worldwide amongst all human cancers causing one million deaths annually. Despite many promising treatment options, long-term prognosis remains dismal for the majority of patients who develop recurrence or present with advanced disease. Notch signaling is an evolutionarily conserved pathway crucial for the development and homeostasis of many organs including liver. Herein we showed that aberrant Notch1 is linked to HCC development, tumor recurrence and invasion, which might be mediated, at least in part, through the Notch1-E-Cadherin pathway. Collectively, these findings suggest that targeting Notch1 has important therapeutic value in hepatocellular carcinoma. In this regard, comparative analysis of the secretome of HepG2 and HepG2 Notch1 depleted cells identified novel secreted proteins related to Notch1 expression. Soluble E-Cadherin (sE-Cad) and Thrombospondin-1 (Thbs1) were further validated in human serum as potential biomarkers to predict response to Notch1 inhibitors for a tailored individualized therapy.

4-methylumbelliferone Prevents Liver Fibrosis by Affecting Hyaluronan Deposition, FSTL1 Expression and Cell Localization

“…Our paper complements this data with RNA-seq analysis of 4MU-treated mice with CCl 4 -induced fibrosis. Downregulation of FSTL1 that we demonstrate here is correlated with possible downregulation of Notch1, demonstrated by its knockout in the proteomic screening [32]. We also identify nuclear RXR, PPARa, LXR and PXR receptors as possible targets for 4MU.…”

MicroRNAs in Animal Models of HCC

“…In this context, we compared transcriptomic data from human and DEN-induced rat HCCs. Among common deregulated genes, the activation of Notch pathway and the aberrant expression of a panel of HCC-associated miRNAs (e.g., miR-122, miR-221, and let-7a) suggested this model to be suitable to explore miRNA contribution to disease progression and treatment response [77][78][79]. Remarkably, most of miRNAs deregulated in the DEN-induced rat model are aberrantly expressed in human HCC cohorts from several studies, as summarized in Table 1 and Table 2.…”

“…In this context, we compared transcriptomic data from human and DEN-induced rat HCCs. Among common deregulated genes, the activation of Notch pathway and the aberrant expression of a panel of HCC-associated miRNAs (e.g., miR-122, miR-221, and let-7a) suggested this model to be suitable to explore miRNA contribution to disease progression and treatment response [77][78][79]. Remarkably, most of miRNAs deregulated in the DEN-induced rat model are aberrantly expressed in human HCC cohorts from several studies, as summarized in Tables 1 and 2. In particular, members of both paralogous clusters, miR-17-92 and miR-25-106b, showing oncogenic properties [54], were upregulated in our DEN-HCC rat model (miR-18a-5p and miR-106b-5p; raw data are available in ArrayExpress repository, accession number E-MTAB-7624), as well as in our HCC patient datasets (miR-18a and miR-25) [3].…”

Proteomics biomarkers for solid tumors: Current status and future prospects

“…Further assessment of PAI‐3, ICAM‐5, THBS1 and CDH1 was conducted by ELISA in an independent small set of serum samples from 7 cirrhosis, 7 early and 7 advanced stage HCC patients. PAI‐3, CDH1, and THBS1 discriminated HCC from cirrosis, whereas CDH1 and ICAM‐5 discriminated early from advanced stage HCC ( P < 0.05) …”

“…Based on the hypothesis that the Notch pathway is a main driver in cell proliferation and is involved in hepatocellular carcinoma (HCC), Giovanni et al compared the culture media of HepG2 cells with Notch 1 depleted cells (applying short hairpin oligonucleotides targeting different Notch 1 exons) . Using LC‐MS/MS, 89 proteins were found significantly altered, 37 at increased and 52 at decreased levels following Notch 1 depletion ( P < 0.05).…”