Abstract 3045
Background
Colorectal cancer (CRC) is one of the most common malignancies worldwide. Investigations revealed that the steep rise of CRC incidence was significantly linked to increased obesity rates. However, the molecular interactions of obesity with CRC are still not well understood. The Notch signaling pathway is critical for many cellular processes. It is also a key player in regulating body energy metabolism. Therefore, we aimed to investigate the potential interaction and mechanism of Notch signal between obesity and CRC tumorigenesis.
Methods
In the present study, we randomly recruited 968 cases of CRC specimens, 262 cases of colorectal intraepithelial neoplasia specimens and 185 cases of normal epithelium specimens. Target protein expression was investigated by immunohistochemistry. C57BL/6J mice were randomly allocated intogroups fed with standard rodent chow, high-fat diet (HFD), and HFD treated with DBZ or DAPT. Potential differentially expressed proteins were screened by iTRAQ, and these identified proteins were then analyzed.
Results
Notch1 intracellular domain and DLL4 was up-regulated in overweight participants compared with normal-weight ones. In overweight participants, Notch1 was increased from normal epithelium, intraepithelial neoplasia to CRC. Obesity was identified at week 5 in mice fed with HFD, which began to lead to upregulation of DLL4 and consequent increased Notch1 activity in colorectal tissues. While mice treated with DBZ and DAPT were almost resistant to HFD-induced obesity then. After 10 weeks, Notch1 activity in mice fed with HFD was significantly up-regulated compared with those fed with standard rodent chow. In addition, glucose tolerance and insulin sensitivity were also ameliorated by DBZ and DAPT treatment, through a PP2A-SHIP2 dependent manner.
Conclusions
Notch signaling activation is linked to obesity in both nonmalignant participants and CRC patients. Obesity induced by HFD can increase Notch activity by DLL4-Notch1 pathway. While inhibition of Notch signaling can attenuate high fat diet–induced obesity by improving insulin resistance.These results indicate that activation of Notch signaling by its positive feedback with obesity could be a molecular bridge that connecting obesity and CRC.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Xian Jiaotong University.
Funding
National Nature Science Foundation of China.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
2185 - Sequential treatment with afatinib followed by 3rd generation EGFR-TKI – subgroup analysis of the GIDEON trial: a prospective non-interventional study (NIS) in EGFR mutated NSCLC patients in Germany
Presenter: Wolfgang Brückl
Session: Poster Display session 1
Resources:
Abstract
1524 - Effectiveness of sequencing TKIs in patients with EGFR mutation-positive Non-small-Cell Lung Cancer (NSCLC): A French National medico administrative claim database analysis
Presenter: Nicolas Girard
Session: Poster Display session 1
Resources:
Abstract
5733 - Phase II study of osimertinib in NSCLC patients with EGFR exon 20 insertion mutation: A multicenter trial of the Korean Cancer Study Group (LU17-19)
Presenter: Tae Min Kim
Session: Poster Display session 1
Resources:
Abstract
5440 - Different stories for different EGFR exon 19 deletion variants
Presenter: Chao Zhao
Session: Poster Display session 1
Resources:
Abstract
2982 - Safety and activity of alflutinib in patients with advanced EGFR T790M mutation non-small cell lung cancer who progressed after EGFR-TKI therapy
Presenter: Yuan-Kai Shi
Session: Poster Display session 1
Resources:
Abstract
4002 - Afatinib followed by osimertinib in patients with EGFR mutation-positive (EGFRm+) advanced NSCLC: updated data from the GioTag real-world study
Presenter: Maximilian Hochmair
Session: Poster Display session 1
Resources:
Abstract
2941 - Treatment patterns of EGFR mt+ NSCLC IV pts: Real world data of the NOWEL network
Presenter: Julia Roeper
Session: Poster Display session 1
Resources:
Abstract
4154 - TP53 mutations predicts worse prognosis in EGFR-mutated NSCLC patients receiving TKIs in first- or further line of treatment
Presenter: Matteo Canale
Session: Poster Display session 1
Resources:
Abstract
1175 - HER3 ligand heregulin expression and clinical implication in patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer treated with EGFR-tyrosine kinase inhibitors
Presenter: Kimio Yonesaka
Session: Poster Display session 1
Resources:
Abstract
2023 - Patients with brain metastases treated with afatinib in clinical practice – results from the prospective non-interventional study GIDEON
Presenter: Eckart Laack
Session: Poster Display session 1
Resources:
Abstract