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
3887 - First Real Life Data on Durvalumab after definitive concomitant ChemoRadiotherapy (cCRT) in unresectable Stage (St) III Non-Small Cell Lung Cancer (NSCLC) in France: Analysis of 591 patients (pts) enrolled in the French cohort (c) Temporary Authorization of Use (ATU)
Presenter: Virginie Avrillon
Session: Poster Display session 1
Resources:
Abstract
682 - EGFR Inhibitor Versus Chemotherapy as Adjuvant Treatment for Locally-advanced EGFR-mutant Non-Small Cell Lung Cancer
Presenter: Peng Xie
Session: Poster Display session 1
Resources:
Abstract
2509 - Afatinib in EGFR TKI-naïve patients with EGFR mutation-positive (EGFRm+) NSCLC: interim analysis of a Phase IIIb, multi-national, open-label study
Presenter: Filippo de Marinis
Session: Poster Display session 1
Resources:
Abstract
3300 - First-line ceritinib versus chemotherapy in patients (pts) with advanced ALK rearranged (ALK+) non-small cell lung cancer (NSCLC): ASCEND-4 Asian subgroup analysis
Presenter: Daniel SW Tan
Session: Poster Display session 1
Resources:
Abstract
2653 - A combined analysis of two Phase IIIb studies of afatinib in EGFR TKI-naïve patients (pts) with EGFR mutation-positive (EGFRm+) NSCLC
Presenter: Filippo de Marinis
Session: Poster Display session 1
Resources:
Abstract
3663 - Impact of plasma EGFR mutation fractions on response to first generation tyrosine-kinase inhibitor in treatment of naïve non-small cell lung cancer patients
Presenter: Xiaohong Wang
Session: Poster Display session 1
Resources:
Abstract
5921 - Definition of an afatinib trough concentration threshold in the treatment of NSCLC
Presenter: Stephane Bouchet
Session: Poster Display session 1
Resources:
Abstract
2852 - A Phase Ib Trial of Neoadjuvant Chemoradiotherapy and Durvalumab(MEDI4736) for Potentially Resectable stage III Non-Small Cell Lung Cancer (NSCLC)
Presenter: Beung chul AHN
Session: Poster Display session 1
Resources:
Abstract
3273 - Low expression of Notch1 and combined Notch1/HES1 are associated with adverse survival factor for limited stage small cell lung cancer
Presenter: Jinsoo Lee
Session: Poster Display session 1
Resources:
Abstract
5141 - Mutational profiling of tumor tissue and sequential plasma illustrates emergent clones during treatment in late stage small cell lung cancer (SCLC)
Presenter: Stephanie Yaung
Session: Poster Display session 1
Resources:
Abstract