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
3683 - Impact of Radiotherapy on efficacy of anti-programmed death 1 (PD-1) antibodies in metastatic NSCLC
Presenter: Evangeline Samuel
Session: Poster Display session 1
Resources:
Abstract
3924 - Pembrolizumab frontline monotherapy in patients with NSCLC and high PD-L1 expression: Real World Data from a European Cohort with focus on subgroups of interest
Presenter: Giannis Mountzios
Session: Poster Display session 1
Resources:
Abstract
3970 - Patients with metastatic non-small cell lung cancer and PD-L1 expression in Germany. Treatment and first outcome from the prospective German Registry Platform CRISP (AIO-TRK-0315)
Presenter: Martin Sebastian
Session: Poster Display session 1
Resources:
Abstract
5350 - The efficacy and safety of pembrolizumab as a first-line therapy in PD-L1 50% positive advanced NSCLC (HOPE-001)
Presenter: Motohiro Tamiya
Session: Poster Display session 1
Resources:
Abstract
3832 - Osimertinib in epidermal growth factor receptor (EGFR) T790M advanced non-small cell lung cancer (NSCLC): analysis of patients with central nervous system (CNS) metastases in a real-world study (ASTRIS)
Presenter: Giulio Metro
Session: Poster Display session 1
Resources:
Abstract
4082 - Real-world (RW) treatment patterns and outcomes for second-line (2L) therapy and beyond in patients (pts) with epidermal growth factor receptor-mutated (EGFRm) advanced NSCLC receiving a first-line (1L) first- or second-generation (1G/2G) EGFR tyrosine kinase inhibitor (TKI)
Presenter: Riyaz Shah
Session: Poster Display session 1
Resources:
Abstract
2855 - Impact of ramucirumab (RAM) + erlotinib (ERL) on EGFR mutations in circulating tumor DNA – The 1st report of a biomarker study in Japanese patients from RELAY: Global Ph3 study of ERL + RAM or placebo (PL) in 1L metastatic NSCLC with EGFR activating mutations
Presenter: Kazuto Nishio
Session: Poster Display session 1
Resources:
Abstract
2911 - Apatinib combined with EGFR - TKI in treating advanced non-small cell lung cancer with EGFR - TKI resistance
Presenter: Ruifen Tian
Session: Poster Display session 1
Resources:
Abstract
2100 - Updated analysis of a phase I trial of afatinib (Afa) and bevacizumab (Bev) in chemo-naïve patients (pts) with advanced non-small-cell lung cancer (NSCLC) harboring EGFR-mutations: OLCSG1404
Presenter: Takashi Ninomiya
Session: Poster Display session 1
Resources:
Abstract
4325 - Multiple synchronous mechanisms may contribute to osimertinib resistance in non-small cell lung cancer (NSCLC) patients: insights of the MATCH-R study
Presenter: Diego Enrico
Session: Poster Display session 1
Resources:
Abstract