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
2066 - Second-line (2L) real-world treatment (tx) patterns and outcomes in patients (pts) with advanced/metastatic non-small cell lung cancer (NSCLC) treated with first line (1L) immuno-oncology (IO) monotherapy (mono tx)
Presenter: Denis Talbot
Session: Poster Display session 1
Resources:
Abstract
5919 - Real-world effectiveness of nivolumab monotherapy after prior systemic therapy in advanced non-small cell lung cancer (NSCLC) in the United States
Presenter: David Stenehjem
Session: Poster Display session 1
Resources:
Abstract
3368 - Pembrolizumab as first-line treatment in NSCLC with PD-L1 ≥50%: Real life results from an all-comer population
Presenter: Nikolaj Frost
Session: Poster Display session 1
Resources:
Abstract
3775 - Patients with metastatic non-small cell lung cancer without molecular alterations or PD-L1 expression in Germany. Treatment and first outcome from the prospective German Registry Platform CRISP (AIO-TRK-0315)
Presenter: Frank Griesinger
Session: Poster Display session 1
Resources:
Abstract
3926 - Impact of second-line (2L) immune checkpoint inhibitors (ICIs) on the treatment (Tx) of advanced non-small cell lung cancer (NSCLC) in a UK centre: a REAL-Oncology analysis from the I-O Optimise initiative
Presenter: Michael Snee
Session: Poster Display session 1
Resources:
Abstract
5068 - First line pembrolizumab for NSCLC with PD-L1 TPS > 50% in a first French real life cohort
Presenter: Karim Amrane
Session: Poster Display session 1
Resources:
Abstract
1182 - Interstitial lung disease induced by immune-checkpoint inhibitors correlates with prognosis of advanced non-small-cell lung cancer patients
Presenter: Teppei Sugano
Session: Poster Display session 1
Resources:
Abstract
2297 - Phase II study to evaluate the peripheral blood mononuclear cell biomarker for nivolumab efficacy on previously treated non-small cell lung cancer subjects (NEJ029B: IMMUNITY-ONE)
Presenter: Yosuke Kawashima
Session: Poster Display session 1
Resources:
Abstract
2739 - Efficacy and safety of nintedanib + docetaxel in lung adenocarcinoma patients (pts) following treatment with immune checkpoint inhibitors (ICIs): Updated results of the ongoing non-interventional study (NIS) VARGADO (NCT02392455)
Presenter: Christian Grohe
Session: Poster Display session 1
Resources:
Abstract
1357 - Upfront atezolizumab chemoimmunotherapy-associated Immune-related adverse events in patients with advanced non-small cell lung cancer
Presenter: Francis Mogollon-Duffo
Session: Poster Display session 1
Resources:
Abstract