Autocrined leptin promotes proliferation of non-small cell lung cancer (NSCLC) via PI3K/AKT and p53 pathways.

Abstract

BACKGROUND:

Circulating leptin can directly act on tumor cells. However, a recent meta-analysis showed that plasma leptin concentration had no significant effect on the survival of lung cancer patients. So does Leptin have an effect on lung cancer? Or there may be other factors that influence the effect.

METHODS:

Genome sequencing database Oncomine was searched to learn the differential expression of leptin between tumors and normal lungs. Fresh tumor specimens and paired normal lung tissue from six lung adenocarcinoma patients were collected, and validate the expression level of leptin. Clinicopathological information and tumor slices from 60 non-small cell lung cancer (NSCLC) patients were analyzed to evaluate the prognostic value of autocrined leptin. Whole genome sequencing data from the cancer genome atlas (TCGA) was analyzed to predict the underlying mechanism of leptin regulating tumor proliferation. Finally, these findings were confirmed by using cell lines H1299, A549, H460, and H322 to explore the promoting effect and mechanism of leptin on cell proliferation in vitro.

RESULTS:

Five datasets in Oncomine reported the expression of the LEP gene in NSCLC, and 4 datasets showed that leptin was up-regulated in tumors compared with normal lungs. Leptin was also overexpressed in 5 out of 6 clinical lung adenocarcinoma specimens. The analysis of the 60 NSCLC patients revealed that autocrined leptin could serve as an auxiliary prognostic factor, and a higher expression of leptin indicated a higher survival risk. Gene set enrichment analysis (GSEA) showed that the PI3K/AKT/mTOR signaling pathway was positively enriched when the LEP gene was highly expressed, while the P53 signaling pathway was negatively enriched. Leptin promoted cell cycle and clone formation in H1299 and A549 cells, up-regulation or down-regulation of leptin in these two cell lines led to enhanced or declined proliferation. Finally, it was confirmed that the PI3K/AKT/mTOR signaling pathway was positively regulated by leptin expression, while the P53 signaling pathway was negatively regulated.

CONCLUSIONS:

Autocrined leptin was observed in majority of NSCLC tissue, which could serve as an auxiliary prognostic factor for NSCLC patients. Autocrined leptin had a promoting effect on the proliferation of NSCLC cells, which probably positively regulating the PI3K/AKT/mTOR signaling pathway and negatively regulate the P53 signaling pathway.

• Authors: Jin Wang, Fachen Zhou, Fengzhou Li, Bing Wang, Yiying Hu, Xia Li
• Journal: Annals of translational medicine (Ann Transl Med) Vol. 9 Issue 7 Pg. 568 (Apr 2021) ISSN: 2305-5839 [Print] China
• PMID: 33987266 (Publication Type: Journal Article)
• Copyright: 2021 Annals of Translational Medicine. All rights reserved.