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, upregulation 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.

Effects of GLP-1 Receptor Agonists on Biological Behavior of Colorectal Cancer Cells by Regulating PI3K/AKT/mTOR Signaling Pathway

“…The reverse transcription kit was purchased from Thermo Fisher. It was operated according to the user guide of the fluorescence quantitative kit, U6 and GAPDH were taken as internal parameters, and the relative content of PI3K/Akt/mTOR in CRC was calculated by using the 2 -△△Ct method ( Wang et al, 2021 ).…”

“…At present, academic circles believe that the accelerated progress of CRC is caused by PIK3CA gene mutation of the PI3K/Akt/mTOR signal pathway and the loss of expression of phosphatase and tensin homolog deleted on chromosome 10 (PTEN). PIK3CA mutation is closely related to the location, degree of tissue differentiation, and immunohistochemical type of CRC lesions ( Zhihang Chen et al, 2020 ; Li et al, 2021 ; Wang et al, 2021 ; Jing Zhang et al, 2021 ). Cells carry out biological activities through proliferation, migration, invasion, and apoptosis, as well as cancer cells ( Xie et al, 2021 ).…”

The prognostic value and mechanisms of centromere protein M in patients with lung adenocarcinoma

“…In NSCLC, the PI3K/AKT/mTOR pathway has been heavily implicated in both tumorigenesis and the progression of disease (30,31). Previous studies have shown that the expression of PI3K, AKT and mTOR upregulated in NSCLC (31,32). The preclinical studies showed that AKT activation attributed to loss of PTEN, EGFR, PIK3CA mutation or HER2 amplification in NSCLC cell lines (29,33).…”

Leptin: A Heavyweight Player in Obesity-Related Cancers

“…The authors, by investigating a total of 12,643 subjects, 4172 lung cancer cases, and 8471 controls, aged 35 to 74 years, from four cohort studies in the USA, Europe, China, and Singapore, found a statistical association between BMI and lung cancer risk both in current smokers (Odd Ratio, OR for overweight group: 0.79, 95% CI: 0.68-0.92, and obese group: 0.75, 95% CI: 0.60-0.93), former smokers (overweight group: 0.70, 95% CI: 0.53-0.93, and obese group: 0.55, 95% CI: 0.37-0.80), and lifelong non-smokers (overweight group: 0.77, 95% CI: 0.59-0.99, and obese group: 0.71, 95% CI: 0.44-1.14) [21]. Interestingly, levels of leptin, a major obesity-related adipokine, have been documented to positively correlate with non-small cell lung cancer (NSCLC) [22][23][24][25]. On the contrary, it has also been demonstrated that central or visceral adiposity, measured by visceral fat index (VFI), is associated with decreased recurrence-free and overall survival (OS) in lung cancer patients.…”

“…Leptin induced lung cancer cell proliferation by the activation of the PI3K/AKT/mTOR signaling pathway and through down-regulation of the P53 signaling pathway [25]. (iii) Leptin deletion induced a reduced cell growth and apoptosis in non-small-cell lung cancer (NSCLC) cell lines partially involving the Notch and JAK/STAT3 signaling pathways [156].…”