Abstract
Previous studies showed that low PPARG expression was associated with poor prognosis of lung adenocarcinoma (LA) with limited mechanisms identified. We first conducted a large-scale literature-based data mining to identify potential molecular pathways where PPARG could exert influence on the pathological development of LA. Then a mega-analysis using 13 independent LA expression datasets and a Pathway Enrichment Analysis (PEA) was conducted to study the gene expression levels and the functionalities of PPARG and the PPARG-driven triggers within the molecular pathways. Finally, a protein-protein interaction (PPI) network was established to reveal the functional connection between PPARG and its driven molecules. We identified 25 PPARG-driven molecule triggers forming multiple LA-regulatory pathways. Mega-analysis using 13 LA datasets supported these pathways and confirmed the downregulation of PPARG in the case of LA (p = 1.07e−05). Results from the PEA and PPI analysis suggested that PPARG might inhibit the development of LA through the regulation of tumor cell proliferation and transmission-related molecules, including an LA tumor cell suppressor MIR145. Our results suggested that increased expression of PPARG could drive multiple molecular triggers against the pathologic development and prognosis of LA, indicating PPARG as a valuable therapeutic target for LA treatment.
Highlights
Lung adenocarcinoma is one of the most common histological subtypes of Nonsmall-cell lung carcinoma that accounts for about 85% of all cases of lung cancer worldwide [1]
It has been shown that the expression of PPARG was reduced in lung adenocarcinoma (LA) progression cells [4], and the low PPARG expression was strictly correlated with poor prognosis of stage IA LA [3]
To investigate the biological functions of the 26 genes within the PPARG-LA regulatory pathways (Figures 1 and 2), a pathway enrichment analysis was executed by using Pathway Studio
Summary
Lung adenocarcinoma is one of the most common histological subtypes of Nonsmall-cell lung carcinoma that accounts for about 85% of all cases of lung cancer worldwide [1]. The overall 5-year survival rate of lung cancer is low even after surgical treatment (about 69.6%) [2]. Locating on chromosome 3 (base pairs 12,287,485 to 12,434,356), PPARG encodes a member of the peroxisome proliferator-activated receptor (PPAR) subfamily of nuclear receptors—Peroxisome proliferator-activated receptor γ (PPARγ), which have been shown to possesses an antagonistic function against LA (PMID: 22843091). Limited knowledge of this PPARG-inhibiting-LA mechanism is known [3]. It has been shown that the expression of PPARG was reduced in LA progression cells [4], and the low PPARG expression was strictly correlated with poor prognosis of stage IA LA [3]. On the other hand, increased expression of PPARG has been positively associated with a better survival rate of LA patients [4]. Ni et al.’s work showed that overexpression of PPARγ could inhibit
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