Abstract
BackgroundAutophagy is a double-edged sword during the initiation and progression of multiple tumors. The Hippo pathway effector YAP has been proved to be involved in autophagy processes. The present study aimed to investigate how YAP regulates cell proliferation via autophagy in lung adenocarcinomas (LUAD).MethodsData of LUAD chip GSE43458 was obtained from Gene Expression Omnibus (GEO). RT-qPCR and Western blot were performed to assess YAP expression in LUAD cell lines. CCK-8 assay, xenograft tumor model, immunochemistry and GFP-mRFP-LC3 fusion proteins were utilized to evaluate the effect of YAP on autophagy of LUAD cells in vitro and in vivo. Autophagy inhibitor treatment and rescue experiments were carried out to elucidate the mechanism by which YAP manipulates autophagy in LUAD cells.ResultsYAP was significantly overexpressed in samples of LUAD patients and its expression level is related to 5-year survival. YAP manipulated the proliferation and autophagy in A549 and H1299 LUAD cells. YAP could induce activation of Akt/mTOR signaling pathway via suppressing PTEN in a Hippo-pathway-dependent manner. 3-Methyladenine impeded autophagy flux and promoted the proliferation in vitro and in vivo.ConclusionsHippo pathway critical transcriptional coactivators YAP manipulates the proliferation of lung adenocarcinoma, which is regulated by PTEN/AKT/mTOR autophagic signaling.
Highlights
Yes-associated protein (YAP, known as YAP1) is a downstream transcriptional coactivator of the Hippo pathway, which plays a key role in embryogenesis, tissue homeostasis and organ regeneration [1, 2]
YAP is upregulated in Lung adenocarcinomas (LUADs) tissues and is associated with poor prognosis of 5‐year survival We investigated YAP expression data gathered from tissue specimens of patients with lung adenocarcinomas and normal lung tissues from Gene Expression Omnibus (GEO) database
Independent samples t-test performed for GSE43458 data, the result showed that YAP mRNA expression of LUAD tissues was significantly higher than that of normal lung
Summary
Yes-associated protein (YAP, known as YAP1) is a downstream transcriptional coactivator of the Hippo pathway, which plays a key role in embryogenesis, tissue homeostasis and organ regeneration [1, 2]. In addition to its physiological functions during tissue repair and organ regeneration, there are accumulating evidences shown that overexpression of YAP plays an important role in oncogenesis of a variety of cancer types [6,7,8]. YAP stimulates tumor cell proliferation by amplifying the expressions of oncogenes, such as MYC and AP-1 family members (JUN and FOS-like factors), affecting DNA duplication, DNA repair and mitosis in cancers [7, 10, 11]. Lung adenocarcinoma (LUAD), accounting for approximately 40% of lung cancers with poor prognosis, is reported to highly express YAP, which is relative to the rapid progression according to the latest studies [15, 16]. The present study aimed to investigate how YAP regulates cell proliferation via autophagy in lung adenocarcinomas (LUAD)
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