title: YES-associated protein 1 promotes adenocarcinoma growth and metastasis through activation of the receptor tyrosine kinase Axl.
abstract: Yes-associated protein 1 (YAP1), a nuclear effector of the Hippo pathway, plays an important role in tumorigenesis and progression of multiple cancers. The present study aimed to investigate the clinical significance of YAP1 and receptor tyrosine kinase Axl expression in human lung adenocarcinomas (LAC). We further explored possible molecular mechanisms mediated by YAP1 in LAC and gastric adenocarcinoma (GAC) cells. Forty-nine cases of human LAC and normal lung tissue (NLT) were collected. The expression of YAP1 and Axl was assessed by immunohistochemical assay through tissue microarray procedure and the clinicopathologic characteristics of all patients were analyzed. Using a loss of function approach, we investigated the effects of small hairpin RNA (shRNA)-mediated knockdown of YAP1 on the expression of Axl, proliferating cell nuclear antigen (PCNA) and matrix metalloproteinase-9 (MMP-9), and the proliferative activities and invasive potential in LAC A549 and GAC SGC-7901 cell lines. As a result, the expression of YAP1 and Axl was found in LAC tissues with higher strong reactivity rate compared to the NLT (87.8 percent vs.60.8 percent, P=0.000; 77.6 percent vs 0.0 percent, P=0.000), but they did not associate with the age, gender, tumor size, TNM staging or lymph node metastases of LAC patients (each P&#62;0.05). Spearman rank correlation analysis showed a positive correlation between YAP1 and Axl expression. Furthermore, knockdown of YAP in vitro markedly down-regulated the expression of Axl, PCNA and MMP-9, and inhibited the proliferation and invasion of LAC and GAC cells. Taken together, YAP1 and Axl are highly expressed in LAC compared to the NLT, and knockdown of YAP1 may inhibit the proliferation and invasion of adenocarcinoma cells through downregulation of the Axl pathway, representing a potential therapeutic target for the treatment of cancer.
authors.affiliation: Department of Respiratory Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Z-L
authors.initials: ZL
authors.lastname: Cui
authors.forename: F-F
authors.initials: FF
authors.lastname: Han
authors.forename: X-H
authors.initials: XH
authors.lastname: Peng
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.forename: C-Y
authors.initials: CY
authors.lastname: Luan
authors.forename: R-C
authors.initials: RC
authors.lastname: Han
authors.forename: W-G
authors.initials: WG
authors.lastname: Xu
authors.forename: X-J
authors.initials: XJ
authors.lastname: Guo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis / Q000502:physiology*; D000230:Adenocarcinoma / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010750:Phosphoproteins / Q000032:analysis / Q000502:physiology*; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis / Q000502:physiology*; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D010750:Phosphoproteins; D018809:Proliferating Cell Nuclear Antigen; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase; C000722289:AXL protein, human