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J Cell Mol Med. 2018 Jun;22(6):3073-3085. doi: 10.1111/jcmm.13582. Epub 2018 Mar 24.

Inhibition of yes-associated protein suppresses brain metastasis of human lung adenocarcinoma in a murine model.

Author information

1
Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
2
Department of Thoracic Medicine, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan.
3
Department of Thoracic Surgery, Beijing Chao-Yang Hospital, Affiliated with Capital Medical University, Beijing, China.
4
Department of Hepatobiliary Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
5
Department of Pathology, University of California, San Francisco, CA, USA.

Abstract

Yes-associated protein (YAP) is a main mediator of the Hippo pathway and promotes cancer development and progression in human lung cancer. We sought to determine whether inhibition of YAP suppresses metastasis of human lung adenocarcinoma in a murine model. We found that metastatic NSCLC cell lines H2030-BrM3(K-rasG12C mutation) and PC9-BrM3 (EGFRΔexon19 mutation) had a significantly decreased p-YAP(S127)/YAP ratio compared to parental H2030 (K-rasG12C mutation) and PC9 (EGFRΔexon19 mutation) cells (P < .05). H2030-BrM3 cells had significantly increased YAP mRNA and expression of Hippo downstream genes CTGF and CYR61 compared to parental H2030 cells (P < .05). Inhibition of YAP by short hairpin RNA (shRNA) and small interfering RNA (siRNA) significantly decreased mRNA expression in downstream genes CTGF and CYR61 in H2030-BrM3 cells (P < .05). In addition, inhibiting YAP by YAP shRNA significantly decreased migration and invasion abilities of H2030-BrM3 cells (P < .05). We are first to show that mice inoculated with YAP shRNA-transfected H2030-BrM3 cells had significantly decreased metastatic tumour burden and survived longer than control mice (P < .05). Collectively, our results suggest that YAP plays an important role in promoting lung adenocarcinoma brain metastasis and that direct inhibition of YAP by shRNA suppresses H2030-BrM3 cell brain metastasis in a murine model.

KEYWORDS:

Hippo signalling; K-ras mutation; lung adenocarcinoma; metastasis; yes-associated protein

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