Yes-associated protein (YAP), the nuclear effector of the Hippo pathway, is a key regulator of organ size and a candidate human oncogene. This study aimed to assess the clinical significance and biological functions of YAP in non-small-cell lung cancer (NSCLC). We investigated the expression of YAP in 92 cases of NSCLC tissue by immunohistochemistry and found that YAP was expressed in 66.3% (61 ⁄ 92) cases and predominantly presented in the nucleus. The expression of YAP in NSCLC was significantly correlated with p-TNM stage (P = 0.0037) and lymph node metastasis (P = 0.0093). Importantly, YAP expression was associated with short overall survival. Further study in NSCLC cell lines in which YAP was either overexpressed or depleted confirmed that YAP markedly promoted cell proliferation and invasion. These results indicate that YAP plays an important role in NSCLC and might be a useful therapeutic target of NSCLC. (Cancer Sci 2010; 101: 1279-1285 L ung cancer is one of the leading causes of malignancyrelated deaths. (1,2) Non-small-cell lung cancer (NSCLC) accounts for up to 80% of all lung cancer cases. Despite progress made in the past decades, the 5-year survival rate for lung cancer remains under 15%. (3) Recent studies suggest that conventional therapies may have reached a therapeutic plateau, (3) so the demanding tasks are to elucidate the mechanisms of tumor biology and to identify new therapeutic targets.The Hippo signaling pathway, initially identified in Drosophila, is a highly conserved potent regulator of cell growth and apoptosis. (4,5) Acting downstream of the Hippo pathway, yes-associated protein (YAP) functions as a transcription co-activator (5,6) which interacts with the PPXY-motif-containing transcription factors, including ErbB4, P73, TEAD, P53BP-2, and Runx2. (7)(8)(9)(10)(11)(12)(13) In mammals, the Hippo pathway kinase cascade phosphorylates YAP and induces its cytoplasmic translocation; thus attenuating its interaction with the nuclear binding partners and inhibiting its function. (4)(5)(6) YAP is a key regulator of organ size by orchestrating cell proliferation and death. YAP induced the transcription of genes that promote proliferation in murine livers including Ki-67, c-myc, SOX4, and AFP. At the same time, it induced expression of negative regulators of apoptosis, such as the IAP family members BIRC5 ⁄ survivin and BIRC2 ⁄ cIAP1, and the BCL2 family gene MCL1 . (4) In addition, YAP is vitally required for development as mice deficient in YAP have an embryonic lethal phenotype. (14) Recently, YAP has been shown to be a candidate oncogene in the human chromosome 11q22 amplicon. (15)(16)(17) YAP expression and nuclear localization was found to be elevated in hepatocellular carcinoma, prostate cancer, colon cancer, ovary cancer, and breast cancer. (18)(19)(20) Moreover, some studies have further confirmed the oncogenic function of YAP in vivo and in vitro. YAP overexpression was able to overcome cell contact inhibition, (20) therefore providing a growth advantage for YAP-overexpressing canc...