Reply to: “YAP in tumorigenesis: Friend or foe?”
Authors: Andrea Perra, Marta A. Kowalik, Silvia Giordano, Amedeo Columbano
Journal: Journal of Hepatology (2015)

YAP in tumorigenesis: Friend or foe?Journal of HepatologyVol. 62Issue 6PreviewWe read with great interest the recent Journal of Hepatology article published by Perra et al. [1]. The authors proved that yes-associated protein (YAP) accumulated in early preneoplastic lesions and oval cells in the resistant-hepatocyte rat model and in early dysplastic nodules and adenomas in human, respectively. Moreover, verteporfin which disrupted the formation of YAP-TEAD complex was proven to decrease the accumulation of YAP. It seemed that YAP was a pernicious factor in an experimental model or in humans with tumors. Full-Text PDF Open AccessYAP activation is an early event and a potential therapeutic target in liver cancer developmentJournal of HepatologyVol. 61Issue 5PreviewAlthough the growth suppressing Hippo pathway has been implicated in hepatocellular carcinoma (HCC) pathogenesis, it is unknown at which stage of hepatocarcinogenesis its dysregulation occurs. We investigated in rat and human preneoplastic lesions whether overexpression of the transcriptional co-activator Yes-associated protein (YAP) is an early event. Full-Text PDF We read with interest the letter by Liu et al., commenting on our study about the activation of YAP in early stages of hepatocellular carcinoma (HCC) development and its potential role as a therapeutic target in liver cancer development, recently published in Journal of Hepatology [[1]Perra A. Kowalik M.A. Ghiso E. Ledda-Columbano G.M. Di Tommaso L. Angioni M.M. et al.YAP. Activation is an early event and a potential therapeutic target in liver cancer development.J Hepatol. 2014; 61: 1088-1096Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar]. In their letter, Liu et al. cite some papers and reviews proposing an oncosuppressive role of YAP. Although these studies suggest a role for YAP as a tumor suppressor in certain contexts, the literature demonstrating an oncogenic role of YAP in solid experimental and human tumors is undoubtedly overwhelming. This is particularly true in the case of HCC. Indeed, many transgenic mice with liver-specific YAP overexpression or knockout for Mst1/Mst2 develop primary liver tumors, morphologically resembling human HCC or cholangiocarcinomas (CCs) [2Dong J. Feldmann G. Huang J. Wu S. Zhang N. Comerford S.A. et al.Elucidation of a universal size-control mechanism in Drosophila and mammals.Cell. 2007; 130: 1120-1133Abstract Full Text Full Text PDF PubMed Scopus (1793) Google Scholar, 3Zhou D. Conrad C. Xia F. Park J.S. Payer B. Yin Y. et al.Mst1 and Mst2 maintain hepatocyte quiescence and suppress hepatocellular carcinoma development through inactivation of the Yap1 oncogene.Cancer Cell. 2009; 16: 425-438Abstract Full Text Full Text PDF PubMed Scopus (708) Google Scholar, 4Song H. Mak K.K. Topol L. Yun K. Hu J. Garrett L. et al.Mammalian Mst1 and Mst2 kinases play essential roles in organ size control and tumor suppression.Proc Natl Acad Sci U S A. 2010; 107: 1431-1436Crossref PubMed Scopus (435) Google Scholar, 5Lu L. Li Y. Kim S.M. Bossuyt W. Liu P. Qiu Q. et al.Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver.Proc Natl Acad Sci U S A. 2010; 107: 1437-1442Crossref PubMed Scopus (572) Google Scholar]. Moreover, increased YAP expression and its nuclear translocation in neoplastic cells were observed in chemically-induced HCCs in non-transgenic mice [[6]Kowalik M.A. Saliba C. Pibiri M. Perra A. Ledda-Columbano G.M. Sarotto I. et al.Yes-associated protein regulation of adaptive liver enlargement and hepatocellular carcinoma development in mice.Hepatology. 2011; 53: 2086-2096Crossref PubMed Scopus (71) Google Scholar]. In relation to human HCC, many studies have shown a clear association between YAP expression and tumor development [7Zender L. Spector M.S. Xue W. Flemming P. Cordon-Cardo C. Silke J. et al.Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach.Cell. 2006; 125: 1253-1267Abstract Full Text Full Text PDF PubMed Scopus (915) Google Scholar, 8Xu M.Z. Yao T.J. Lee N.P. Ng I.O. Chan Y.T. Zender L. et al.Yes-associated protein is an independent prognostic marker in hepatocellular carcinoma.Cancer. 2009; 115: 4576-4585Crossref PubMed Scopus (417) Google Scholar, 9Tschaharganeh D.F. Chen X. Latzko P. Malz M. Gaida M.M. Felix K. et al.Yes-associated protein up-regulates Jagged-1 and activates the Notch pathway in human hepatocellular carcinoma.Gastroenterology. 2013; 144: 1530-1542Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar], with poor prognosis associated with YAP expression. Notably, a recent study showed that overall survival rate was lower in HCCs and combined HCC-CCs (cHC-CCs) that were overexpressing YAP, compared to those that were not [[10]Kim G.J. Kim H. Park Y.N. Increased expression of Yes-associated protein 1 in hepatocellular carcinoma with stemness and combined hepatocellular-cholangiocarcinoma.PLoS One. 2013; 8: e75449Crossref PubMed Scopus (39) Google Scholar]. The latter study also provided clinicopathological evidence that YAP is overexpressed more frequently in HCCs displaying stemness-related markers (EpCAM and CK-19) and in cHC-CCs, compared to HCCs lacking such expression. Finally, YAP expression is associated to poor prognosis in several other human malignancies, including non-small cell lung cancer, gastric cancer and colorectal cancer [11Wang Y. Dong Q. Zhang Q. Li Z. Wang E. Qiu X. Overexpression of yes associated protein contributes to progression and poor prognosis of non-small cell lung cancer.Cancer Sci. 2010; 101: 1279-1285Crossref PubMed Scopus (280) Google Scholar, 12Kang W. Tong J.H. Chan A.W. Lee T.L. Lung R.W. Leung P.P. et al.Yes-associated protein 1 exhibits oncogenic property in gastric cancer and its nuclear accumulation associates with poor prognosis.Clin Cancer Res. 2011; 17: 2130-2139Crossref PubMed Scopus (208) Google Scholar, 13Wang L. Shi S. Guo Z. Zhang X. Han S. et al.Overexpression of YAP and TAZ Is an independent predictor of prognosis in colorectal cancer and related to the proliferation and metastasis of colon cancer cells.PLoS One. 2013; 8: e65539Crossref PubMed Scopus (223) Google Scholar]. Interestingly, some studies provided evidence for the therapeutic benefits of YAP inhibition in cancer. Indeed, verteporfin (that inhibits the transcriptional activity of YAP) blocked YAP-induced liver tumorigenesis in mice and rats [1Perra A. Kowalik M.A. Ghiso E. Ledda-Columbano G.M. Di Tommaso L. Angioni M.M. et al.YAP. Activation is an early event and a potential therapeutic target in liver cancer development.J Hepatol. 2014; 61: 1088-1096Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar, 14Liu-Chittenden Y. Huang B. Shim J.S. Chen Q. Lee S.J. Anders R.A. et al.Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP.Genes Dev. 2012; 26: 1300-1305Crossref PubMed Scopus (973) Google Scholar]; VGLL4-mimicking peptide (a natural inhibitor of the YAP-TEAD interaction) prevented YAP-induced liver tumorigenesis in mouse models [[15]Koontz L.M. Liu-Chittenden Y. Yin F. Zheng Y. Yu J. Huang B. et al.The Hippo effector Yorkie controls normal tissue growth by antagonizing scalloped-mediated default repression.Dev Cell. 2013; 25: 388-401Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar] and in human primary gastric cancer models [[16]Jiao S. Wang H. Shi Z. Dong A. Zhang W. Song X. et al.A peptide mimicking VGLL4 function acts as a YAP antagonist therapy against gastric cancer.Cancer Cell. 2014; 25: 166-180Abstract Full Text Full Text PDF PubMed Scopus (367) Google Scholar]; cyclic YAP-like peptides (preventing YAP-TEAD interaction) inhibited tumor growth in a HCC xenograft model [[17]Zhou Z. Hu T. Xu Z. Lin Z. Zhang Z. Feng T. et al.Targeting Hippo pathway by specific interruption of YAP-TEAD interaction using cyclic YAP-like peptides.FASEB J. 2014; ([Epub ahead of print])Google Scholar]. In conclusion, while YAP might exert a dual role on tumorigenesis, depending on the specific tissues or cancer types, the results of our work, together with a vast existing literature, support the notion that YAP acts as an oncogene in HCC. Moreover, based on our novel finding that YAP is overexpressed at very early stages of the carcinogenic process, YAP can be considered critical for the development of HCCs and, thus, as a potential therapeutic target. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.