title: Overexpression of Yes-associated protein confers doxorubicin resistance             in hepatocellullar carcinoma.
abstract: Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies             worldwide and is highly resistant to chemotherapy. Yes-associated protein (YAP)             is the downstream effector of the Hippo signaling pathway, which is frequently             overexpressed in many types of cancers. Amplification of the YAP gene and overexpression             of YAP in HCC have previously been reported to contribute to hepatocyte malignant             transformation and tumor progression. In this study, we aimed to investigate the             potential role of YAP in HCC chemoresistance. Overexpression of YAP resulted in             resistance against doxorubicin-induced apoptosis in HCC cell lines, whereas suppression             of the endogenous YAP expression by RNA interference demonstrated the reverse             effect. Western blotting revealed that, following exposure to doxorubicin, YAP-overexpressing             cells exhibited decreased cleaved PARP, increased phosphorylation of Akt and ERK1/2,             and elevated Bcl-xL expression in comparison to the vector control. Inhibition             of YAP expression sensitized HCC cells to doxorubicin, by exhibiting increased             cleaved PARP, decreased levels of phosphorylated Akt, phosphorylated ERK1/2 and             Bcl-xL expression. In addition, pretreatment with the MEK1/2 inhibitor U0126 but             not the PI3-K inhibitor LY294002 significantly enhanced doxorubicin-induced apoptosis             and decreased Bcl-xL expression in YAP-overexpressing HCC cells. Our data provide             evidence that overexpression of YAP plays an important role in conferring doxorubicin             resistance to HCC, which is at least partially mediated by YAP-induced activation             of the MAP kinase pathway. Targeting YAP may be a promising adjunct for overcoming             doxorubicin resistance in HCC.
authors.affiliation: Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, PR China.
authors.forename: Xinying
authors.initials: X
authors.lastname: Huo
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.forename: Angela M
authors.initials: AM
authors.lastname: Liu
authors.forename: Cuiju
authors.initials: C
authors.lastname: Tang
authors.forename: Yongling
authors.initials: Y
authors.lastname: Gong
authors.forename: Jianmin
authors.initials: J
authors.lastname: Bian
authors.forename: John M
authors.initials: JM
authors.lastname: Luk
authors.forename: Zhi
authors.initials: Z
authors.lastname: Xu
authors.forename: Jinfei
authors.initials: J
authors.lastname: Chen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002070:Butadienes / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000903:Antibiotics, Antineoplastic; C494811:BCL2L1 protein, human; D002070:Butadienes; D002867:Chromones; D009025:Morpholines; D009570:Nitriles; D010750:Phosphoproteins; D014157:Transcription Factors; C113580:U 0126; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D051020:bcl-X Protein; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D004317:Doxorubicin; D011065:Poly(ADP-ribose) Polymerases; D051057:Proto-Oncogene Proteins c-akt; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3