title: YAP1 acts as oncogenic target of 11q22 amplification in multiple cancer subtypes.
abstract: The transcriptional coactivator YAP1 is a critical effector of the human Salvador-Warts-Hippo pathway. Literature data report apparently discrepant results on the carcinogenic role of YAP1, which acts either as oncogene or as tumor suppressor in different in vitro and in vivo models. Furthermore, genomic amplification events of 11q22 locus encompassing YAP1 gene have been detected in multiple tumor types but there is limited direct evidence about the oncogenic role of endogenous YAP1 within in the amplicon. We screened a panel of human tumor samples and cancer cell lines and identified that the YAP1 amplification event is actually present in up to 23% of the cases. We exploited EKVX (lung cancer), CaSki (cervical cancer) and RO82 (thyroid cancer) cell lines harboring both genomic YAP1 amplification and YAP1 protein overexpression, in order to study the effects of downregulation of endogenous YAP1 by RNA-interference strategies. Class comparison analysis of gene expression profiling data identified 707 statistically significantly modulated genes (multivariable global test p-value = 0.002) that were functionally annotated for cell proliferation and cellular movement ontologies. Mechanistic studies of the identified perturbed pathways revealed that YAP1 silencing significantly decreased cell proliferation and cell cycle perturbation associated with upregulation of p21 and p27 cell-cycle inhibitors, reduced cell migration (p<0.048) and anchorage-independent growth (p<0.02). In CaSki cell line, YAP1 silencing induced significantly increased sensitivity and cell-death response to cisplatin treatment (p=0.011) as well as reduction of in-vivo tumorigenic potential (p=0.027). Overall, these results establish that YAP1 is a direct oncogenic target of the 11q22 amplicon in previously unreported cancer types and support the relevance of such genetic aberration in carcinogenesis in a fraction of multiple tumor types.
authors.affiliation: Experimental Oncology 1, Aviano National Cancer Institute, Aviano (PN), Italy.
authors.forename: Erica
authors.initials: E
authors.lastname: Lorenzetto
authors.forename: Monica
authors.initials: M
authors.lastname: Brenca
authors.forename: Mattia
authors.initials: M
authors.lastname: Boeri
authors.forename: Carla
authors.initials: C
authors.lastname: Verri
authors.forename: Elena
authors.initials: E
authors.lastname: Piccinin
authors.forename: Patrizia
authors.initials: P
authors.lastname: Gasparini
authors.forename: Federica
authors.initials: F
authors.lastname: Facchinetti
authors.forename: Sabrina
authors.initials: S
authors.lastname: Rossi
authors.forename: Giuliana
authors.initials: G
authors.lastname: Salvatore
authors.forename: Maura
authors.initials: M
authors.lastname: Massimino
authors.forename: Gabriella
authors.initials: G
authors.lastname: Sozzi
authors.forename: Roberta
authors.initials: R
authors.lastname: Maestro
authors.forename: Piergiorgio
authors.initials: P
authors.lastname: Modena
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology*; D002633:Chemotaxis / Q000187:drug effects; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D002945:Cisplatin / Q000494:pharmacology; D005260:Female; D005784:Gene Amplification; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D010750:Phosphoproteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D014157:Transcription Factors; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D014945:Wound Healing / Q000187:drug effects; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D010750:Phosphoproteins; D012333:RNA, Messenger; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D002945:Cisplatin