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Abstract
Papillary renal cell carcinomas (PRCC) are a histologically and genetically heterogeneous group of tumors that represent 15–20% of all kidney neoplasms and may require diverse therapeutic approaches. Alteration of the NF2 tumor suppressor gene, encoding a key regulator of the Hippo signaling pathway, is observed in 22.5% of PRCC. The Hippo signaling pathway controls cell proliferation by regulating the transcriptional activity of Yes-Associated Protein, YAP1. Loss of NF2 results in aberrant YAP1 activation. The Src family kinase member Yes also regulates YAP1 transcriptional activity. This study investigated the importance of YAP and Yes activity in three NF2-deficient PRCC cell lines. NF2-deficency correlated with increased expression of YAP1 transcriptional targets and siRNA-based knockdown of YAP1 and Yes1 downregulated this pathway and dramatically reduced cell viability. Dasatinib and saracatinib have potent inhibitory effects on Yes and treatment with either resulted in downregulation of YAP1 transcription targets, reduced cell viability, and G0-G1 cell cycle arrest. Xenograft models for NF2-deficient PRCC also demonstrated reduced tumor growth in response to dasatinib. Thus, inhibiting Yes and the subsequent transcriptional activity of YAP1 had a substantial anti-tumor cell effect both in vitro and in vivo and may provide a viable therapeutic approach for patients with NF2-deficient PRCC.
Highlights
Papillary renal cell carcinoma (PRCC) is the second most common type of kidney cancer representing approximately 15–20% of all cases
This identified one cell line derived from a patient with type 1 PRCC, UOK342, with a homozygous Neurofibromatosis type 2 (NF2) insertion/deletion alteration that resulted in frameshift mutation and the loss of a splice site (Figure 2A) and one cell line derived from a patient with type 2 PRCC, UOK275, with a homozygous NF2 single nucleotide insertion that resulted in frameshift mutation (Figure 2B)
Mutation of NF2, a key regulator of the Hippo signaling pathway was observed in 3.6% of PRCC and, in combination with copy number loss, NF2 alterations were present in 22.5% PRCC, including both type 1 and type 2 PRCC histologies [2]
Summary
Papillary renal cell carcinoma (PRCC) is the second most common type of kidney cancer representing approximately 15–20% of all cases. PRCC can present as both sporadic disease or as a component of a hereditary syndrome, such as hereditary papillary renal cell carcinoma (HPRC) or hereditary leiomyomatosis and renal cell carcinoma (HLRCC) [3]. HPRC patients carry germline activating mutations within the tyrosine kinase domain of the MET oncogene and presents with bilateral, multifocal type 1 PRCC [4, 5], while HLRCC patients inherit germline inactivating mutation of the FH tumor suppressor gene and can have an aggressive variant of type 2 PRCC [6, 7]. Numerous studies have been done on familial forms of PRCC, little was known about the genes responsible for the sporadic forms of PRCC until a recent report from the Cancer Genome Atlas (TCGA) in which 161 PRCC tumors were sequenced and analyzed [2]. This study highlighted that amplification of chromosome 7 and 17 and activating mutations of the MET gene, on chromosome 7, are associated with type 1 www.impactjournals.com/oncotarget
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