title: Loss of the actin regulator HSPC300 results in clear cell renal cell carcinoma protection in Von Hippel-Lindau patients.
abstract: Clear cell renal cell carcinoma (ccRCC) is the most common malignant neoplasm of the kidney. The majority of hereditary and sporadic ccRCC cases are associated with germline and somatic mutations in the Von Hippel-Lindau gene (VHL), respectively. Gross deletions at the VHL locus can result either in ccRCC or in a mild clinical phenotype, with the absence of ccRCC development. Our goal in this study was to identify the molecular basis responsible for these differences in the clinical behavior in order to predict patients' phenotype. Using multiplex ligation-dependent amplification (MLPA), we identified and characterized gross VHL deletions in Spanish VHL families. A candidate gene related to this clinical association, HSPC300, was identified and depleted by RNA interference. It was possible to narrow the susceptibility region related to the mild clinical phenotype down to approximately 14 kb that included HSPC300 (C3orf10), a regulator of actin dynamics and cytoskeleton organization. Whereas 9 out of 10 families with ccRCC retained HSPC300 in the germline, loss of the HSPC300 locus was associated with mild clinical presentation of the disease in 6 out of 8 families. In fact, genetic depletion of HSPC300 resulted in cytoskeleton abnormalities and cytokinesis arrest in several tumor cell lines including ccRCC cells, suggesting that tumor cell proliferation was compromised in the absence of HSPC300. These clinical and functional data indicate a relevant function of HSPC300 in tumor cell progression, and suggest future therapeutic strategies based upon the inhibition of HSPC300 in renal cell carcinoma and possibly on other cancers.
authors.affiliation: Hereditary Endocrine Cancer Group, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Cascón
authors.forename: Beatriz
authors.initials: B
authors.lastname: Escobar
authors.forename: Cristina
authors.initials: C
authors.lastname: Montero-Conde
authors.forename: Cristina
authors.initials: C
authors.lastname: Rodríguez-Antona
authors.forename: Sergio
authors.initials: S
authors.lastname: Ruiz-Llorente
authors.forename: Ana
authors.initials: A
authors.lastname: Osorio
authors.forename: Fátima
authors.initials: F
authors.lastname: Mercadillo
authors.forename: Rocío
authors.initials: R
authors.lastname: Letón
authors.forename: José M
authors.initials: JM
authors.lastname: Campos
authors.forename: José M
authors.initials: JM
authors.lastname: García-Sagredo
authors.forename: Javier
authors.initials: J
authors.lastname: Benítez
authors.forename: Marcos
authors.initials: M
authors.lastname: Malumbres
authors.forename: Mercedes
authors.initials: M
authors.lastname: Robledo
mesh_terms: D000199:Actins / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D000368:Aged; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology; D002455:Cell Division / Q000235:genetics; D045744:Cell Line, Tumor; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000235:genetics*; D003599:Cytoskeleton / Q000235:genetics / Q000473:pathology; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D034622:RNA Interference; D017384:Sequence Deletion; D013030:Spain; D006623:von Hippel-Lindau Disease / Q000235:genetics*
chemical_list: D000199:Actins; C519848:BRK1 protein, human; D003598:Cytoskeletal Proteins