%0 Journal Article
%T Tumor suppressor FLCN inhibits tumorigenesis of a FLCN-null renal cancer cell line and regulates expression of key molecules in TGF-¦Â signaling
%A Seung-Beom Hong
%A HyoungBin Oh
%A Vladimir A Valera
%A Jaime Stull
%A Duy-Tan Ngo
%A Masaya Baba
%A Maria J Merino
%A W Marston Linehan
%A Laura S Schmidt
%J Molecular Cancer
%D 2010
%I BioMed Central
%R 10.1186/1476-4598-9-160
%X To examine the tumor suppressor function of FLCN, wild-type or mutant FLCN (H255R) was stably expressed in a FLCN-null renal tumor cell line, UOK257, derived from a BHD patient. When these cells were injected into nude mice, tumor development was inversely dependent upon the level of wild-type FLCN expression. We identified genes that were differentially expressed in the cell lines with or without wild-type FLCN, many of which are involved in TGF-¦Â signaling, including TGF-¦Â2 (TGFB2), inhibin ¦Â A chain (INHBA), thrombospondin 1 (THBS1), gremlin (GREM1), and SMAD3. In support of the in vitro data, TGFB2, INHBA, THBS1 and SMAD3 expression levels were significantly lower in BHD-associated renal tumors compared with normal kidney tissue. Although receptor mediated SMAD phosphorylation was not affected, basal and maximal TGF-¦Â-induced levels of TGFB2, INHBA and SMAD7 were dramatically reduced in FLCN-null cells compared with FLCN-restored cells. Secreted TGF-¦Â2 and activin A (homo-dimer of INHBA) protein levels were also lower in FLCN-null cells compared with FLCN-restored cells. Consistent with a growth suppressive function, activin A (but not TGF-¦Â2) completely suppressed anchorage-independent growth of FLCN-null UOK257 cells.Our data demonstrate a role for FLCN in the regulation of key molecules in TGF-¦Â signaling and confirm deregulation of their expression in BHD-associated renal tumors. Thus, deregulation of genes involved in TGF-¦Â signaling by FLCN inactivation is likely to be an important step for tumorigenesis in BHD syndrome.Birt-Hogg-Dub¨¦ (BHD) syndrome is a familial disorder that predisposes patients to develop hair follicle hamartomas (84-90% penetrance), lung cysts (85% penetrance) and renal neoplasia (29-34% penetrance) [1-5]. BHD patients are at risk to develop bilateral, multifocal renal tumors with a variety of histologies, mainly chromophobe (34%) and oncocytic hybrid (50%) tumors with features of both chromophobe renal cell carcinoma (RCC) and renal o
%U http://www.molecular-cancer.com/content/9/1/160