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The First Birt-Hogg-Dubé Tumor Cell Line and Wild Type Folliculin-restored Renal Cell Line as In Vitro and In Vivo Models

Scientists at the National Institutes of Health (NIH) have developed a novel renal cell carcinoma (RCC) cell line designated UOK257, which was derived from the surgical kidney tissue of a patient with hereditary Birt-Hogg-Dubé (BHD) syndrome and companion cell line UOK257-2 in which folliculin (FLCN) expression has been restored by lentivirus infection. These cell lines harbors a germline mutation of FLCN gene (alias BHD) and displays loss of heterozygosity, can grow as xenograft in nude mice. Patients affected with BHD develop skin papules (fibrofolliculomas), lung cysts, spontaneous pneumothorax and an increased risk for bilateral multifocal renal tumors. Loss of both copies of the FLCN gene has been documented in BHD renal tumors; however, the molecular mechanisms by which inactivation of the encoded protein, folliculin, leads to the BHD phenotype are currently unknown. They have developed an important research tool for in vitro folliculin functional studies. The companion cell line will be extremely useful for comparative biochemical analyses of cell culture systems in which the FLCN gene is either expressed or inactivated, including identification of renal tumor biomarkers, alteration of biochemical pathways resulting from loss of FLCN function, tumorigenicity of FLCN null versus FLCN restored cells, preclinical therapeutic drug testing in xenograft animal models produced from injection of these cell lines, etc. UOK 257 and UOK257-2 are thus useful cell models for studying the underlying molecular derangements associated with mTOR pathways and other biogenesis pathways in human kidney cancer and for evaluating novel therapeutic approaches for this disease. UOK257 is also one of the 40-member renal cancer cell lines in the Tumor Cell Line Repository of the Urologic Oncology Branch (UOB), National Cancer Institute (NCI).

Cell line is derived from a BHD patient: These cell lines are anticipated to retain many features of primary BHD samples and novel BHD antigens identified from this cell line are likely to correlate with antigens expressed on human BHD type of RCC tumors. Studies performed using these cell lines may have a direct correlation to the initiation, progression, treatment, and prevention of BHD type of RCC in humans. -Molecular and genetic features are well characterized: This cell line is part of NCI Urologic Oncology Branch's Tumor Cell Line Repository. The inventor has elucidated many physical characteristics of the cell lines, including chromosomal attributes and valuable studies on functions ofBHDgene, their data suggest thatFLCN, mutated in the BHD syndrome, and its novel interacting partner,folliculin-interactingprotein (FNIP1), may be involved in energy and/or nutrient sensing through the AMPK and mTOR signaling pathways.

William Marston Linehan

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