BARC and kidney cancer

描述（由申请人提供）：BARC （BMP Antagonist Regulated in Cancer）是我们最近发现的一种新型BMP（骨形态发生蛋白）拮抗剂，作为研究癌症中分泌基因改变的一部分。BARC在肾癌中显著下调（在19/20个测试的人体组织中），与生长调节蛋白的超家族具有序列相似性，并且包含与胱氨酸结基序完美匹配的序列，该基序在已知的结合和灭活bmp的蛋白质中起作用。此外，我们的初步数据显示，BARC的过表达可以显著抑制肾癌细胞的生长。这一初步证据表明BARC参与肾脏的生长调节，并提示BARC功能障碍可能与肾癌有关。本研究拟验证的假设是，BARC在正常肾脏中发挥生理性生长拮抗剂的作用，其下调可诱导肾上皮细胞增殖，这是肾肿瘤发生的重要前提。我们的具体目标是：(1)通过条件表达、重组蛋白和shRNA检测BARC在正常肾脏和肾癌生长调节中的作用；(2)利用SMAD报告基因检测和激活SMAD的免疫印迹技术鉴定BARC抑制的生长调节信号转导通路；(3)应用免疫组织化学方法评估BARC在正常和恶性肾组织中的表达。虽然还有很多工作要做，但我们目前的初步观察表明，BARC可能是一种新的肿瘤抑制基因，这种基因的正常功能是抑制正常肾脏的增殖，而缺乏BARC则会导致肾癌的发生。本课题的实验将验证这一假设，为BARC在肾癌预后和治疗中的潜在应用奠定基础。

DESCRIPTION (provided by applicant): BARC (BMP Antagonist Regulated in Cancer) is a novel BMP (bone morphogenic protein) antagonist we recently discovered as part of a search for secretory genes altered in cancer. BARC is strikingly downregulated in kidney cancers [in 19/20 human tissues tested], has sequence similarity to a superfamily of growth regulatory proteins, and contains a perfect sequence match for a cystine knot motif that functions in proteins known to bind and inactivate BMPs. Further, our preliminary data show that overexpression of BARC substantially inhibits kidney cancer cell growth. This preliminary evidence points to the involvement of BARC in growth regulation of the kidney, and suggests that BARC dysfunction may be associated with kidney cancer. The hypothesis to be tested in this proposal is that BARC functions as a physiologic growth antagonist in the normal kidney, and that its down-regulation induces proliferation in kidney epithelium, an important prerequisite for renal oncogenesis. Our Specific Aims are to (1) Test the role of BARC in growth regulation of normal kidney and kidney cancer using conditional expression, recombinant protein, and shRNA; (2) Identify growth-regulatory signal transduction pathways inhibited by BARC using SMAD reporter assays and immunoblots for activated SMAD; (3) Assess expression of BARC in normal and malignant kidney tissue using immunonhistochemistry. Although much remains to be accomplished, our preliminary observations thus far suggests that BARC may be a novel tumor suppressor gene - a gene whose normal function is to suppress proliferation in the normal kidney, and whose absence is permissive for kidney cancer development. The experiments in this proposal will test this hypothesis, and lay the groundwork for the potential use of BARC in kidney cancer prognosis and therapy.