Hepatitis D virus genomic RNA in the etiology of liver cancer

描述（由申请人提供）：该提案基于早期研究，该研究描述了一种新的“开-关”可逆开关机制，该机制调节多个基因的转录，主要是控制细胞分裂和肿瘤发生的原癌基因。该机制涉及PSF蛋白的阻遏和结合并从基因释放PSF的内源RNA的阻遏逆转。R21提案的总体目标是确定丁型肝炎病毒的基因组RNA（HDV gRNA）是否具有与内源性PSF结合RNA相同的致瘤功能，包括与PSF结合和逆转原癌基因的抑制。流行病学研究表明，HDV和HCV的感染可导致HCC，并且需要与HBV的共感染来帮助产生HDV颗粒，这与HBV导致HCC的流行观点相矛盾。流行病学证据得到了分子证据的支持，表明HDV gRNA在体外优先结合PSF蛋白，功能证据表明用HDV gRNA转基因转染NIH 3 T3细胞导致NIH 3 T3细胞转化为致瘤细胞。受这些开创性发现的鼓舞，我们提出了以下实验。(i)在用HDV gRNA转基因转染的NIH 3 T3细胞中测试HDV gRNA与PSF蛋白的结合和原癌基因Rab 23的诱导转录;（ii）通过将HDV gRNA转基因转染到肝脏中来测试小鼠肝脏中肿瘤的形成。我们希望这些实验将为HDV gRNA在HCC病因学中的致瘤作用提供进一步的支持，并为诊断和治疗HDV感染诱导的HCC提供新的分子靶点。 公共卫生相关性：该提案将测试由丁型肝炎病毒（HDV）感染引起的肝细胞癌（HCC）的新机制，这与HBV导致HCC的流行观点相矛盾。我们希望这些结果能为肝癌的诊断和治疗提供新的分子靶点。

DESCRIPTION (provided by applicant): The proposal is based on earlier studies describing a novel "on-off" reversible switch mechanism that regulates transcription of multiple genes, mainly proto-oncogenes that control cell division and tumorigenesis. The mechanism involves repression by PSF protein and reversal of repression by endogenous RNAs that bind and release PSF from a gene. The general aim of the R21 proposal is to determine whether the genomic RNA of hepatitis D virus (HDV gRNA) has the same tumorigenic function as endogenous PSF-binding RNAs, involving binding to PSF and reversing repression of proto-oncogenes. Epidemiological studies suggest that infection by HDV, and also by HCV, can cause HCC, and co-infection with HBV is required to provide help for producing HDV particles, contradicting the prevailing view that HBV causes HCC. The epidemiological evidence is bolstered by molecular evidence showing that HDV gRNA binds preferentially to PSF protein in vitro, and by functional evidence showing that transfection of NIH3T3 cells with a HDV gRNA transgene results in transformation of the NIH3T3 cells to tumorigenic cells. Encouraged by these seminal findings, we propose the following experiments. (i) Test for binding of HDV gRNA to PSF protein and induced transcription of the proto- oncogene Rab23 in NIH3T3 cells transfected with a HDV gRNA transgene; (ii) Test for formation of tumors in a mouse liver by transfecting a HDV gRNA transgene into the liver. We expect these experiments will provide further support for the proposed tumorigenic role of HDV gRNA in the etiology of HCC and lead to new molecular targets for diagnosing and treating HCC induced by HDV infection. PUBLIC HEALTH RELEVANCE: The proposal will test a novel mechanism that generates hepatocellular carcinoma (HCC) resulting from infection with hepatitis D virus (HDV), which contradicts the prevailing view that HBV causes HCC. We expect the results will identify new molecular targets for diagnosis and therapy of HCC.