(PQ5) Role of HIV-associated cellular miRNAs in HPV 16-induced pathogenesis

(PQ5) HIV 相关细胞 miRNA 在 HPV 16 诱导的发病机制中的作用

• 批准号: 9127765
• 负责人: JOEL Michael PALEFSKY
• 金额: $ 23.78万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9127765
• 关键词: Anus; Anus Neoplasms; Archives; Biological Assay; Biopsy; Cancerous; Cell model; Cells; Cervical; Clinic; Code; Data; Development; Diagnosis; Diagnostic; Epigenetic Process; Epithelial; Epithelial Cells; Epithelium; Exposure to; Genes; Genetic Translation; HIV; HIV-2; HPV-High Risk; Human; Human Genome; Human Papillomavirus; Human papillomavirus 16; Immunosuppression; In Vitro; Incidence; Individual; Infection; Knowledge; Lead; Lesion; Light; Malignant Neoplasms; Malignant neoplasm of anus; Measures; MicroRNAs; Neoplasms; Normal tissue morphology; Nucleotides; Pathogenesis; Pathologic; Pathological Staging; Pathology; Pathway interactions; Patients; Pattern; Phenotype; Play; Population; Premalignant; Prevention; Prognostic Marker; Proteins; Proto-Oncogenes; Risk; Role; Squamous intraepithelial lesion; Staging; Techniques; Testing; Therapeutic; Time; Tissues; Tumor Suppressor Genes; Viral Proteins; Virus Diseases; Work; antiretroviral therapy; biomarker development; cell growth regulation; cellular targeting; co-infection; differential expression; education research; functional genomics; in vitro Model; interest; mRNA Decay; metaplastic cell transformation; mortality; nef Protein; novel; novel diagnostics; novel therapeutic intervention; public health relevance; tat Protein; therapeutic biomarker; transcriptome; tumor; tumor progression

 DESCRIPTION (provided by applicant): This project is focused on understanding of why HIV-positive versus HIV-negative individuals are more likely to progress to human papillomavirus 16 (HPV 16)-associated anal high-grade squamous intraepithelial lesions (HSIL) and anal cancer. Although HPV-associated anal HSIL and cancers from HIV-positive and HPV- negative individuals are histopathologically similar, epithelial exposure to HIV, before or after infection with HPV, may lead to cellular changes in the epithelium that are more likely to result in cellular transformation, thus increasing the incidence of anal cancer in this population. Several studies have suggested that exogenous HIV proteins (e.g. tat and nef) interfere with cellular proteins and pathways that are known to be dys-regulated in HPV 16-associated cancers. One way that tat and nef interfere with cellular proteins and their corresponding pathways is through modulation of microRNA (miRNA) expression. The human genome encodes over 3,707 miRNAs, which frequently target many genes related to cancer development or prevention. Differentially-expressed miRNAs have been detected in several types of tumors and at different stages of those tumors. We hypothesize that HIV proteins modulate the miRNA profile of anal epithelial cells leading to dys-regulation of cellular pathways that regulate host oncogenes and tumor suppressor genes. Co-infection with HPV 16 further enhances this dys-regulation of cellular miRNAs and their corresponding pathways. Partnered with the Anal Neoplasia Clinic, Research and Education (ANCRE) and the Sandler Functional Genomics Facility at UCSF, we will perform miRNA profiling in archived anal biopsies from HIV- positive and HIV-negative individuals. We will compare the cellular miRNA profiles in tissues of different grades of pathology, including normal tissues, HSIL and cancer using the HTG EdgeSeq miRNA whole transcriptome assay, a novel technique that measures the expression of 2,275 human miRNAs. This will allow us to delineate the differences and similarities in HPV 16-positive anal tumors that arise from HIV-positive versus HIV-negative individuals. In addition we will use an anal epithelial in-vitro model to: 1) Identify HIV proteins that lead to dys-regulation of cellular miRNAs, 2) Validate the expression of a subset of miRNAs of interest in the setting of HIV/HPV 16 infection alone and during co-infection, and 3) Demonstrate the effects of individual miRNAs on cellular pathways and proteins that are involved in HPV 16-associated anal cancer progression. This will be the first study to establish a miRNAome specific to anal cancer in the setting of HIV infection. The identification of HIV-associated cellular miRNAs that are involved in HPV 16-associated anal cancer progression could lead to development of new diagnostic/prognostic markers, as well as therapies to treat anal cancers, particularly in HIV-positive individuals.

 描述(由申请者提供)：这个项目的重点是了解为什么HIV阳性和HIV阴性的人更有可能进展为HPV16相关的肛门高级别鳞状上皮内病变(HSIL)和肛门癌。尽管hpv相关的肛门HSIL和来自hvv阳性和hpv阴性个体的癌症在组织病理学上是相似的，但在感染hpv之前或之后，上皮暴露于hpv可能会导致上皮细胞的变化，这更有可能导致细胞。 转化，从而增加了该人群中肛门癌的发病率。一些研究表明，外源性HIV蛋白(如Tat和nef)干扰了已知在HPV16相关癌症中受到异常调节的细胞蛋白和途径。TAT和nef干扰细胞蛋白质及其相应途径的一种方式是通过调节microRNA(MiRNA)的表达。人类基因组编码超过3707个miRNAs，这些miRNAs经常针对许多与癌症发展或预防相关的基因。已经在几种类型的肿瘤和这些肿瘤的不同阶段检测到差异表达的miRNAs。我们假设HIV蛋白调节肛门上皮细胞的miRNA图谱，导致调节宿主癌基因和肿瘤抑制基因的细胞通路的失调。与HPV16的混合感染进一步增强了细胞miRNAs及其相应途径的这种失调调节。我们将与加州大学旧金山分校的肛门新生症临床、研究和教育中心(ANCRE)和桑德勒功能基因组学设施合作，对HIV阳性和HIV阴性患者的存档肛门活检组织进行miRNA图谱分析。我们将使用HTG EdgeSeq miRNA全转录组实验比较不同病理级别的组织中细胞miRNA的谱，包括正常组织、HSIL和癌症。HTG EdgeSeq miRNA全转录组分析是一种新的技术，可以测量2,275个人类miRNAs的表达。这将使我们能够描绘出HPV16阳性的肛门肿瘤中HIV阳性和HIV阴性的个体之间的区别和相似之处。此外，我们将使用肛门上皮体外模型：1)确定导致细胞miRNAs调控异常的HIV蛋白；2)验证在HIV/HPV16单独感染和联合感染期间感兴趣的miRNAs子集的表达；以及3)展示单独的miRNAs对与HPV16相关的肛门癌进展相关的细胞途径和蛋白质的影响。这将是第一次在HIV感染的背景下建立针对肛门癌的miRNAome的研究。HIV相关细胞miRNAs的鉴定 HPV16相关的肛门癌进展可能导致新的诊断/预后标记物的开发，以及治疗肛门癌的治疗，特别是在艾滋病毒阳性的个人中。