Project 3: Skin hypoxia, MCPyV infection, and MCC tumorigenesis

项目3：皮肤缺氧、MCPyV感染和MCC肿瘤发生

• 批准号: 10714175
• 负责人: Jianxin You
• 金额: $ 41.86万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10714175
• 关键词: AIDS related cancer; Affect; Automobile Driving; Cancer Etiology; Cell Hypoxia; Cell Proliferation; Cells; ChIP-seq; Clustered Regularly Interspaced Short Palindromic Repeats; DNA; DNA Binding; DNA Sequence Alteration; Data; Dermis; Development; Disseminated Malignant Neoplasm; Environment; Epigenetic Process; Gene Expression; Genes; Genetic Transcription; Genome; Hair follicle structure; Human; Hypoxia; Immunosuppression; In Vitro; Incidence; Infectious Skin Diseases; Knock-out; Knowledge; Malignant Neoplasms; Mediating; Merkel Cells; Merkel cell carcinoma; Messenger RNA; Metabolic; Modeling; Neoplasm Metastasis; Oncogenes; Oncogenic; Oncogenic Viruses; Organoids; Polyomavirus; Polyomavirus Infections; Proliferating; Reader; Risk Factors; Skin; Skin Cancer; Small Interfering RNA; Subcutaneous Tissue; Testing; Therapeutic Intervention; Transcriptional Regulation; Tumor Promotion; Up-Regulation; VEGFA gene; Vascular Endothelial Growth Factors; Viral; Viral Genome; Viral Oncogene; Virus; Virus Diseases; Virus Integration; Virus Replication; Xenograft Model; angiogenesis; carbonate dehydratase; carcinogenesis; chronic infection; coping; improved; insight; knock-down; laser capture microdissection; lipid nanoparticle; metaplastic cell transformation; mortality; nanoparticle delivery; neoplastic cell; novel strategies; pressure; prevent; recruit; response; transcriptome; tumor; tumor growth; tumor hypoxia; tumor microenvironment; tumor progression; tumorigenesis; tumorigenic

Project Abstract Merkel cell carcinoma (MCC) is one of the most aggressive skin cancers. Clonal integration of Merkel cell polyomavirus (MCPyV) genome into the host DNA has been observed in ~80% of MCCs, and represents a key causal factor for MCC development. LT and sT encoded by MCPyV genome have been shown to support not only viral replication but also MCPyV-induced tumorigenesis. Immune suppression is another important risk factor for the development of MCPyV-associated MCC. MCC has a nearly 50% mortality rate. The incidence of MCC has increased by >95% in the US since 2000. MCC is highly prone to metastasis. The metastatic cancers are more difficult to treat and can often be fatal. Thus, there is a need to better understand the oncogenic mechanisms of MCPyV and MCC in order to develop new strategies to prevent and treat this highly lethal skin cancer. MCC tumors are usually detected in the human dermis, which maintain a hypoxic microenvironment. Hypoxia supports tumor progression partly by driving metabolic adaptation, angiogenesis and metastasis, through upregulation of hypoxia-regulated genes. Importantly, we found that a large number of hypoxia genes are highly induced in MCC, suggesting that the hypoxic skin microenvironment represents an important starting point for MCC progression and metastatic spread. Some of these genes such as carbonic anhydrase 9 (CA9) and vascular endothelial growth factor A (VEGF-A) are critical for promoting tumor growth and metastasis. However, how MCPyV infected cells and MCC tumor cells respond to hypoxia and the impact of hypoxia-regulated gene expression on MCPyV infection and MCC tumorigenesis remain largely unknown. We showed that MCPyV oncogene LT is associated with epigenetic reader BRD4, which functionally interacts with HIF-1α, a key regulator of hypoxic responses, to control the transcription of hypoxic genes such as CA9 and VEGF-A. We also found that MCPyV sT can induce hypoxic gene expression. Building on these findings, we hypothesize that collaborative interactions between MCPyV LT and sT with their host partners, such as BRD4 and HIF-1α, collectively regulate hypoxia gene expression in MCPyV-infected and MCC origin cells to promote viral infection and MCC tumorigenesis. In this project, we propose to determine how MCPyV interacts with the host cells in the hypoxic skin environment (Aim 1), characterize the impact of LT-BRD4-HIF-1α interaction on hypoxic gene expression in skin cells (Aim 2), and investigate the function of MCPyV oncogenes in controlling MCC hypoxic reprograming and the impact on MCC tumorigenesis (Aim 3). These results will fill the gap in our understanding of hypoxic response mechanism in MCPyV-infected cells and associated MCC. Our study may provide new insights into viral and cellular factors that support hypoxia-mediated metabolic reprogramming during MCPyV infection and MCC oncogenic development, revealing new strategies to improve therapeutic intervention of MCPyV-induced cancers.

项目摘要 默克尔细胞癌（MCC）是最具侵袭性的皮肤癌之一。默克尔细胞的克隆整合 已经在约80%的MCC中观察到多瘤病毒（MCPyV）基因组进入宿主DNA，并且代表了一个关键的 MCC发展的因果因素。由MCPyV基因组编码的LT和sT已显示不支持 不仅是病毒复制，而且还有MCPyV诱导的肿瘤发生。免疫抑制是另一个重要的风险 MCPyV相关MCC发展的因素。MCC的死亡率接近50%。的发生率 自2000年以来，MCC在美国增长了95%以上。MCC非常容易转移。转移性 癌症更难治疗，而且往往是致命的。因此，有必要更好地了解 MCPyV和MCC的致癌机制，以开发新的策略来预防和治疗这种高度 致命的皮肤癌MCC肿瘤通常在人类真皮中检测到，其维持低氧环境。 微环境低氧支持肿瘤进展部分是通过驱动代谢适应，血管生成 和转移，通过低氧调节基因的上调。重要的是，我们发现， 低氧基因在MCC中被高度诱导，这表明低氧皮肤微环境代表了 MCC进展和转移扩散的重要起点。其中一些基因，如碳 脱水酶9（CA 9）和血管内皮生长因子A（VEGF-A）是促进肿瘤生长的关键 和转移。然而，MCPyV感染的细胞和MCC肿瘤细胞如何响应缺氧和缺氧的影响， 低氧调节基因表达对MCPyV感染和MCC肿瘤发生的影响在很大程度上仍然未知。 我们发现MCPyV癌基因LT与表观遗传阅读器BRD 4相关，其在功能上相互作用， 与缺氧反应的关键调节因子HIF-1α一起控制缺氧基因如CA 9的转录， 和VEGF-A。我们还发现MCPyV sT可以诱导低氧基因的表达。在这些发现的基础上， 我们假设MCPyV LT和sT与它们的宿主伙伴之间的协同相互作用，例如 BRD 4和HIF-1α共同调节MCPyV感染和MCC起源细胞中的缺氧基因表达， 促进病毒感染和MCC肿瘤发生。在这个项目中，我们建议确定MCPyV如何相互作用 与宿主细胞在缺氧的皮肤环境（目的1），表征LT-BRD 4-HIF-1α的影响， 目的2：研究MCPyV癌基因的功能 控制MCC缺氧重编程和对MCC肿瘤发生的影响（目的3）。这些结果将填补 我们对MCPyV感染细胞和相关MCC中缺氧反应机制的理解存在差距。 我们的研究可能会为支持缺氧介导的代谢的病毒和细胞因子提供新的见解 MCPyV感染和MCC致癌发展过程中的重编程，揭示了新的策略， 改进MCPyV诱导癌症的治疗干预。