An investigation into YB-1 and its role in tumour progression in medulloblastoma.

YB-1 及其在髓母细胞瘤肿瘤进展中的作用的研究。

• 批准号: 1945010
• 金额: --
• 依托单位: University of Nottingham
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1945010
• 关键词: investigation; into; YB; its; role

Medulloblastoma is the most frequent malignant childhood brain tumour. Tumours commonlydisseminate; one-third of medulloblastoma cases display metastatic disease at diagnosis and themajority of patients exhibitmetastases at relapse.Whilst long term survival rates amongst averageriskpatients have significantly improved in recent years, outcome for high- and very high-riskpatients with metastatic and recurrent disease remains invariably poorer. Clearly, new treatmentoptions are required to improve survival rates and reduce the life-long cognitive and functionalcomplications associated with current therapies.ATP Binding Cassette (ABC) transporters are highly expressed in numerous cancers, where theyconfer multi-drug resistance in malignant cells. ATP binding cassette subfamily B member 1(ABCB1) expression correlates with high-risk medulloblastoma and is known to efflux a number ofchemotherapeutics currently used in medulloblastoma treatment protocols. Y-box binding protein1 (YB-1) represents a potential regulator of the ABCB1 gene. Correlation between YB-1 nuclearexpression and ABCB1 expression has been demonstrated in several cancers and depletion ofYB-1 is associated with reduced activity of the ABCB1 gene. YB-1 is also over-expressed innumerous cancers, with elevated nuclear expression frequently associated with poor prognosis.Although well researched in other cancers, very little is known about the role of YB-1 inmedulloblastoma. In the first year of this project, I have investigated YB-1 expression inmedulloblastoma and found YB-1 to be expressed at both mRNA and protein level in allmedulloblastoma subgroups. For the first time, cellular localisation of YB-1 inmedulloblastoma hasbeen explored and YB-1 and pYB-1(S102) detected in both nuclear and cytoplasmic subcellularcompartments in a range of Group 3, 4 and Sonic Hedgehog (SHH) derived cell lines. Further tothis, treatment with chemotherapeutic and ABCB1 substrate vincristine was found to promotenuclear localisation of YB-1 in SHH cell line DAOY. Finally, utilising chromatin immunoprecipitation(ChIP) analysis, we have shown that YB-1 binds to an inverted CCAAT box in the ABCB1 promoter,suggesting that YB-1 may represent a novel regulator of the ABCB1 gene in medulloblastoma.Although further experiments are required, these findings identify YB-1 as a compelling target forfurther research into drug resistance in medulloblastoma.

髓母细胞瘤是最常见的儿童恶性脑肿瘤。肿瘤多为播散性;三分之一的髓母细胞瘤病例在诊断时显示转移性疾病，大多数患者在复发时发现转移。尽管近年来平均风险患者的长期生存率显著提高，但高风险和极高风险的转移性和复发性疾病患者的预后仍然较差。显然，需要新的治疗选择来提高生存率并减少与当前治疗相关的终身认知和功能并发症。ATP结合盒（ABC）转运蛋白在许多癌症中高度表达，它们赋予恶性细胞多药耐药性。ATP结合盒亚家族B成员1（ABCB 1）的表达与高危髓母细胞瘤相关，并且已知其外排目前用于髓母细胞瘤治疗方案的许多化疗药物。Y-box binding protein 1（YB-1）是ABCB 1基因的一个潜在调节因子。YB-1核表达和ABCB 1表达之间的相关性已在几种癌症中得到证实，YB-1的缺失与ABCB 1基因活性的降低有关。YB-1在许多癌症中也过度表达，细胞核表达的升高常常与预后不良有关，尽管在其他癌症中研究得很好，但对YB-1在髓母细胞瘤中的作用知之甚少。在本项目的第一年，我研究了YB-1在髓母细胞瘤中的表达，发现YB-1在所有髓母细胞瘤亚群中都有mRNA和蛋白水平的表达。首次探索了YB-1在髓母细胞瘤中的细胞定位，并在一系列第3、4组和Sonic Hedgehog（SHH）衍生细胞系的细胞核和细胞质亚细胞区室中检测到YB-1和pYB-1（S102）。此外，用化疗药物和ABCB 1底物长春新碱处理SHH细胞系DAOY，发现可促进YB-1的核定位。最后，利用染色质免疫沉淀（ChIP）分析，我们发现YB-1与ABCB 1启动子中的反向CCAAT盒结合，提示YB-1可能是成神经管细胞瘤中ABCB 1基因的一种新的调节因子。