Role of High Mobility Group A2 (HMGA2) in Prostate Cancer

项目摘要 包括非裔美国人(AA)、加勒比海人和非洲人在内的黑人男性遭受的伤害不成比例 与高加索男性(CA)相比，前列腺癌的死亡率更高，呈现出 确诊时更具侵袭性的疾病。大多数死于前列腺癌的男性体内都有激素 难治性骨转移性疾病。高迁移率族蛋白A2(HMGA2)属于高迁移率族 重排染色质的染色体蛋白质，在各种癌症中增加。截断的异构体 HMGA2也可以通过染色体重排或选择性剪接产生。此外，HMGA2 单核苷酸多态(SNP)rs1042725与骨密度的变化有关， 其中，CC基因(在黑人男性和CA中更常见)与更高的骨密度相关，如 与CA中更常见的‘TT’型相比。此前已有研究表明，骨骼增加 密度与特立尼达和多巴哥老年男性的前列腺癌发病率有关，而且很好 众所周知，黑人男性的骨密度比其他任何种族都要高；然而，还没有人研究过这一点 关于前列腺癌转移的问题。此外，HMGA2 SNP rs1042725已经与 宫颈癌的发病率，但还没有关于前列腺癌的研究。我们有初步的 数据表明，HMGA2的表达随着前列腺癌的进展和患者组织的转移而增加。 此外，我们还发现，在LNCaP细胞中过表达全长(野生型)HMGA2会促进细胞核 HMGA2的表达与上皮间质转化(EMT)，而截短型HMGA2过表达 导致HMGA2的细胞质定位，通过增加Jun-D和活性氧增加细胞迁移 种(ROS)。最后，用共同培养的条件培养液培养侵袭力较弱的LNCaP细胞。 含羟基磷灰石的转移性C4-2癌细胞HMGA2表达和旁分泌细胞增加 在体外迁移，而在体内，更多的癌细胞迁移到较高骨羟基磷灰石植入物 密度。我们假设HMGA2亚型可以不同地介导前列腺癌的进展， HMGA2单核苷酸多态与黑人男性前列腺癌的高发病率有关。首先， 我们将检测HMGA2，野生型和截短型HMGA2在临床样本中的表达 不同的小种，以及野生型与截短型HMGA2的作用机制(特异性目标1)。其次，我们 将研究HMGA2 SNPs与前列腺癌发病率的相关性(特定目标2)。第三， 我们将确定HMGA2可能介导前列腺癌与 体外和体内小鼠骨利用模型(特定目的3)。这些研究将揭示一种新的功能作用 HMGA2在前列腺健康差异中的作用。

Project Summary Black men which includes African American men (AA), Caribbean and African men suffer disproportionately from prostate cancer and have higher mortality rates as compared to Caucasian men (CA), presenting with more aggressive disease at the time of diagnosis. Most men who die of prostate cancer present with hormone refractory and bone metastatic disease. High mobility group protein A2 (HMGA2) belongs to the high mobility chromosomal proteins that rearrange chromatin and is increased in various cancers. A truncated isoform of HMGA2 can also be generated by chromosomal rearrangements or alternative splicing. Additionally, HMGA2 single nucleotide polymorphism (SNP) rs1042725 has been associated with variation in bone mineral density, where the ‘CC’ genotype (more common in Black men vs CA) is associated with higher bone density as compared to ‘TT’ genotype that is more common in CA. Previously it has been shown that increased bone density is associated with prostate cancer incidence in older men from Trinidad and Tobago, and it is well known that Black men have higher bone density than any other race; however it has not been studied with regards to prostate cancer metastasis. Moreover, HMGA2 SNP rs1042725 has been associated with the incidence of cervical cancer, but has not been studied with respect to prostate cancer. We have preliminary data that HMGA2 expression increases with prostate cancer progression and metastasis in patient tissue. Additionally, we found that overexpression of full-length (wild-type) HMGA2 in LNCaP cells promoted nuclear expression of HMGA2 and epithelial mesenchymal transition (EMT), while truncated HMGA2 overexpression led to cytoplasmic localization of HMGA2, increased cell migration via increased Jun-D and reactive oxygen species (ROS). Finally, culturing less aggressive LNCaP cells with conditioned media from a co-culture of metastatic C4-2 cancer cells with hydroxyapatite bone increased HMGA2 expression and paracrine cell migration in vitro, while in vivo, more cancer cells migrated towards hydroxyapatite implant of higher bone density. We hypothesize that HMGA2 isoforms can differentially mediate prostate cancer progression, and that HMGA2 SNPs will be associated with higher prostate cancer incidence in Black men. Firstly, we will examine the expression of HMGA2, both wild-type and truncated in clinical samples of patients from different races, and the mechanism of action of wild-type vs truncated HMGA2 (Specific Aim 1). Secondly, we will examine the correlation between HMGA2 SNPs with prostate cancer incidence (Specific Aim 2). Thirdly, we will determine the molecular mechanisms by which HMGA2 may mediate prostate cancer interactions with bone using in vitro and in vivo mouse models (Specific Aim 3). These studies will reveal a novel functional role for HMGA2 in prostate health disparities.