A Role for De Novo Purine Metabolic Enzyme PAICS in Bladder Cancer Progression.
A Role for De Novo Purine Metabolic Enzyme PAICS in Bladder Cancer Progression.
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DOI：
10.1016/j.neo.2018.07.006
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发表时间：
2018-09
期刊：
影响因子：
--
通讯作者：
Varambally S
中科院分区：
文献类型：
--
作者：
Chakravarthi BVSK;Rodriguez Pena MDC;Agarwal S;Chandrashekar DS;Hodigere Balasubramanya SA;Jabboure FJ;Matoso A;Bivalacqua TJ;Rezaei K;Chaux A;Grizzle WE;Sonpavde G;Gordetsky J;Netto GJ;Varambally S
膀胱癌的基因组和转录组测序(BLCA)已经发现了癌症进展过程中的多个分子变化。其中许多已确定的遗传和表观遗传变化在这种疾病的发展过程中发挥了作用。研究发现，肌肉浸润性膀胱癌(MIBC)的分子亚型对一线治疗具有不同的敏感性，提示了这些肿瘤的异质性以及MIBC分子特征对提供有效治疗的重要性。具体地说，正如癌症基因组图谱项目所证明的那样，越来越明显的是，在BLCA中，代谢酶通常是失调的。多种代谢酶的表达增加是由于快速增殖的BLCA细胞需要广泛的核苷酸合成而增加的需求。癌细胞利用从头合成的嘌呤和嘧啶生物合成途径作为其核苷酸需求的来源。在这项研究中，我们发现参与嘌呤从头合成途径的磷酸核糖基氨基咪唑琥珀酸甲酰胺合成酶(PAICS)在BLCA中高表达。石蜡包埋组织切片免疫组织化学染色显示PAICS在MIBC中高表达。此外，我们还发现抑癌基因miR-128通过与其3‘-非翻译区结合，负向调控PAICS的表达。我们还发现，PAICS通过正向调节SNAI1和减少E-钙粘附素的表达来诱导EMT。此外，我们的体外功能研究和体内鸡绒毛膜尿囊膜检测表明，PAICS在BLCA细胞的增殖、侵袭和肿瘤生长中发挥关键作用。总体而言，我们的数据表明，靶向PAICS可能为BLCA提供了一种治疗选择。
Genomic and transcriptome sequencing of bladder cancer (BLCA) has identified multiple molecular alterations during cancer progression. Many of these identified genetic and epigenetic changes play a role in the progression of this disease. Studies have identified molecular subtypes in muscle-invasive bladder cancer (MIBC) with different sensitivities to frontline therapy suggesting the heterogeneity in these tumors and the importance of molecular characterization of MIBC to provide effective treatment. Specifically, it has become increasingly evident, as demonstrated by The Cancer Genome Atlas project, that metabolic enzymes are commonly dysregulated in BLCA. Elevated expression of multiple metabolic enzymes is due to the increased demand from rapidly proliferating BLCA cells requiring extensive nucleotide synthesis. Cancer cells utilize the de novo purine and pyrimidine biosynthetic pathway as a source of their nucleotide needs. In this study, we show that phosphoribosyl aminoimidazole succinocarboxamide synthetase (PAICS), an enzyme involved in de novo purine biosynthetic pathway, is significantly overexpressed in BLCA. Immunohistochemical staining of paraffin-embedded tissue sections showed that PAICS is overexpressed in MIBC. Furthermore, we found that tumor suppressor miR-128 negatively regulated PAICS expression by binding to its 3′-untranslated region. We also found that PAICS induces EMT by positively regulating SNAI1 and by a reduction in E-cadherin expression. Additionally, our in vitro functional studies and in vivo chicken chorioallantoic membrane assay show that PAICS plays a critical role in BLCA cell proliferation, invasion, and tumor growth. Collectively, our data suggest that targeting PAICS may provide a therapeutic option in BLCA.
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影响因子：
--
作者：
Barfeld SJ;Fazli L;Persson M;Marjavaara L;Urbanucci A;Kaukoniemi KM;Rennie PS;Ceder Y;Chabes A;Visakorpi T;Mills IG
通讯作者：
Mills IG
影响因子：
5.9
作者：
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13.8
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2.4
作者：
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通讯作者：
Dinney, Colin P. N.
影响因子：
28.2
作者：
Cantor JR;Sabatini DM
通讯作者：
Sabatini DM