Pascal Laura E, Frahm Krystle A, Skalitzky Kegan O, DeFranco Donald B, Rigatti Lora H, Lu Ray, Liu Teresa T
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine Pittsburgh, PA, USA.
UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine Pittsburgh, PA, USA.
Am J Clin Exp Urol. 2023 Feb 25;11(1):27-39. eCollection 2023.
Risk factors for prostate cancer include age, environment, race and ethnicity. Genetic variants in cyclic-adenosine-monophosphate-response-element-binding protein 3 regulatory factor (CREBRF) gene are frequently observed in Pacific Islanders, a population with elevated prostate cancer incidence. CREBRF has been shown to play a role in other cancers, however its function in prostate homeostasis and tumorigenesis has not been previously explored. We determined the incidence of CREBRF alterations in publicly available databases and examined the impact of CREBRF deletion on the murine prostate in order to determine whether CREBRF impacts prostate physiology or pathophysiology.
Alterations in CREBRF were identified in prostate cancer patients via in silico analysis of several publicly available datasets through cBioPortal. Male knockout and wild-type littermate mice were generated and examined for prostate defects at 4 months of age. Immunohistochemical staining of murine prostate sections was used to determine the impact of knockout on proliferation, apoptosis, inflammation and blood vessel density in the prostate. Serum adipokine levels were measured using a Luminex Multiplex Assay.
CREBRF alterations were identified in up to 4.05% of prostate tumors and the mutations identified were categorized as likely damaging. Median survival of prostate cancer patients with genetic alterations in CREBRF was 41.23 months, compared to 131 months for patients without these changes. In the murine model, the prostates of knockout mice had reduced epithelial proliferation and increased TUNEL apoptotic cells. Circulating adipokines PAI-1 and MCP-1 were also altered in knockout mice compared to age-matched controls.
Prostate cancer patients with genetic alterations in CREBRF had a significantly decreased overall survival suggesting that wild type CREBRF may play a role in limiting prostate tumorigenesis and progression. The murine knockout model demonstrated that CREBRF could modulate proliferation and apoptosis and macrophage density in the prostate. Serum levels of adipokines PAI-1 and MCP-1 were also altered and may contribute to the phenotypic changes observed in the prostates of knockout mice. Future studies focused on populations susceptible to CREBRF mutations and mechanistic studies will be required to fully elucidate the potential role of CREBRF in prostate tumorigenesis.
前列腺癌的风险因素包括年龄、环境、种族和民族。环磷酸腺苷反应元件结合蛋白3调节因子（CREBRF）基因中的遗传变异在太平洋岛民中经常被观察到，这是一个前列腺癌发病率较高的人群。CREBRF已被证明在其他癌症中发挥作用，然而其在前列腺稳态和肿瘤发生中的功能此前尚未被探索。我们在公开可用的数据库中确定了CREBRF改变的发生率，并研究了CREBRF缺失对小鼠前列腺的影响，以确定CREBRF是否影响前列腺生理或病理生理。
通过cBioPortal对几个公开可用的数据集进行计算机分析，在前列腺癌患者中识别CREBRF的改变。生成雄性基因敲除和野生型同窝小鼠，并在4个月大时检查前列腺缺陷。使用小鼠前列腺切片的免疫组织化学染色来确定基因敲除对前列腺增殖、凋亡、炎症和血管密度的影响。使用Luminex多重检测法测量血清脂肪因子水平。
在高达4.05%的前列腺肿瘤中发现了CREBRF改变，所识别的突变被归类为可能具有损害性。CREBRF基因发生改变的前列腺癌患者的中位生存期为41.23个月，而没有这些改变的患者为131个月。在小鼠模型中，基因敲除小鼠的前列腺上皮增殖减少，TUNEL凋亡细胞增加。与年龄匹配的对照相比，基因敲除小鼠的循环脂肪因子PAI-1和MCP-1也发生了改变。
CREBRF基因发生改变的前列腺癌患者的总生存期显著降低，这表明野生型CREBRF可能在限制前列腺肿瘤发生和进展中发挥作用。小鼠基因敲除模型表明，CREBRF可以调节前列腺中的增殖、凋亡和巨噬细胞密度。血清脂肪因子PAI-1和MCP-1水平也发生了改变，可能导致在基因敲除小鼠前列腺中观察到的表型变化。未来需要针对易发生CREBRF突变的人群进行研究以及进行机制研究，以充分阐明CREBRF在前列腺肿瘤发生中的潜在作用。
