Li Zhuo, Xiao He, Wang Kebing, Zheng Yuelan, Chen Ping, Wang Xinghuan, DiSanto Michael E, Zhang Xinhua
Zhongnan Hospital of Wuhan University, Wuhan, China.
Shenzhen Key Laboratory for Endogenous Infection, Department of Urology, Shenzhen Sixth People's Hospital, The Sixth Affiliated Hospital of Shenzhen University Health Science Center, Affiliated Shenzhen Sixth Hospital of Guangdong Medical University, Shenzhen, China.
Front Endocrinol (Lausanne). 2018 Aug 3;9:403. doi: 10.3389/fendo.2018.00403. eCollection 2018.
The etiology of benign prostatic hyperplasia (BPH) is complex, both age and androgen are thought to be important. However, the failure of androgen blockade treatments suggests other paracrine/autocrine factors involved in BPH. Oxytocin was found to have a paracrine/autocrine role in prostate in recent years. The influence of BPH on prostatic oxytocin receptor (OTR) expression has never been studied. A testosterone-estradiol induced rat model of BPH was employed and human hyperplastic prostate specimens were harvested. Expressions of OTR, α-adrenoreceptor subtypes and nitric oxide synthase isoforms were determined via real-time RT-PCR. OTR was further analyzed with Western-Blotting and histological examination. Subsequently, rat epithelial cells, human stromal cells and epithelial cells were cultured and treated with gradient concentrations of OT from 1 to 5 days. Cell proliferation was tested by Cell Counting Kit-8 and Flow Cytometry. The rat BPH model was validated with significant increased prostate weight. H-E stain revealed a different histopathology between human and rat BPH. Masson's trichrome staining demonstrated that smooth muscle (SM) cells, epithelium cells and collagen fibers were simultaneously augmented in this rat BPH model and human BPH samples. OTR mainly localized in epithelium in rat prostate whereas it mainly localized in stroma in human prostate. OTR gene was upregulated 3.3-fold in rat BPH and 3.0-fold in human BPH, along with increased expression of 2.0-fold αARs and 3.0-fold eNOS for rat BPH and 5.0-fold αARs for human BPH. The expression of OTR protein was upregulated 1.4-fold in rat BPH and 3.9-fold in human BPH, respectively. Increased concentrations of exogenous OT can accelerate proliferation of rat epithelial cells and human stromal cells but has no impact on human epithelial cells . Flow Cytometry showed oxytocin could significantly increase G/M period cell number. Our novel data demonstrates a significant and previously undocumented upregulation of OTR in both rat and human BPH. Moreover, exogenous OT accelerates proliferation of rat prostate epithelial cells and human prostate stromal cells. It is suggested OTR is involved in the development of BPH and OT regulatory system could be a potential new target for the BPH treatment.
良性前列腺增生（BPH）的病因复杂，年龄和雄激素都被认为是重要因素。然而，雄激素阻断治疗的失败提示还有其他旁分泌/自分泌因素参与BPH。近年来发现催产素在前列腺中具有旁分泌/自分泌作用。BPH对前列腺催产素受体（OTR）表达的影响从未被研究过。本研究采用睾酮 - 雌二醇诱导的大鼠BPH模型，并获取人类增生前列腺标本。通过实时RT-PCR测定OTR、α - 肾上腺素能受体亚型和一氧化氮合酶同工型的表达。进一步用蛋白质免疫印迹法和组织学检查分析OTR。随后，培养大鼠上皮细胞、人类基质细胞和上皮细胞，并用1至5天的梯度浓度OT处理。通过细胞计数试剂盒 - 8和流式细胞术检测细胞增殖。大鼠BPH模型通过前列腺重量显著增加得到验证。苏木精 - 伊红染色显示人类和大鼠BPH的组织病理学不同。Masson三色染色表明，在该大鼠BPH模型和人类BPH样本中，平滑肌（SM）细胞、上皮细胞和胶原纤维同时增加。OTR在大鼠前列腺中主要定位于上皮，而在人类前列腺中主要定位于基质。OTR基因在大鼠BPH中上调3.3倍，在人类BPH中上调3.0倍，同时大鼠BPH中αARs表达增加2.0倍，eNOS增加3.0倍，人类BPH中αARs增加5.0倍。OTR蛋白表达在大鼠BPH中上调1.4倍，在人类BPH中上调3.9倍。外源性OT浓度增加可加速大鼠上皮细胞和人类基质细胞的增殖，但对人类上皮细胞无影响。流式细胞术显示催产素可显著增加G/M期细胞数量。我们的新数据表明，在大鼠和人类BPH中OTR均有显著且此前未被记录的上调。此外，外源性OT加速大鼠前列腺上皮细胞和人类前列腺基质细胞的增殖。提示OTR参与BPH的发生发展，OT调节系统可能是BPH治疗的潜在新靶点。
