Icaritin reduces prostate cancer progression via inhibiting high-fat diet-induced serum adipokine in TRAMP mice model.
Icaritin reduces prostate cancer progression via inhibiting high-fat diet-induced serum adipokine in TRAMP mice model.
复制标题
在 TRAMP 小鼠模型中，淫羊藿素通过抑制高脂饮食诱导的血清脂肪因子来减少前列腺癌的进展
DOI：
10.7150/jca.48413
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发表时间：
2020
影响因子：
3.9
通讯作者：
Jiang H
中科院分区：
文献类型：
--
作者：
Wu X;Long X;Yang C;Chen H;Sharkey C;Rashid K;Hu M;Liu Y;Huang Q;Chen Q;Hu J;Jiang H
目的：高脂饮食引起的肥胖与男性前列腺癌（PCa）的发病率和死亡率密切相关。淫羊藿苷（ICT，一种传统的中草药）的抗癌作用已被报道在几种类型的癌症，包括前列腺癌。脂肪因子是一种新型的脂肪细胞特异性分泌蛋白，在肥胖、糖尿病、动脉粥样硬化和癌症等多种疾病的发生发展中起着重要作用。然而，ICT的功能及其通过调节脂肪因子在PCa消退中的作用的分子机制尚未研究。在此，我们评估了ICT在肥胖PCa模型中在人表皮生长因子受体2型（HER 2）途径调节脂肪因子影响下的抗癌特性。材料与方法：在这项研究中，我们使用转基因小鼠前列腺腺癌（TRAMP），一个完善的动物模型的研究PCa的发病机制。所有动物均饲喂高脂饲料（含40%脂肪的HFD），并分为两组，一组接受30 mg/kg体重的ICT溶液（i.p），另一组作为对照组，不接受任何ICT治疗。于20、24、28周不同时间点行病理组织学检查和磁共振成像检查，评价各组动物的死亡率、肿瘤形成率和脂肪率。采用蛋白质印迹法、免疫组化法和多重免疫分析法测定HER 2蛋白表达和血清脂肪因子水平。纵向评估12只TRAMP小鼠中的PCa等级，以使用PET/CT扫描在手术后可视化PCa发展和进展。结果如下：我们观察到ICT治疗显著降低了TRAMP小鼠的总死亡率（p = 0.045）和前列腺上皮内瘤变（PIN）或PCa的百分比（p = 0.029）。有趣的是，ICT治疗后，在不同的亚组中观察到瘦素水平显著降低（p = 0.006@20th wk）和脂联素水平升高（p = 0.030@20th wk），并呈时间依赖性。此外，ICT治疗组中还检测到HER 2水平降低（p = 0.032@28wk）和PEA 3水平升高（p = 0.014@28wk）。基于PET/CT的成像显示ICT与非ICT处理的小鼠具有不同的标准摄取值和转移。讨论和结论：我们的研究结果表明，ICT通过调节脂肪因子分泌的有效抗癌特性可能会改变HER 2通路的表达和激活，作为预防PCa进展的替代机制。总之，我们的研究结果表明，ICT可能是一种有前途的癌症预防剂，有可能靶向和根除肥胖PCa患者的肿瘤细胞。
Objective: Obesity resulting from high-fat diets has a close relationship with the morbidity and mortality associated with Prostate cancer (PCa) in males. The anti-cancer role of Icaritin (ICT, a traditional Chinese herbal medicine) has been reported in several types of cancer including PCa. Adipokines are novel adipocyte-specific secretory protein, which plays a key role in the development of various diseases including obesity, diabetes, atherosclerosis, and cancer. However, the function of ICT and the molecular mechanisms underlying its role in PCa regression through modulation of adipokines have not been studied. Here, we assessed the anti-cancer properties of ICT under the influence of human epidermal growth factor receptor type 2 (HER2) pathway modulating adipokines in obese PCa models. Materials and Methods: In this study, we used transgenic adenocarcinoma of mouse prostate (TRAMP), a well-established animal model for the study of PCa pathogenesis. All the animals were fed on a high-fat diet (HFD with 40% fat) and divided into two groups, one received ICT solution of 30 mg/kg body bwt (i.p) while the other group served as control without any ICT treatment. The mortality rate, tumor formation and fat ratio were assessed by histopathological and magnetic resonance analysis at different time points of 20th, 24th and 28th weeks. The protein expression of HER2 and serum levels of adipokines were measured using western blotting, IHC and multiplex immunoassays. The PCa grade in 12 TRAMP mice were longitudinally evaluated to visualize PCa development and progression upon post-surgery using PET/CT scanning. Results: We observed that ICT treatment significantly reduces the total mortality rate of TRAMP mice (p = 0.045) and the percentage of prostate intraepithelial neoplasia (PIN) or PCa (p = 0.029). Interestingly, significantly decreased levels of leptin (p = 0.006 @20th wk) and the elevated levels of adiponectin (p = 0.030 @20th wk) were observed in different subgroups upon ICT treatment in a time-dependent manner. In addition, a decrease level of HER2 (p = 0.032 @28th wk) and an elevated level of PEA3 (p = 0.014 @28th wk) were also detected in ICT treated group. The PET/CT-based imaging showed that ICT vs non-ICT treated mice had different standard uptake value and metastasis. Discussion and Conclusion: Our results showed potent anti-cancer properties of ICT through the modulation of adipokine secretion may alter the expression and activation of HER2 pathway as an alternative mechanism to prevent PCa progression. Altogether, our findings indicate that ICT could be a promising cancer preventive agent with the potential to target and eradicate tumor cells in obese PCa patients.