Phloretin suppresses metastasis by targeting protease and inhibits cancer stemness and angiogenesis in human cervical cancer cells
Phloretin suppresses metastasis by targeting protease and inhibits cancer stemness and angiogenesis in human cervical cancer cells
复制标题
DOI：
10.1016/j.phymed.2019.152964
复制
发表时间：
2019-09-01
期刊：
影响因子：
7.9
通讯作者：
Chen, Pei-Ni
中科院分区：
文献类型：
--
作者：
Hsiao, Yi-Hsuan;Hsieh, Ming-Ju;Chen, Pei-Ni
背景：根皮素是一种二氢查耳酮类黄酮，具有抗炎活性和抑制多种癌症的生长。然而，黄酮类化合物对宫颈癌转移和血管生成的影响仍不清楚。目的：在这项研究中，我们提供了与根皮素抗转移和抗血管生成作用相关的分子证据。本研究探讨根皮素的抗侵袭作用（0-60 μ M）在子宫颈癌细胞中的作用使用Matrigel侵袭测定、明胶酶谱法、细胞-基质粘附测定、伤口愈合测定和Western印迹。根皮素（0-100 μ M）的抗血管生成潜力通过Matrigel管形成测定来评估。根皮素（10或20 mg/kg）的体内抗肿瘤作用，通过口服灌胃喂养，并确定使用皮下接种和尾静脉注射在免疫缺陷nukemies.Results：根皮素（60 μ M）表现出显着的抑制侵袭和迁移，通过下调基质金属蛋白酶（MMP）-2，MMP-3，和组织蛋白酶S在人SiHa宫颈癌细胞。根皮素（60 μ M）逆转了转化生长因子β 1诱导的上皮-间充质转化，并下调了间充质标志物，如纤连蛋白、波形蛋白和RhoA。根皮素（100 μ M）治疗显着抑制SiHa细胞的醛脱氢酶1活性，减少自我更新特性和干细胞的CD 44和Sox-2的签名在球形形成宫颈癌衍生的肿瘤起始细胞，并抑制人脐静脉内皮细胞的侵袭，MMP-2活性和管形成能力。根皮素的能力在肿瘤异种移植模型中，通过尾静脉注射和皮下接种证明了在SiHa细胞中，在20 mg/kg的剂量下，抑制肺转移和肿瘤生长。总之，研究结果表明根皮素抑制SiHa细胞的转移和血管生成能力以及癌症的干性，从而表明这种类黄酮是一种有希望的治疗人宫颈癌细胞的治疗剂。
Background: Phloretin, a dihydrochalcone flavonoid, possesses anti-inflammatory activity and inhibits the growth of various cancers. However, the flavonoid's effect on cervical cancer metastasis and angiogenesis remains unknown.Purpose: In this study, we provide molecular evidence associated with the antimetastatic and antiangiogenic effects of phloretin.Methods: In this study, the anti-invasive effect of phloretin (0-60 mu M) in cervical cancer cells was evaluated using the Matrigel invasion assay, gelatin zymography, cell-matrix adhesion assay, wound healing assay, and Western blotting. Antiangiogenic potential of phloretin (0-100 mu M) was assessed by the Matrigel tube formation assay. The in vivo antitumor effect of phloretin (10 or 20 mg/kg) was fed by oral gavage and determined using subcutaneous inoculation and tail vein injection in immunodeficient nude mice.Results: Phloretin (60 mu M) showed marked suppression of invasion and migration through downregulation of matrix metalloproteinase (MMP)-2, MMP-3, and cathepsin S in human SiHa cervical cancer cells. Phloretin (60 mu M) reversed the epithelial-mesenchymal transition induced by transforming growth factor-beta 1 and down-regulated mesenchymal markers, such as fibronectin, vimentin, and RhoA. Phloretin (100 mu M) treatment significantly inhibited the aldehyde dehydrogenase 1 activity of SiHa cells, reduced the self-renewal properties and stemness signatures of CD44 and Sox-2 in sphere-forming cervical cancer-derived tumor-initiating cells, and inhibited the invasion, MMP-2 activity, and tube formation capacity of human umbilical vein endothelial cells. The ability of phloretin (20 mg/kg) to suppress lung metastasis and tumor growth in SiHa cells was evidenced by tail vein injection and subcutaneous inoculation in a tumor xenograft model.Conclusion: In summary, the findings indicate that phloretin inhibits the metastatic and angiogenic abilities and cancer stemness of SiHa cells, thereby suggesting that this flavonoid is a promising therapeutic agent for the treatment of human cervical cancer cells.