Zhang Yu, Li Kaiqiang, Ying Youmin, Chen Bingyu, Hao Ke, Chen Boxu, Zheng Yu, Lyu Jianxin, Tong Xiangming, Chen Xiaopan, Wang Ying, Zhan Zhajun, Zhang Wei, Wang Zhen
Research Center of Blood Transfusion Medicine, Education Ministry Key Laboratory of Laboratory Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, China.
Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, China.
Oncotarget. 2017 Nov 30;8(66):110576-110591. doi: 10.18632/oncotarget.22833. eCollection 2017 Dec 15.
extraction (MTE), a traditional herbal medicine, has exhibited anti-tumor effects on a variety of cancers. However, its effectiveness and the mechanism of action in Hepatocellular carcinoma (HCC) has not been fully understood. In the present study, we demonstrate that C21 steroid-enriched fraction from MTE, which contains five main C21 steroids (FR5) exhibits obvious pharmacological activities on HCC cells . FR5 induces apoptosis and inhibits proliferation and migration of HepG2 and Bel7402 cells in a dose and time dependent manner. Furthermore, in HCC cells, we found that FR5 inhibits Hippo pathway, leading to inactivation of YAP and increase of PTEN. Enhanced PTEN results in the inhibition of PI3K/AKT signaling pathway, inhibiting cell proliferation by FR5 and FR5-induced apoptosis. Moreover, it was proved that FR5 treatment could inhibit tumor growth in a HCC xenograft mouse model, and immunohistochemistry results showed FR5 treatment resulted in down-regulation of Bcl-2 and YAP, and up-regulation of PTEN and PI3K. Taken together, we found that FR5 effectively inhibits proliferation and induces apoptosis of HCC cells through coordinated inhibition of YAP in the Hippo pathway and AKT in the PI3K-PTEN-mTOR pathway, and suggest FR5 as a potential therapy for HCC.
提取物（MTE）是一种传统草药，已对多种癌症表现出抗肿瘤作用。然而，其在肝细胞癌（HCC）中的有效性和作用机制尚未完全明确。在本研究中，我们证明了MTE中富含C21甾体的组分，其中含有五种主要的C21甾体（FR5），对肝癌细胞具有明显的药理活性。FR5以剂量和时间依赖性方式诱导HepG2和Bel7402细胞凋亡并抑制其增殖和迁移。此外，在肝癌细胞中，我们发现FR5抑制Hippo通路，导致YAP失活和PTEN增加。增强的PTEN导致PI3K/AKT信号通路受到抑制，从而抑制FR5诱导的细胞增殖和凋亡。此外，已证明FR5处理可抑制HCC异种移植小鼠模型中的肿瘤生长，免疫组织化学结果显示FR5处理导致Bcl-2和YAP下调，PTEN和PI3K上调。综上所述，我们发现FR5通过协同抑制Hippo通路中的YAP和PI3K-PTEN-mTOR通路中的AKT，有效抑制肝癌细胞增殖并诱导其凋亡，并提示FR5作为HCC的潜在治疗方法。
