GPX2 is a potential therapeutic target to induce cell apoptosis in lenvatinib against hepatocellular carcinoma.
GPX2 is a potential therapeutic target to induce cell apoptosis in lenvatinib against hepatocellular carcinoma.
复制标题
DOI：
10.1016/j.jare.2022.03.012
复制
发表时间：
2023-03
影响因子：
10.7
通讯作者：
Shang, Changzhen
中科院分区：
文献类型：
--
作者：
Tan, Wenliang;Zhang, Kelin;Chen, Xinming;Yang, Lei;Zhu, Sicong;Wei, Yingcheng;Xie, Zhiqin;Chen, Yajin;Shang, Changzhen
Lenvatinib 抑制 HCC 中 GPX2 表达并诱导 ROS 相关细胞凋亡。 GPX2的高表达是HCC总体生存的独立危险因素。 Lenvatinib 通过抑制 HCC 中的 β-catenin/GPX2 轴诱导细胞凋亡。 GPX2 水平可以预测 HCC 患者对乐伐替尼的敏感性。仑伐替尼最近已成为晚期肝细胞癌（HCC）的一线治疗药物，但其治疗 HCC 的分子机制仍很大程度上未知。目前的研究旨在确定乐伐替尼治疗 HCC 的分子机制。使用基因表达微阵列、流式细胞术、蛋白质印迹、qRT-PCR、免疫组织化学和免疫荧光来研究HCC细胞对乐伐替尼的反应。还建立了Huh7细胞的异种移植瘤来检测乐伐替尼的体内作用。在此，我们发现乐伐替尼可以通过增加肝癌细胞中的活性氧（ROS）水平来诱导细胞凋亡。然后，微阵列分析和 qRT-PCR 结果证实 GPX2 是乐伐替尼抗 HCC 的重要靶点。损失和获得功能实验表明，调节GPX2水平显着影响lenvatinib诱导的HCC细胞ROS水平和凋亡。此外，对癌症基因组图谱数据库和我们队列中的 qRT-PCR 结果的分析均表明，GPX2 在肿瘤组织中显着过度表达，并与 HCC 较差的总生存率相关。从机制上讲，我们的研究结果进一步证明GPX2是β-catenin调控的下游基因，而乐伐替尼可以阻止β-catenin的核转位并进一步抑制HCC细胞中GPX2的表达。更重要的是，在22例接受乐伐替尼治疗的HCC患者中进一步分析了GPX2表达与乐伐替尼应答的相关性，结果显示低GPX2表达患者的客观缓解率（ORR）为44.4%（4/9），而高GPX2水平患者的ORR仅为7.7%（1/13）。我们的研究结果表明，GPX2 在乐伐替尼诱导的 HCC 细胞凋亡中发挥重要作用，这可能作为指导 HCC 患者乐伐替尼治疗的生物标志物。
Lenvatinib inhibits GPX2 expression and induces ROS related apoptosis in HCC. High expression of GPX2 is an independent risk factor for overall survival in HCC. Lenvatinib induces cell apoptosis through inhibiting β-catenin/GPX2 axis in HCC. GPX2 levels could predict lenvatinib sensibility for HCC patients. Lenvatinib has recently become available as the first-line therapy for advanced hepatocellular carcinoma (HCC), but its molecular mechanism in HCC remains largely unknown. The current study aims to identify the molecular mechanisms of lenvatinib in HCC. Gene expression microarrays, flow cytometry, western blot, qRT-PCR, immunohistochemistry and immunofluorescence were used to study the response of HCC cells to lenvatinib. Xenograft tumor of Huh7 cells was also established to detect the effect of lenvatinib in vivo. Herein, we found that lenvatinib could induce apoptosis via increasing reactive oxygen species (ROS) levels in HCC cells. Then, microarray analysis and qRT-PCR results confirmed that GPX2 was a vital target for lenvatinib against HCC. Loss and gain function of experiment showed that regulating GPX2 levels markedly affected the lenvatinib-induced ROS levels and apoptosis in HCC cells. In addition, analyses of The Cancer Genome Atlas database and the qRT-PCR results in our cohort both showed that GPX2 markedly overexpressed in tumor tissues and correlated with poor overall survival in HCC. Mechanistically, our findings further demonstrated that GPX2 was a downstream gene regulated by β-catenin, while lenvatinib could prevent nuclear translocation of β-catenin and further inhibit GPX2 expression in HCC cells. More importantly, the correlation of GPX2 expression with lenvatinib response was further analyzed in 22 HCC patients who received lenvatinib therapy, and the results showed that the objective response rate (ORR) in patients with low GPX2 expression was 44.4% (4/9), while the ORR in patients with high GPX2 levels was only 7.7% (1/13). Our findings indicated that GPX2 plays an important role in lenvatinib-induced HCC cell apoptosis, which might serve as a biomarker for instruction of lenvatinib therapy in HCC patients.
登录
查看更多内容
影响因子：
3.8
作者：
Miura S;Mitsuhashi N;Shimizu H;Kimura F;Yoshidome H;Otsuka M;Kato A;Shida T;Okamura D;Miyazaki M
通讯作者：
Miyazaki M
影响因子：
9.7
作者：
Okamoto, Kiyoshi;Kodama, Kotaro;Tsuruoka, Akihiko
通讯作者：
Tsuruoka, Akihiko
影响因子：
158.5
作者：
Llovet, Josep M.;Ricci, Sergio;Bruix, Jordi
通讯作者：
Bruix, Jordi
索拉非尼对亚太地区晚期肝细胞癌患者的疗效和安全性：一项 III 期随机、双盲、安慰剂对照试验
影响因子：
51.1
作者：
Cheng, Ann-Lii;Kang, Yoon-Koo;Guan, Zhongzhen
通讯作者：
Guan, Zhongzhen
影响因子：
4.2
作者：
Ferrari, Silvia Martina;Bocci, Guido;Fallahi, Poupak
通讯作者：
Fallahi, Poupak