KSR2-14-3-3ζ complex serves as a biomarker and potential therapeutic target in sorafenib-resistant hepatocellular carcinoma.
KSR2-14-3-3ζ complex serves as a biomarker and potential therapeutic target in sorafenib-resistant hepatocellular carcinoma.
复制标题
DOI：
10.1186/s40364-022-00361-9
复制
发表时间：
2022-04-25
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
Ras 2 激酶抑制因子 (KSR2) 是 MAPK 信号传导的调节因子，在大多数肝细胞癌 (HCC) 中过度激活。我们试图确定 KSR2 在 HCC 发病机制中的作用。我们通过组织微阵列、qPCR 和蛋白质印迹测试了 HCC 组织和细胞系中 KSR2 的水平。在功能上，我们通过集落形成试验、划痕试验、Transwell迁移试验和异种移植肿瘤模型确定了KSR2对HCC细胞增殖、迁移和侵袭的影响。采用免疫共沉淀 (co-IP) 实验评估磷酸丝氨酸结合蛋白 14-3-3 z 和 KSR2 的相互作用，并通过共过表达和敲低实验测试这种相互作用对人 HCC 细胞生长和增殖的影响。此外，我们使用流式细胞术检查 KSR2 和 14-3-3ze 相互作用是否传递 HCC 对索拉非尼的耐药性。 KSR2 在 HCC 组织和细胞系中显着上调，KSR2 高表达与 HCC 患者预后不良相关。 KSR2 敲低显着抑制体外和体内 HCC 细胞的增殖、迁移和侵袭。从机制上讲，co-IP 实验发现 14-3-3ze 与 KSR2 复合，并且 14-3-3ze 升高会增加 HCC 细胞中 KSR2 蛋白水平。重要的是，Kaplan-Meier 生存分析表明，KSR2 和 14-3-3ze 表达水平高的患者的生存时间最短，预后最差。有趣的是，同时过度表达 KSR2 和 14-3-3 z 的 HCC 细胞（而不是单独表达其中任何一种蛋白）表现出高度激活的 MAPK 信号传导和对索拉非尼的耐药性。我们的结果为 KSR2 的促肿瘤作用及其对 HCC 中 MAPK 通路的调节提供了新的见解。 KSR2-14-3-3ze 相互作用可能是增强 HCC 索拉非尼敏感性的治疗靶点。在线版本包含可在 10.1186/s40364-022-00361-9 获取的补充材料。
Kinase suppressor of Ras 2 (KSR2) is a regulator of MAPK signaling that is overactivated in most hepatocellular carcinoma (HCC). We sought to determine the role of KSR2 in HCC pathogenesis. We tested the level of KSR2 in HCC tissues and cell lines by tissue microarray, qPCR, and western blotting. Functionally, we determined the effects of KSR2 on the proliferation, migration, and invasion of HCC cells through colony formation assays, scratch assays, transwell migration assays, and xenograft tumor models. Co-immunoprecipitation (co-IP) experiments were used to assess the interaction of phospho-serine binding protein 14–3-3ζ and KSR2, and the effects of this interaction on growth and proliferation of human HCC cells were tested by co-overexpression and knockdown experiments. Additionally, we used flow cytometry to examine whether the KSR2 and 14–3-3ζ interaction conveys HCC resistance to sorafenib. KSR2 was significantly upregulated in HCC tissues and cell lines, and high KSR2 expression associated with poor prognosis in HCC patients. KSR2 knockdown significantly suppressed HCC cell proliferation, migration, and invasion in vitro and in vivo. Mechanistically, co-IP experiments identified that 14–3-3ζ complexed with KSR2, and elevated 14–3-3ζ increased KSR2 protein levels in HCC cells. Importantly, Kaplan–Meier survival analysis showed that patients with both high KSR2 and high 14–3-3ζ expression levels had the shortest survival times and poorest prognoses. Interestingly, HCC cells overexpressing both KSR2 and 14–3-3ζ, rather than either protein alone, showed hyperactivated MAPK signaling and resistance to sorafenib. Our results provide new insights into the pro-tumorigenic role of KSR2 and its regulation of the MAPK pathway in HCC. The KSR2–14–3-3ζ interaction may be a therapeutic target to enhance the sorafenib sensitivity of HCC. The online version contains supplementary material available at 10.1186/s40364-022-00361-9.
登录
查看更多内容
磷酸化 ERK 是肝细胞癌索拉非尼反应的潜在预后生物标志物
影响因子：
4
作者：
Liang Y;Chen J;Yu Q;Ji T;Zhang B;Xu J;Dai Y;Xie Y;Lin H;Liang X;Cai X
通讯作者：
Cai X
影响因子：
16
作者：
Dougherty, Michele K.;Ritt, Daniel A.;Zhou, Ming;Specht, Suzanne I.;Monson, Daniel M.;Veenstra, Timothy D.;Morrison, Deborah K.
通讯作者：
Morrison, Deborah K.
影响因子：
9.2
作者：
Ohmachi, M;Rocheleau, CE;Sundaram, MV
通讯作者：
Sundaram, MV
影响因子：
16
作者：
Hao, Nan;Nayak, Sujata;Dohlman, Henrik G.
通讯作者：
Dohlman, Henrik G.
影响因子：
64.8
作者：
Brennan, Damian F.;Dar, Arvin C.;Barford, David
通讯作者：
Barford, David