14-3-3η is a novel growth-promoting and angiogenic factor in hepatocellular carcinoma

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• 作者：Jian Shen¹ ; ^&dagger ; ; Fei Jiang² ; ^&dagger ; ; Ye Yang² ; ^&dagger ; ; Guangming Huang³ ; ^&dagger ; ; Fuxing Pu³ ; ^&dagger ; ; Qinqiang Liu¹ ; ^&dagger ; ; Lijun Chen² ; Liang Ju¹ ; Ming Lu¹ ; Fei Zhou¹ ; Chi Zhang¹ ; Xiagang Luo¹ ; Xiaojun Yang¹ ; Chengyu Jiao⁴ ; Xiangcheng Li⁴ ; Zhong Li² ; Yuan Li² ; ^{liyuan@njmu.edu.cn" class="auth_mail" title="E-mail the corresponding author} ; Jianping Zhang¹ ; ^{zjpnjmu@hotmail.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Cxcl1 ; C-X-C motif-ligand 1 ; ECs ; endothelial cells ; EMT ; epithelial to mesenchymal transition ; ERK ; extracellular signal-regulated kinase ; FAK ; focal adhesion kinase ; FRA-1 ; fos related antigen 1 ; NK-κB ; nuclear factor kappa B ; PCNA ; proliferating cell nuclear antigen ; TGF-β ; transforming growth factor beta ; TUNEL ; transferase-mediated deoxyuridine triphosphate-biotin nick end labeling ; VEGF ; vascular endothelial growth factor ; Zeb-1 ; zinc finger E-box-binding protein-1
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：November 2016
• 年：2016
• 卷：65
• 期：5
• 页码：953-962
• 全文大小：3752 K

文摘

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. The continued search for novel therapeutic strategies for HCC is urgently required. In this study, we aimed to investigate the functions and clinical significance of 14-3-3η protein in HCC.

Methods

Expressions of genes and proteins were determined by quantitative reverse transcription polymerase chain reaction, Western blot, and immunohistochemistry. Their functions were assessed by endothelial cell recruitment, tube formation, wound healing, flow cytometry, immunostaining, immunoprecipitation, and xenograft assay. A tissue microarray followed by univariate and multivariate analyses was performed to indicate the clinical significance.

Results

In HCC specimens, overexpression of 14-3-3η was observed not only in tumors but also in intratumoral vessels. In HCC and vascular endothelial cells, 14-3-3η stimulated proliferation and angiogenesis, but attenuated the functions of sorafenib. Briefly, 14-3-3η facilitated the phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2). Then, by binding to the phosphorylated-ERK1/2 (p-ERK1/2), formed a functional positive feed-back loop. A xenograft model showed that, blockage of either 14-3-3η or ERK1/2 inhibited the tumor growth. Finally, tissue microarray analyses showed that overexpression of 14-3-3η, either in tumors or intratumoral vessels, contributed to the poor survival.

Conclusions

The 14-3-3η-ERK1/2 feedback loop played a characteristic growth-promoting role in HCC, not only in tumors but also in intratumoral vessels. Further, 14-3-3η could be a potential therapeutic target for HCC and a biomarker for predicting sorafenib treatment response.

Lay summary

Here we found that, 14-3-3η protein exhibited a characteristic growth-promoting effect in both tumor and intratumoral vessels of hepatocellular carcinoma by interacting with ERK1/2 signaling.