Jian Shen1, Fei Jiang2, Ye Yang2, Guangming Huang3, Fuxing Pu3, Qinqiang Liu1, Lijun Chen2, Liang Ju1, Ming Lu1, Fei Zhou1, Chi Zhang1, Xiagang Luo1, Xiaojun Yang1, Chengyu Jiao4, Xiangcheng Li4, Zhong Li2, Yuan Li5, Jianping Zhang6. 1. Department of General Surgery, The Second Affiliated Hospital, Nanjing Medical University, China. 2. Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, China. 3. Department of Medical Center for Digestive Diseases, The Second Affiliated Hospital, Nanjing Medical University, China. 4. Department of Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. 5. Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, China. Electronic address: liyuan@njmu.edu.cn. 6. Department of General Surgery, The Second Affiliated Hospital, Nanjing Medical University, China. Electronic address: zjpnjmu@hotmail.com.
Abstract
BACKGROUND & AIMS: 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.
BACKGROUND & AIMS: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.
Authors: Ye Yang; Ming Jin; Yi Dai; Wenqi Shan; Shuai Chen; Rong Cai; Haojun Yang; Liming Tang; Lei Li Journal: Front Oncol Date: 2021-07-29 Impact factor: 6.244