Research Paper Volume 13, Issue 7 pp 10672—10687

NET1 promotes HCC growth and metastasis in vitro and in vivo via activating the Akt signaling pathway

Zhen-Hua Chen1,2, *, , Qian-Zhi Ni1,3, *, , Xiu-Ping Zhang1, *, , Ning Ma4, , Jing-Kai Feng1, , Kang Wang1, , Jing-Jing Li4, , Dong Xie4, , Xing-Yuan Ma3, , Shu-Qun Cheng1, ,

  • 1 Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, China
  • 2 Department of General Surgery, Zhejiang Provincial Armed Police Corps Hospital, Hangzhou 310051, Zhejiang Province, China
  • 3 State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China
  • 4 CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
* Equal contribution

Received: June 1, 2020       Accepted: February 13, 2021       Published: April 11, 2021
How to Cite

Copyright: © 2021 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Neuroepithelial cell transforming gene 1 (NET1), a member of the guanine nucleotide exchange factor family, is involved in various cancers, including gastric cancer, breast cancer and glioma. However, the role of NET1 in hepatocellular carcinoma (HCC) remains largely uncovered. In this study, we found that NET1 expression was upregulated in HCC, and that upregulated NET1 expression was closely associated with poor prognosis and some clinical characteristics in HCC patients. Whilst forced expression of NET1 in HCC cells was observed to significantly promote cell growth and metastasis in vitro and in vivo; downregulation of NET1 was shown to exhibit an opposite inhibitory effect. RNA-seq analysis and gene set enrichment analysis demonstrated that knockdown of NET1 significantly suppressed the level of Akt phosphorylation level and the expression of Akt downstream genes in HCC cells. Moreover, MK2206, a potent Akt inhibitor was shown to block the NET1-induced effects in HCC. Taken together, this study demonstrated that, through the Akt signaling pathway, NET1 plays an oncogenic role in HCC progression and metastasis. Hence, NET1 may potentially be used as a potential therapeutic target and prognostic marker of HCC.


HCC: Hepatocellular carcinoma; NET1: Neuroepithelial cell transforming gene 1; GEF: Guanine nucleotide exchange factor; ECM: Extracellular matrix; LPA: Lysophosphatidic Acid; EHBH: Eastern Hepatobiliary Surgery Hospital; TMA: Tissue microarray; IHC: Immunohistochemistry; DMEM: Dulbecco's modified Eagle's medium; AFP: α-fetoprotein.