J Cancer 2020; 11(15):4614-4624. doi:10.7150/jca.44492

Research Paper

Overexpression of Platelet-Derived Growth Factor Receptor Α D842V Mutants Prevents Liver Regeneration and Chemically Induced Hepatocarcinogenesis via Inhibition of MET and EGFR

Zhao-Qing Du1,2, Jian Dong1,2, Mu-Xing Li2,3, Jian-Fei Zhang2,4, Jian-Bin Bi1,2, Yi-Fan Ren1,2, Li-Na Zhang5, Rong-Qian Wu1,2, Satdarshan P.S. Monga6, Yi Lv1,2, Xu-Feng Zhang1,2✉, Hai-Chen Wang7✉

1. Department of Hepatobiliary Surgery and Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University. Xi'an, Shaanxi Province, 710061, China;
2. National-Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, The First Affiliated Hospital of Xi'an Jiaotong University. Xi'an, Shaanxi Province, 710061, China;
3. Department of General Surgery, Peking University Third Hospital, Beijing, 100083, China;
4. Department of Surgical Oncology, Shaanxi Provincial People's Hospital, Xi'an, 710068, China;
5. Department of Pharmacy, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China;
6. Department of Pathology and Medicine and Pittsburgh Liver Research Center, University of Pittsburgh, School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA;
7. Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University. Xi'an, Shaanxi Province, 710061, China.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Du ZQ, Dong J, Li MX, Zhang JF, Bi JB, Ren YF, Zhang LN, Wu RQ, Monga SPS, Lv Y, Zhang XF, Wang HC. Overexpression of Platelet-Derived Growth Factor Receptor Α D842V Mutants Prevents Liver Regeneration and Chemically Induced Hepatocarcinogenesis via Inhibition of MET and EGFR. J Cancer 2020; 11(15):4614-4624. doi:10.7150/jca.44492. Available from http://www.jcancer.org/v11p4614.htm

File import instruction

Abstract

Platelet-derived growth receptor α (PDGFRα) is a key factor in many pathophysiological processes. The expression level of PDGFRα is significantly elevated in the early stage of liver development and maintained at a lower level in adult normal livers. In this study, we constructed a liver-specific PDGFRαD842 mutant transgenic (TG) mice model to explore the effect of continuous activation of PDGFRα on liver regeneration and hepatocarcinogenesis. 14-day-old TG and wild-type (WT) mice were intraperitoneally injected with diethylnitrosamine (DEN) at a dose of 25 μg/g body weight. Two-month-old male TG and WT mice were subjected to partial hepatectomy (PH). The liver tissues were collected for further analysis at different time points. Overexpression of PDGFRαD842V and its target genes, Akt, c-myc and cyclin D1 in hepatocytes with no overt phenotype versus WT mice were compared. Unexpectedly, a dramatic decrease in hepatocyte proliferation was noted after PH in TG versus WT mice, possibly due to the downregulation of hepatocyte growth factor receptor (MET) and epidermal growth factor receptor (EGFR). No TG mice developed HCC spontaneously after 14 months follow-up. However, TG mice were more resistant to DEN-induced hapatocarcinogenesis at 6, 10, and 12 months of age, showing delayed hepatocyte proliferation and apoptosis, lower tumor incidence, smaller size and fewer number, compared with age-matched WTs, partially through downregulation of MET and EGFR. In conclusion, continuous activation of PDGFRα signaling by expression of PDGFRαD842V does not promote, but inhibit hepatic regeneration and hepatocarcinogenesis, possibly through compensatory downregulation of MET and EGFR.

Keywords: platelet-derived growth factor receptor α, liver, transgenic, hepatocyte growth factor receptor, epidermal growth factor receptor