pSTAT3 Y705 is a prognostic biomarker identified from time-series gene expression profiles of a chemically induced mouse model of hepatocellular carcinoma

Hai Zhu; Zhentao Yang; Xinyi Zhao; Liang Zhang; Zhigang Ren; Ke Zhou; Penghong Song; Xiao Xu; Haiyang Xie; Shusen Zheng

pSTAT3 Y705 is a prognostic biomarker identified from time-series gene expression profiles of a chemically induced mouse model of hepatocellular carcinoma

Am J Transl Res. 2020 Apr 15;12(4):1443-1458. eCollection 2020.

Authors

Hai Zhu^{1

2

3

4}, Zhentao Yang^{1

2

3

4}, Xinyi Zhao⁵, Liang Zhang^{1

2

3

4}, Zhigang Ren^{1

2

6

7}, Ke Zhou^{1

2

3

4}, Penghong Song^{1

2

3

4}, Xiao Xu^{1

2

3

4}, Haiyang Xie^{1

2

3

4}, Shusen Zheng^{1

2

3

4}

Affiliations

¹ Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University Hangzhou, China.
² NHC Key Laboratory of Combined Multi-Organ Transplantation Hangzhou, China.
³ Key Laboratory of The Diagnosis and Treatment of Organ Transplantation, CAMS Hangzhou, China.
⁴ Key Laboratory of Organ Transplantation, Zhejiang Province Hangzhou, China.
⁵ State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine Hangzhou, China.
⁶ Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University Zhengzhou, China.
⁷ Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University Zhengzhou, China.

PMID: 32355553
PMCID: PMC7191170

Abstract

Development of hepatocellular carcinoma (HCC) is a dynamic process that includes a spectrum ranging from precancerous exposure to carcinogenesis and metastasis stages. In this process, numerous dysregulated genes resulted in aberrant activation or inhibition of signaling pathways. Herein, time-series gene expression profiles of dimethylnitrosamine (DEN)-induced mice with HCC covering different stages are provided. Gene expression patterns of liver tissues were detected at different time intervals [0 (negative control; NC), 15, 28, 30, and 42 weeks]. A comparison of gene expression between DEN-treated groups and NC yielded a total of 726 differentially expressed genes (DEGs), 76 of which were enriched in 10 statistically significant Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways (adjusted p value <0.05). After assessing regulation among these cascades, we found that Stat3 was a crucial transcription factor. Additionally, it was a connector in the PPI network constituting the 76 DEGs. Western blotting and immunohistochemistry suggested that the phosphorylation of Stat3 at tyrosine 705 (pStat3 Y705) was down-regulated in early stage HCC. Following, survival analysis revealed that patients with down-regulated pSTAT3 Y705 exhibited reduced overall survival rates in both the early stage and well-differentiated groups (p=0.00022 and p=0.0026, respectively). This is the first study evaluating dynamic gene expression profiles in a time-series DEN-induced mouse HCC model. Stat3 was identified as a crucial node during HCC progression, and pSTAT3 Y705 serves as a prognostic biomarker for early-stage HCC.

Keywords: Hepatocellular carcinoma; gene expression profiles; mouse models; pSTAT3 Y705; prognostic biomarkers.