Integrated bioinformatical and in vitro study on drug targets for liver cirrhosis based on unsupervised consensus clustering and immune cell infiltration

Qingjia Chi; Di Wang; Ting Sun; Hua-Ping Liang

doi:10.3389/fphar.2022.909668

Integrated bioinformatical and in vitro study on drug targets for liver cirrhosis based on unsupervised consensus clustering and immune cell infiltration

Front Pharmacol. 2023 Jan 4:13:909668. doi: 10.3389/fphar.2022.909668. eCollection 2022.

Authors

Qingjia Chi^{1

2}, Di Wang³, Ting Sun⁴, Hua-Ping Liang²

Affiliations

¹ Department of Engineering Structure and Mechanics, School of Science, Wuhan University of Technology, Wuhan, China.
² State Key Laboratory of Trauma, Burns and Combined Injury, Department of Wound Infection and Drug, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China.
³ School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, Sichuan, China.
⁴ Surgical Laboratory, General Hospital of Ningxia Medical University,, Yinchuan, Ningxia, China.

Abstract

Liver cirrhosis is one of the most common cause of death in the world. The progress of liver cirrhosis involves health, liver cirrhosis and liver cancer, leading to great challenges in the diagnosis of the disease. Drug targets, which could be obtained conveniently, can help clinicians improve prognosis and treatment. Liver cirrhosis is associated with serum calcium levels. And studies reported Tanshinone IIA plays a therapeutic role in liver injury through activating calcium-dependent apoptosis. In this study, we explored the diagnostic key targets of Tanshinone IIA in liver cirrhosis through exploration of comprehensive dataset including health, liver cirrhosis and liver cancer patients. The unsupervised consensus clustering algorithm identified 3 novel subtypes in which differentially expressed genes (DEGs) between both subtypes were found by pairwise comparison. Then, 4 key drug targets of Tanshinone IIA were determined through the intersection of these DEGs. The diagnostic performance of target genes was assessed and further verified in the external dataset. We found that the 4 key drug targets could be used as effective diagnostic biomarkers. Then the immune scores in the high and low expression groups of target genes were estimated to identify significantly expressed immune cells. In addition, the immune infiltration of high and low target gene expression groups in several immune cells were significantly different. The findings suggest that 4 key drug targets may be a simple and useful diagnostic tool for predicting patients with cirrhosis. We further studied the carcinogenesis role of AKR1C3 and TPX2 in vitro. Both mRNA and protein expression in hepatoma carcinoma cells was detected using qRT-PCR and Western blot. And the knockdown of AKR1C3 and TPX2 significantly suppressed cell proliferation, migration and invasion.

Keywords: gene expression; immune microenvironment; liver cirrhosis; prognostic value; unsupervised clustering.