Identifying the Prognostic Risk Factors of Synaptojanin 2 and Its Underlying Perturbations Pathways in Hepatocellular Carcinoma

ABSTRACT

Synaptojanin 2 (SYNJ2) regulates cell proliferation and apoptosis via dephosphorylating plasma membrane phosphoinositides. Aim of this study is to first seek the full-scale expression levels and potential emerging roles of SYNJ2 in hepatocellular carcinoma (HCC). We systematically analyzed SYNJ2 mRNA expression and protein levels in HCC tissues based on large-scale data and in-house immunohistochemistry (IHC). The clinical significance and risk factors for SYNJ2-related HCC cases were identified. A nomogram of prognosis was created and its performance was validated by concordance index (C-index) and shown in calibration plots. Based on the identified differentially coexpressed genes (DCGs) of SYNJ2, enriched annotations and potential pathways were predicted, and the protein interacting networks were mapped. Upregulated SYNJ2 in 3,728 HCC and 3,203 non-HCC tissues were verified and in-house IHC showed higher protein levels of SYNJ2 in HCC tissues. Pathologic T stage was identified as a risk factor. Upregulated mRNA levels and mutated SYNJ2 might cause a poorer outcome. The C-index of the nomogram model constructed by SYNJ2 level, age, gender, TNM classification, grade, and stage was evaluated as 0.643 (95%CI = 0.619–0.668) with well-calibrated plots. A total of 2,533 DCGs were extracted and mainly functioned together with SYNJ2 in metabolic pathways. Possible transcriptional axis of CTCF/POLR2A-SYNJ2/INPP5B (transcription factor-target) in metabolic pathways was discovered based on ChIP-seq datasets. In summary, transcriptional regulatory axis CTCF/POLR2A-SYNJ2 might influence SYNJ2 expression levels. Increased SYNJ2 expression level could be utilized for predicting HCC prognosis and potentially accelerates the occurrence and development of HCC via metabolic perturbations pathways.

Graphical abstract

KEYWORDS:

• Synaptojanin 2
• hepatocellular carcinoma
• nomogram predicting
• differentially coexpressed genes
• metabolism

Disclosure statement

The authors report no conflicts of interest.

Data availability

The data used to support the findings during the current study are available from the corresponding author upon reasonable request.

Ethical approval

This study was approved by the ethics committee of the First Affiliated Hospital of Guangxi Medical University.

Consent

Written informed consent was obtained from all study participants.

Authors’ contributions

Conception and design: Rui Zhang, Wei-Jia Mo, and Zhen-Bo Feng. Collection of data: Rui Zhang and Lan-Shan Huang. Analysis of data: Wei-Ying He and Wei-Zi Wu. IHC experiment: Lan-Shan Huang. Calculation of IHC score: Ji-Tian Chen and Zhen-Bo Feng. Manuscript writing and revising: all authors.

Research highlights

• First study to find increased levels of SYNJ2 in HCC tissues.

• SYNJ2 interacts with INPP5B in regulating the metabolic process in HCC.

• Underlying CTCF/POLR2A-SYNJ2/INPP5B axis plays a vital part in the metabolism of HCC.

Additional information

Funding

This work was supported by the Funds of National Natural Science Foundation of China [NSFC81860419], Natural Science Foundation of Guangxi, China [2018GXNSFAA050037], Guangxi Zhuang Autonomous Region Health Committee Self-financed Scientific Research Project [Z20190594, Z20190523].