Zc3h12d, a Novel of Hypomethylated and Immune-Related for Prognostic Marker of Lung Adenocarcinoma

Bo Yang; Lin-Lin Ji; Hong-Liang Xu; Xiao-Ping Li; Hong-Gang Zhou; Ting Xiao; Xiao-He Li; Zhou-Yong Gao; Jian-Zhong Li; Wei-Dong Zhang; Guang-Shun Wang; Ming-Jiang Li

doi:10.2147/JIR.S304278

Zc3h12d, a Novel of Hypomethylated and Immune-Related for Prognostic Marker of Lung Adenocarcinoma

J Inflamm Res. 2021 Jun 15:14:2389-2401. doi: 10.2147/JIR.S304278. eCollection 2021.

Authors

Bo Yang^#^{1

2

3}, Lin-Lin Ji^#^{1

2}, Hong-Liang Xu^#¹, Xiao-Ping Li³, Hong-Gang Zhou⁴, Ting Xiao⁴, Xiao-He Li⁴, Zhou-Yong Gao^{1

2}, Jian-Zhong Li⁵, Wei-Dong Zhang³, Guang-Shun Wang¹, Ming-Jiang Li³

Affiliations

¹ Department of Thoracic Surgery, Tianjin Baodi Hospital, Baodi Clinical College of Tianjin Medical University, Tianjin, 301800, People's Republic of China.
² State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing, 102206, People's Republic of China.
³ Department of Thoracic Surgery, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, 300192, People's Republic of China.
⁴ State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key, Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300353, People's Republic of China.
⁵ Department of Thoracic Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, People's Republic of China.

^# Contributed equally.

Abstract

Background: Zc3h12d is a negative regulator which plays a crucial role in immune modulation. However, the role of zc3h12d in lung adenocarcinoma (LUAD) remains unclear. We aim to explore the prognostic of zc3h12d and investigate the relationship between zc3h12d expression and immune infiltration in LUAD.

Methods: TIMER site was used to analyze the expression of zc3h12d in LUAD. The zc3h12d protein levels in patient tissue samples were detected by immunohistochemistry staining assays. Meanwhile, based on UALCAN database and samples' data from our cohort, we explored the relationship of clinicopathological features and zc3h12d expression to determine the clinical effect of zc3h12d in LUAD. Several databases including GEPIA, Kaplan-Meier plotter and our samples' data were used to explore the prognostic value of zc3h12d in LUAD. Cox regression analysis was established to further evaluate the prognostic value of zc3h12d in LUAD. In addition, zc3h12d promoter methylation was analyzed by UALCAN database. Genetic alteration analysis was observed in the cBioPortal web. GO and KEGG analyses were conducted to elucidate the underlying mechanisms. Finally, the correlation between zc3h12d and tumor-infiltrating immune cells in LUAD was investigated by TIMER database. The B cells level was investigated by flow cytometry analysis of peripheral blood from our LUAD cohort.

Results: Zc3h12d expression was significantly higher in LUAD, compared with adjacent normal tissues. The clinical data from the UALCAN database demonstrated that zc3h12d expression was closely related with cancer stage and nodal metastasis. However, patient sample detection revealed that zc3h12d expression was closely related to pathological N (p = 0.0431) and grade (p = 0.004). Moreover, low zc3h12d expression was associated with poorer overall survival in LUAD. We analyzed the methylation level of zc3h12d in LUAD and found that the methylation levels of zc3h12d promoter in LUAD were significantly reduced. In addition, zc3h12d genetic alterations, including deep deletion, could be found in LUAD. GO and KEGG pathway analysis results indicated that zc3h12d has a certain value in immune infiltration. We investigated the expression of zc3h12d in tumor-immune interactions. It was found that zc3h12d might be associated with the immune infiltration and markers of infiltrating immune cells of LUAD. The results of patient sample detection confirmed that B cells level was significantly lower in the patients with low zc3h12d expression than those in the patients with high zc3h12d expression.

Conclusion: zc3h12d might be considered as a potential biomarker for determining prognosis and immune-related therapeutic target in LUAD.

Keywords: hypomethylation; lung adenocarcinoma; prognosis; tumor microenvironment; zc3h12d.