J Cancer 2020; 11(23):7009-7022. doi:10.7150/jca.47895 This issue

Research Paper

Independent prognostic implications of RRM2 in lung adenocarcinoma

Chao Ma1,2,3,6#, Huan Luo2,4#, Jing Cao5, Chengshan Gao1, Xianen Fa1, Guangsuo Wang6✉

1. Department of Cardiothoracic Surgery, Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
2. Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and the Berlin Institute of Health.
3. Charité - Universitätsmedizin Berlin, BCRT - Berlin Institute of Health Center for Regenerative Therapies, Berlin, Germany.
4. Klinik für Augenheilkunde, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
5. Department of Human Anatomy, School of Basic Medicine, Zhengzhou University, Zhengzhou, China.
6. Department of Thoracic Surgery, the First Affiliated Hospital of Southern University of Sciences and Technology, Shenzhen People's Hospital, Shenzhen, China.
#These authors equally contributed to this work.

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.
Ma C, Luo H, Cao J, Gao C, Fa X, Wang G. Independent prognostic implications of RRM2 in lung adenocarcinoma. J Cancer 2020; 11(23):7009-7022. doi:10.7150/jca.47895. Available from https://www.jcancer.org/v11p7009.htm

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Background: Ribonucleoside-diphosphate reductase subunit M2 (RRM2) is the catalytic subunit of ribonucleotide reductase and modulates the enzymatic activity, which is essential for DNA replication and repair. However, the role of RRM2 in lung adenocarcinoma (LUAD) remains unclear.

Methods: In this study, we explored the expression pattern and prognostic value of RRM2 in LUAD across TCGA, GEO, Oncomine, UALCAN, PrognoScan, and Kaplan-Meier Plotter, and confirmed its independent prognostic value via Cox analyses. LinkedOmics and GEPIA2 were applied to investigate co-expression and functional networks associated with RRM2. Besides, we used TIMER to assess the correlation between RRM2 and the main six types of tumor-infiltrating immune cells. Lastly, the correlations between immune signatures of immunomodulators, chemokines, and 28 tumor-infiltrating lymphocytes (TILs) and RRM2 were examined by tumor purity-corrected partial Spearman's rank correlation coefficient through TIMER portal.

Results: RRM2 was found upregulated in tumor tissues in TCGA-LUAD, and validated in multiple independent cohorts. Moreover, whether in TCGA or other cohorts, high RRM2 expression was found to be associated with poor survival. Cox analyses showed that high RRM2 expression was an independent risk factor for overall survival, disease-specific survival, and progression-free survival of LUAD. Functional network analysis suggested that RRM2 regulates RNA transport, oocyte meiosis, spliceosome, ribosome biogenesis in eukaryotes, and cellular senescence signaling through pathways involving multiple cancer-related kinases and E2F family. Also, RRM2 expression correlated with infiltrating levels of B cells, CD4+ T cells, and neutrophils. Subsequent analysis found that B cells and dendritic cells could predict the outcome of LUAD. B cells were identified as an independent risk factor among six types of immune cells through Cox analyses. At last, the correlation analysis showed RRM2 correlated with 67.68% (624/922) of the immune signatures we performed.

Conclusion: Our research showed that RRM2 could independently predict the prognosis of LUAD and was associated with immune infiltration. In particular, the tight relationship between RRM2 and B cell marker genes are the potential epicenter of the immune response and one of the critical factors affecting the prognosis. Our findings laid the foundation for further research on the immunomodulatory role of RRM2 in LUAD.

Keywords: RRM2, lung cancer, lung adenocarcinoma, prognosis, immune infiltrates, TIL