Multi-omics analysis reveals the involvement of origin recognition complex subunit 6 in tumor immune regulation and malignant progression

Front Immunol. 2023 Oct 12:14:1236806. doi: 10.3389/fimmu.2023.1236806. eCollection 2023.

Abstract

Background: Origin recognition complex 6 (ORC6) is one of the six highly conserved subunit proteins required for DNA replication and is essential for maintaining genome stability during cell division. Recent research shows that ORC6 regulates the advancement of multiple cancers; however, it remains unclear what regulatory impact it has on the tumor immune microenvironment.

Methods: Unpaired Wilcoxon rank sum and signed rank tests were used to analyze the differences in the expression of ORC6 in normal tissues and corresponding tumor tissues. Multiple online databases have evaluated the genetic alterations, protein expression and localization, and clinical relevance of ORC6. To evaluate the potential prognostic impact and diagnostic significance of ORC6 expression, we carried out log-rank, univariate Cox regression, and receiver operating characteristic curve analysis. The ICGC-LIRI-JP cohort, CGGA-301 cohort, CGGA-325 cohort, CGGA-693 cohort, and GSE13041 cohort were used for external validation of the study findings. The associations between ORC6 expression and immune cell infiltration, immune checkpoint expression, and immunotherapy cohorts was further analyzed. To explore the functional and signaling pathways related to ORC6 expression, gene set enrichment analysis was performed. To clarify the expression and function of ORC6 in hepatocellular carcinoma (LIHC) and glioma, we conducted in vitro experiments.

Results: Expression of ORC6 is upregulated in the majority of cancer types and is associated with poor patient prognosis, notably in cases of LIHC and gliomas. In addition, ORC6 may be involved in multiple signaling pathways related to cancer progression and immune regulation. High expression of ORC6 correlates with an immunosuppressive state in the tumor microenvironment. The results of further immunotherapy cohort analysis suggested that patients in the ORC6 high-expression group benefited from immunotherapy. Inhibiting ORC6 expression suppressed the proliferative and migratory abilities of LIHC and glioma cells.

Conclusion: High expression of ORC6 may be used as a biomarker to predict the poor prognosis of most tumor patients. The high expression of ORC6 may be involved in the regulation of the tumor immunosuppressive environment, and it is expected to become a molecular target for inhibiting tumor progression.

Keywords: Orc6; immunotherapy; pan-cancer; prognosis; tumor microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Hepatocellular* / genetics
  • Glioma* / genetics
  • Humans
  • Immunosuppressive Agents
  • Liver Neoplasms* / genetics
  • Multiomics
  • Origin Recognition Complex*
  • Tumor Microenvironment

Substances

  • Immunosuppressive Agents
  • Origin Recognition Complex
  • ORC6 protein, human

Grants and funding

This study was funded by the Science and Technology Innovation Program of Hunan Province (Grant No.2021SK2026), the Clinical Medical Boot Technology Innovation Project of Hunan Province (Grant No. 2021SK53504), the Health and Family Planning Commission of Hunan Province (Grant No. . 2022JJ70143), the Clinical Research Special Fund of Wu Jieping Medical Foundation (Grant No. 320.6750.2022-19-29), the Tumor Clinical Research of Public Welfare of Xiaoxiang the Clinical Research (Grant No. HTSF202207275503), the Innovation Platform and Talent Plan of Hunan Province (2023SK4019) and the National Natural Science Foundation of China (Grant No. 82270834, 82000756).