PSENEN influences the progression of renal clear cell carcinoma by regulating the immune microenvironment and oxidative phosphorylation

PeerJ. 2024 Nov 29:12:e18457. doi: 10.7717/peerj.18457. eCollection 2024.

Abstract

Background: Presenilin enhancer gamma-secretase subunit (PSENEN), the straight target of metformin, is highly expressed in several cancers. The role of PSENEN in kidney renal clear cell carcinoma (KIRC) has not been reported.

Methods: PSENEN expression in KIRC specimens was investigated in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, as well as by immunohistochemical analysis and qPCR assay. The relationship between PSENEN expression and patient survival was discussed. The biological function of PSENEN in KIRC and its correlation with immune infiltration of KIRC were then investigated, and possible cellular mechanisms were again analyzed. The effects of metformin on KIRC cell proliferation, migration and invasion were discussed in cellular experiments.

Results: PSENEN was found to be highly expressed in KIRC. The high PSENEN expression was an adverse factor in KIRC. Several immune-related pathways were enriched including immune response, complement and coagulation cascade reactions, and neutrophil extracellular trap formation, as evidenced by enrichment analyses. Immune infiltration analysis revealed that PSENEN expression correlated positively with regulatory T cells. Gene set variation analysis suggested that PSENEN expression correlated positively with oxidative phosphorylation. In addition, a certain concentration of metformin was found to inhibit the proliferation, migration and invasion of KIRC cells, in which PSENEN down-regulation, AMPK up-regulation and mTOR down-regulation were also observed.

Conclusions: PSENEN may be involved in regulating the immune microenvironment of KIRC, and oxidative phosphorylation may also be a pathway for its involvement in cancer development. PSENEN is a novel prognostic marker for KIRC.

Keywords: Immune microenvironment; Kidney renal clear cell carcinoma; Metformin; Oxidative phosphorylation; PSENEN (PEN2); Prognosis.

MeSH terms

  • Carcinoma, Renal Cell* / genetics
  • Carcinoma, Renal Cell* / immunology
  • Carcinoma, Renal Cell* / pathology
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation* / drug effects
  • Disease Progression*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Kidney Neoplasms* / genetics
  • Kidney Neoplasms* / immunology
  • Kidney Neoplasms* / metabolism
  • Kidney Neoplasms* / pathology
  • Male
  • Metformin / pharmacology
  • Metformin / therapeutic use
  • Middle Aged
  • Oxidative Phosphorylation* / drug effects
  • Tumor Microenvironment* / immunology

Substances

  • Metformin

Grants and funding

The study was supported by a university-level research fund from Shanghai University of Medicine & Health Sciences (E3-0200-21-201011-87), the Cultivation Plan for Improving the Quality of Degree Programs in Colleges and Universities (A1-2601-24-203001), and the Teacher Professional Development Project-Industry-University-Research Practice (A3-0200-24-311008-17). The Construction Project of Shanghai Key Laboratory of Molecular Imaging (18DZ2260400) supported the APC of this article. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.