Identification of a serum-induced transcriptional signature associated with metastatic cervical cancer

PLoS One. 2017 Aug 30;12(8):e0181242. doi: 10.1371/journal.pone.0181242. eCollection 2017.

Abstract

Objective: Tumor cells that escape local tissue control can convert inflammatory cells from tumor suppressors to tumor promoters. Moreover, soluble immune-modulating factors secreted from the tumor environment can be difficult to identify in patient serum due to their low abundance. We used an alternative strategy to infer a metastatic signature induced by sera of cervical cancer patients.

Methods: Sera from patients with local and metastatic cervical cancer were used to induce a disease-specific transcriptional signature in cultured, healthy peripheral blood mononuclear cells (PBMCs). An empirical Bayesian method, EBarrays, was used to identify differentially expressed (DE) genes with a target false discovery rate of <5%. Ingenuity Pathway Analysis (IPA) software was used to detect the top molecular and cellular functions associated with the DE genes. IPA and in silco analysis was used to pinpoint candidate upstream regulators, including cancer-related microRNAs (miRNAs).

Results: We identified enriched pathways in the metastatic cervical group related to immune surveillance functions, such as downregulation of engulfment, accumulation, and phagocytosis of hematopoietic cells. The predicted top upstream genes were IL-10 and immunoglobulins. In silco analysis identified miRNAs predicted to drive the transcriptional signature. Two of the 4 miRNAs (miR-23a-3p and miR-944) were validated in a cohort of women with local and metastatic cervical cancer.

Conclusions: This study supports the use of a cell-based assay that uses PBMC "reporters" to predict biologically relevant factors in patient serum. Further, disease-specific transcriptional signatures induced by patient sera have the potential to differentiate patients with local versus metastatic disease.

MeSH terms

  • Adult
  • Bayes Theorem
  • Cells, Cultured
  • Cervix Uteri / pathology*
  • Cohort Studies
  • Female
  • Gene Expression Profiling*
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Immunoglobulins / blood
  • Immunoglobulins / genetics
  • Interleukin-10 / blood
  • Interleukin-10 / genetics
  • Leukocytes, Mononuclear / metabolism
  • MicroRNAs / blood
  • MicroRNAs / genetics*
  • Middle Aged
  • Neoplasm Metastasis / genetics
  • Neoplasm Metastasis / pathology
  • Uterine Cervical Neoplasms / blood
  • Uterine Cervical Neoplasms / genetics*
  • Uterine Cervical Neoplasms / pathology*
  • Young Adult

Substances

  • IL10 protein, human
  • Immunoglobulins
  • MIRN-944 microRNA, human
  • MIRN23a microRNA, human
  • MicroRNAs
  • Interleukin-10

Grants and funding

The authors received no specific funding for this work.