Transcriptional profiling revealed the anti-proliferative effect of MFN2 deficiency and identified risk factors in lung adenocarcinoma

Tumour Biol. 2016 Jul;37(7):8643-55. doi: 10.1007/s13277-015-4702-6. Epub 2016 Jan 6.

Abstract

Mitofusin-2 (MFN2) was initially identified as a hyperplasia suppressor in hyper-proliferative vascular smooth muscle cells (VSMCs) of hypertensive rat arteries, which has also been implicated in various cancers. There exists a controversy in whether it is an oncogene or exerting anti-proliferative effect on tumor cells. Our previous cell cycle analysis and MTT assay showed that cell proliferation was inhibited in MFN2 deficient A549 human lung adenocarcinoma cells, without investigating the changes in regulatory network or addressing the underlying mechanisms. Here, we performed expression profiling in MFN2 knockdown A549 cells and found that cancer-related pathways were among the most susceptible pathways to MFN2 deficiency. Through comparison with expression profiling of a cohort consisting of 61 pairs of tumor-normal matched samples from The Cancer Genome Atlas (TCGA), we teased out the specific pathways to address the impact that MFN2 ablation had on A549 cells, as well as identified a few genes whose expression level associated with clinicopathologic parameters. In addition, transcriptional factor target enrichment analysis identified E2F as a potential transcription factor that was deregulated in response to MFN2 deficiency. Although bioinformatics analysis usually entail further verification, our study provided considerable information for future scientific inquiries in related areas as well as a paradigm for characterizing perturbation in regulatory network.

Keywords: Lung adenocarcinoma; MFN2; Microarray; The Cancer Genome Atlas.

Publication types

  • Comparative Study

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / pathology
  • Animals
  • Apoptosis
  • Biomarkers, Tumor / genetics*
  • Case-Control Studies
  • Cell Proliferation / genetics*
  • Computational Biology
  • GTP Phosphohydrolases / deficiency*
  • GTP Phosphohydrolases / genetics
  • Gene Expression Profiling*
  • Gene Regulatory Networks
  • Humans
  • Lung / metabolism
  • Lung / pathology
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology*
  • Mitochondrial Proteins / deficiency*
  • Mitochondrial Proteins / genetics
  • Rats
  • Risk Factors
  • Tumor Cells, Cultured

Substances

  • Biomarkers, Tumor
  • Mitochondrial Proteins
  • GTP Phosphohydrolases
  • MFN2 protein, human