Ovarian carcinoma immunoreactive antigen domain 2 controls mitochondrial apoptosis in lung adenocarcinoma

Cancer Sci. 2021 Dec;112(12):5114-5126. doi: 10.1111/cas.15160. Epub 2021 Oct 18.

Abstract

Ovarian carcinoma immunoreactive antigen domain 2 (OCIAD2) has been reported to show significantly higher expression in invasive lung adenocarcinoma than in lung adenocarcinoma in situ, and its abnormal expression is associated with poorer prognosis of the patients. However, the cellular function of OCIAD2 in this tumor remains poorly understood. In the present study, we first validated that OCIAD2 showed higher expression in human lung adenocarcinoma tissues or cell lines than in normal lung tissue or immortalized normal bronchial epithelial cells. OCIAD2 was localized predominantly at the mitochondrial membrane in lung adenocarcinoma cells. Interestingly, suppression of OCIAD2 led to loss of mitochondrial structure and a reduction in the number of mitochondria. Moreover, OCIAD2 suppression led to downregulation of cellular growth, proliferation, migration, and invasion, and upregulation of mitochondria-related apoptosis. We also showed that OCIAD2 suppression induced a decrease in mitochondrial membrane potential and release of cytochrome c. Transcriptional profiling using RNA sequencing revealed a total of 137 genes whose expression was commonly altered after OCIAD2 knockdown in three lung adenocarcinoma cell lines (A549, HCC827, and PC9). Pathway enrichment analysis of those genes demonstrated significant enrichment in apoptotic signaling or endoplasmic reticulum (ER) stress pathways. Our data suggest that OCIAD2 inhibits the mitochondria-initiated apoptosis and thus promotes the survival of lung cancer cells. Therefore, OCIAD2 may be an effective target for treatment of lung adenocarcinoma.

Keywords: OCIAD2; apoptosis; electron microscopy; lung adenocarcinoma; mitochondria.

MeSH terms

  • A549 Cells
  • Adenocarcinoma / genetics*
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Apoptosis / genetics*
  • Blotting, Western
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic*
  • Gene Ontology
  • Humans
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Membrane Potential, Mitochondrial / genetics
  • Microscopy, Electron, Transmission
  • Mitochondria / genetics*
  • Mitochondria / metabolism
  • Mitochondria / ultrastructure
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / metabolism
  • RNA-Seq / methods
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • Neoplasm Proteins
  • OCIAD2 protein, human