The Autophagy Protein LC3A Correlates With Hypoxia and Is a Prognostic Marker of Patient Survival in Clear Cell Ovarian Cancer

J Pathol. 2012 Dec;228(4):437-47. doi: 10.1002/path.4090.

Abstract

Clear cell ovarian cancer histotypes exhibit metabolic features associated with resistance to hypoxia and glucose deprivation-induced cell death. This metabolic characteristic suggests that clear cell ovarian cancers activate survival mechanisms not typical of other epithelial ovarian cancers. Here we demonstrate that microtubule-associated protein 1 light chain 3A (LC3A), a marker of autophagy, is related to hypoxia and poor prognosis in clear cell ovarian cancer. In 485 ovarian tumours, we found that LC3A was significantly associated with poor progression-free (p = 0.0232), disease-specific (p = 0.0011) and overall patient survival (p = 0.0013) in clear cell ovarian cancer patients, but not in other subtypes examined. LC3A was an independent prognostic marker of reduced disease-specific [hazard ratio (HR): 2.55 (95% CI 1.21-5.37); p = 0.014] and overall survival [HR: 1.95 (95% CI 1.00-3.77); p = 0.049] in patients with clear cell ovarian carcinoma. We also found a strong link between autophagy and hypoxia as LC3A staining revealed a significant positive association with the hypoxia-related proteins carbonic anhydrase-IX and HIF-1α. The functional link between hypoxia and autophagy was demonstrated using clear cell and high-grade serous cell lines that were subjected to hypoxia or hypoxia + glucose deprivation. Clear cell carcinoma lines displayed greater autophagy induction and were subsequently more sensitive to inhibition of autophagy under hypoxia compared to the high-grade serous lines. Together, our findings indicate that hypoxia-induced autophagy may be crucial to the clinical pathology of clear cell ovarian cancer and is a potential explanation for histological subtype differences in patient disease progression and outcomes.

Keywords: Autophagy; LC3; LC3A; cancer; hypoxia; immunohistochemistry; ovarian cancer; ovarian clear cell carcinoma; prognosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma, Clear Cell* / metabolism
  • Adenocarcinoma, Clear Cell* / mortality
  • Adenocarcinoma, Clear Cell* / pathology
  • Adult
  • Aged
  • Aged, 80 and over
  • Apoptosis / physiology
  • Autophagy / physiology*
  • Biomarkers / metabolism
  • Carbonic Anhydrases / metabolism
  • Cell Hypoxia / physiology
  • Cell Line, Tumor
  • Female
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • Microtubule-Associated Proteins / metabolism*
  • Middle Aged
  • Multivariate Analysis
  • Ovarian Neoplasms* / metabolism
  • Ovarian Neoplasms* / mortality
  • Ovarian Neoplasms* / pathology
  • Prognosis
  • Retrospective Studies

Substances

  • Biomarkers
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Microtubule-Associated Proteins
  • light chain 3, human
  • Carbonic Anhydrases