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

The autophagy protein LC3A correlates with hypoxia and is a prognostic marker of patient survival in clear cell ovarian cancer.

Author information

1
Deeley Research Centre, BC Cancer Agency, Victoria, BC, Canada; Department of Biochemistry and Microbiology, University of Victoria, BC, Canada; Canadian Institutes of Health Research Team in Investigating Autophagy Proteins as Molecular Targets for Cancer Treatments, Simon Fraser University, BC, Canada.

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

PMID:
22926683
DOI:
10.1002/path.4090
[Indexed for MEDLINE]

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