期刊
JOURNAL OF PATHOLOGY
卷 228, 期 4, 页码 437-447出版社
WILEY
DOI: 10.1002/path.4090
关键词
Autophagy; ovarian cancer; ovarian clear cell carcinoma; hypoxia; LC3A; LC3; prognosis; immunohistochemistry; cancer
资金
- CIHR New Investigator Award
- CIHR Operating Grant
- CIHR Emerging Team Grant [GPG 102167]
- British Columbia Cancer Foundation
- Frederick Banting and Charles Best Canada Graduate Scholarship - Master's Award
- Ovarian Cancer Canada Teal Heart Scholarship
- University of Victoria Graduate Fellowship
- University of Victoria Graduate Award
- Cheryl Brown Ovarian Cancer Outcomes Unit of the British Columbia Cancer Agency
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-1 alpha. 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. Copyright (C) 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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