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The autophagy protein LC3A correlates with hypoxia and is a prognostic marker of patient survival in clear cell ovarian cancer
Author(s) -
Spowart Jaeline E,
Townsend Katelin N,
Huwait Hassan,
Eshragh Sima,
West Nathan R,
Ries Jen,
Kalloger Steve,
Anglesio Michael,
Gorski Sharon M,
Watson Peter H,
Gilks C Blake,
Huntsman David G,
Lum Julian J
Publication year - 2012
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.4090
Subject(s) - autophagy , serous fluid , ovarian cancer , hypoxia (environmental) , biology , cancer research , clear cell , programmed cell death , tumor hypoxia , medicine , cancer , pathology , oncology , apoptosis , immunohistochemistry , immunology , radiation therapy , chemistry , biochemistry , organic chemistry , oxygen
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 α . 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 © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.