title: The autophagy protein LC3A correlates with hypoxia and is a prognostic marker of patient survival in clear cell ovarian cancer.
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.
authors.affiliation: 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.
authors.forename: Jaeline E
authors.initials: JE
authors.lastname: Spowart
authors.forename: Katelin N
authors.initials: KN
authors.lastname: Townsend
authors.forename: Hassan
authors.initials: H
authors.lastname: Huwait
authors.forename: Sima
authors.initials: S
authors.lastname: Eshragh
authors.forename: Nathan R
authors.initials: NR
authors.lastname: West
authors.forename: Jenna N
authors.initials: JN
authors.lastname: Ries
authors.forename: Steve
authors.initials: S
authors.lastname: Kalloger
authors.forename: Michael
authors.initials: M
authors.lastname: Anglesio
authors.forename: Sharon M
authors.initials: SM
authors.lastname: Gorski
authors.forename: Peter H
authors.initials: PH
authors.lastname: Watson
authors.forename: C Blake
authors.initials: CB
authors.lastname: Gilks
authors.forename: David G
authors.initials: DG
authors.lastname: Huntsman
authors.forename: Julian J
authors.initials: JJ
authors.lastname: Lum
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000502:physiology; D001343:Autophagy / Q000502:physiology*; D015415:Biomarkers / Q000378:metabolism; D002256:Carbonic Anhydrases / Q000378:metabolism; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008875:Middle Aged; D015999:Multivariate Analysis; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D012189:Retrospective Studies
chemical_list: D015415:Biomarkers; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D002256:Carbonic Anhydrases