期刊
ONCOGENE
卷 36, 期 34, 页码 4843-4858出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2017.102
关键词
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资金
- NIH [P01CA098101, K26RR032714]
- American Cancer Society [RP-10-033-01-CCE]
- NIH/NIDDK Center of Molecular Studies in Digestive and Liver Diseases [P30DK050306]
- Molecular Pathology and Imaging, Molecular Biology/Gene Expression, Cell Culture and Mouse Core Facilities
- Pennsylvania Department of Health, Pennsylvania CURE Program Grant
- Ministry of Education, Culture, Sports, Science and Technology of Japan [15K15501, 26293306, 15K10108]
- University of Pennsylvania Center of Excellence in Environmental Toxicology [P30ES013508, K01DK103953, F32CA174176, T32DK007066]
- Japan Society for the Promotion of Science
- Grants-in-Aid for Scientific Research [15K10108, 15K15501, 26293306] Funding Source: KAKEN
High CD44 expression is associated with enhanced malignant potential in esophageal squamous cell carcinoma (ESCC), among the deadliest of all human carcinomas. Although alterations in autophagy and CD44 expression are associated with poor patient outcomes in various cancer types, the relationship between autophagy and cells with high CD44 expression remains incompletely understood. In transformed oesophageal keratinocytes, CD44(Low)-CD24(High) (CD44L) cells give rise to CD44(High)-CD24(-/Low) (CD44H) cells via epithelial-mesenchymal transition (EMT) in response to transforming growth factor (TGF)-beta. We couple patient samples and xenotransplantation studies with this tractable in vitro system of CD44L to CD44H cell conversion to investigate the functional role of autophagy in generation of cells with high CD44 expression. We report that high expression of the autophagy marker cleaved LC3 expression correlates with poor clinical outcome in ESCC. In ESCC xenograft tumours, pharmacological autophagy inhibition with chloroquine derivatives depletes cells with high CD44 expression while promoting oxidative stress. Autophagic flux impairment during EMT-mediated CD44L to CD44H cell conversion in vitro induces mitochondrial dysfunction, oxidative stress and cell death. During CD44H cell generation, transformed keratinocytes display evidence of mitophagy, including mitochondrial fragmentation, decreased mitochondrial content and mitochondrial translocation of Parkin, essential in mitophagy. RNA interference-mediated Parkin depletion attenuates CD44H cell generation. These data suggest that autophagy facilitates EMT-mediated CD44H generation via modulation of redox homeostasis and Parkin-dependent mitochondrial clearance. This is the first report to implicate mitophagy in regulation of tumour cells with high CD44 expression, representing a potential novel therapeutic avenue in cancers where EMT and CD44H cells have been implicated, including ESCC.
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