期刊
CANCER LETTERS
卷 505, 期 -, 页码 75-86出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2021.01.030
关键词
CD73; Adenosine; TGF-beta; Tumor suppressor; Endometrial cancer
类别
资金
- National Institutes of Health [P50CA098258, TL1RR024147]
- Lupe C. Garcia Fellowship in Cancer Research
- Interdisciplinary Translational Education and Research Training Program Fellowship in the Department of Translational Molecular Pathology, MD Anderson Cancer Center
- International Anesthesia Research Society Mentored Research Award
- Cancer Prevention & Research Institute of Texas (CPRIT) CURE Summer Research Experience Awards [RP140106, RP170067]
- University of Texas McGovern Medical School Dean's Office Stipend Award
The loss of CD73 in endometrial carcinomas shifts the activity of TGF-beta from tumor suppressor to promoter, affecting cell functions and invasiveness.
In many tumors, CD73 (NT5E), a rate-limiting enzyme in adenosine biosynthesis, is upregulated by TGF-beta and drives tumor progression. Conversely, CD73 is downregulated in endometrial carcinomas (EC) despite a TGF beta-rich environment. Through gene expression analyses of normal endometrium samples of the uterine cancer TCGA data set and genetic and pharmacological studies, we discovered CD73 loss shifts TGF-beta 1 from tumor suppressor to promoter in EC. TGF-beta 1 upregulated CD73 and epithelial integrity in vivo in the normal endometrium and in vitro in early stage EC cells. With loss of CD73, TGF-beta 1-mediated epithelial integrity was abrogated. EC cells developed TGF-beta 1-mediated stress fibers and macromolecule permeability, migration, and invasion increased. In human tumors, CD73 is downregulated in deeply invasive stage I EC. Consistent with shifting TGF-beta 1 activity, CD73 loss increased TGF-beta 1-mediated canonical signaling and upregulated cyclin D1 (CCND1) and downregulated p21 expression. This shift was clinically relevant, as CD73(Low)/CCND1(High) expression associated with poor tumor differentiation, increased myometrial and lymphatic/vascular space invasion, and patient death. Further loss of CD73 in CD73Low expressing advanced stage EC cells increased TGF-beta-mediated stress fibers, signaling, and invasiveness, whereby adenosine A1 receptor agonist, CPA, dampened TGF beta-mediated invasion. These data identify CD73 loss as essential for shifting TGF-beta activity in EC.
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