Loss Of Cd73 Shifts Transforming Growth Factor-Β1 (Tgf-Β1) From Tumor Suppressor To Promoter In Endometrial Cancer
Adenosine, CD73, Endometrial cancer, TGF-β, Tumor suppressor
In many tumors, CD73 (NT5E), a rate-limiting enzyme in adenosine biosynthesis, is upregulated by TGF-β and drives tumor progression. Conversely, CD73 is downregulated in endometrial carcinomas (EC) despite a TGF-β-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-β1 from tumor suppressor to promoter in EC. TGF-β1 upregulated CD73 and epithelial integrity in vivo in the normal endometrium and in vitro in early stage EC cells. With loss of CD73, TGF-β1-mediated epithelial integrity was abrogated. EC cells developed TGF-β1-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-β1 activity, CD73 loss increased TGF-β1-mediated canonical signaling and upregulated cyclin D1 (CCND1) and downregulated p21 expression. This shift was clinically relevant, as CD73Low/CCND1High 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-β-mediated stress fibers, signaling, and invasiveness, whereby adenosine A1 receptor agonist, CPA, dampened TGF-β-mediated invasion. These data identify CD73 loss as essential for shifting TGF-β activity in EC.
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Kurnit, Katherine C.; Draisey, Ashley; Kazen, Rebecca C.; Chung, Christine; Phan, Luan H.; Harvey, Jerry B.; Feng, Jiping; Xie, Su Su; Broaddus, Russell R.; and Bowser, Jessica L., "Loss Of Cd73 Shifts Transforming Growth Factor-Β1 (Tgf-Β1) From Tumor Suppressor To Promoter In Endometrial Cancer" (2021). Faculty Publications. 75.