Multiple tumor suppressors regulate a HIF-dependent negative feedback loop via ISGF3 in human clear cell renal cancer.

Autor:	Liao L; Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Pennsylvania, United States.; Department of Pathology, Yale University, Connecticut, United States., Liu ZZ; Department of Pathology, Yale University, Connecticut, United States., Langbein L; Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Pennsylvania, United States., Cai W; Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Pennsylvania, United States., Cho EA; Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Pennsylvania, United States.; Fox Chase Cancer Center, Pennsylvania, United States., Na J; Department of Health Sciences Research, Mayo Clinic, Minnesota, United States., Niu X; Department of Gastrointestinal Surgery, The Sixth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China., Jiang W; Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Pennsylvania, United States., Zhong Z; Sidney Kimmel Cancer Center, Thomas Jefferson University, Pennsylvania, United States., Cai WL; Department of Pathology, Yale University, Connecticut, United States., Jagannathan G; Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Pennsylvania, United States., Dulaimi E; Fox Chase Cancer Center, Pennsylvania, United States., Testa JR; Fox Chase Cancer Center, Pennsylvania, United States., Uzzo RG; Fox Chase Cancer Center, Pennsylvania, United States., Wang Y; Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Ohio, United States., Stark GR; Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Ohio, United States., Sun J; Department of Medicine, Thomas Jefferson University, Pennsylvania, United States., Peiper S; Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Pennsylvania, United States., Xu Y; Department of Biostatistics, Vanderbilt University Medical Center, Tennessee, United States.; Department of Biomedical Informatics, Vanderbilt University Medical Center, Tennessee, United States., Yan Q; Department of Pathology, Yale University, Connecticut, United States., Yang H; Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Pennsylvania, United States.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2018 Oct 25; Vol. 7. Date of Electronic Publication: 2018 Oct 25.
DOI:	10.7554/eLife.37925
Abstrakt:	Whereas VHL inactivation is a primary event in clear cell renal cell carcinoma (ccRCC), the precise mechanism(s) of how this interacts with the secondary mutations in tumor suppressor genes, including PBRM1 , KDM5C / JARID1C , SETD2 , and/or BAP1 , remains unclear. Gene expression analyses reveal that VHL, PBRM1, or KDM5C share a common regulation of interferon response expression signature. Loss of HIF2α, PBRM1, or KDM5C in VHL-/- cells reduces the expression of interferon stimulated gene factor 3 (ISGF3), a transcription factor that regulates the interferon signature. Moreover, loss of SETD2 or BAP1 also reduces the ISGF3 level. Finally, ISGF3 is strongly tumor-suppressive in a xenograft model as its loss significantly enhances tumor growth. Conversely, reactivation of ISGF3 retards tumor growth by PBRM1-deficient ccRCC cells. Thus after VHL inactivation, HIF induces ISGF3, which is reversed by the loss of secondary tumor suppressors, suggesting that this is a key negative feedback loop in ccRCC. Competing Interests: LL, ZL, LL, WC, EC, JN, XN, WJ, ZZ, WC, GJ, ED, JT, RU, YW, GS, JS, SP, YX, QY, HY No competing interests declared (© 2018, Liao et al.)
Databáze:	MEDLINE
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