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Mol Cancer Res. 2019 Jun;17(6):1294-1304. doi: 10.1158/1541-7786.MCR-18-0963. Epub 2019 Feb 18.

MCL1 and DEDD Promote Urothelial Carcinoma Progression.

Author information

1
Boston Children's Hospital, Boston, Massachusetts.
2
Dana-Farber Cancer Institute, Boston, Massachusetts.
3
Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
4
Brigham and Women's Hospital, Boston, Massachusetts.
5
Memorial Sloan Kettering Cancer Center, New York, New York.
6
Weill Cornell Medical College, New York, New York.
7
Dana-Farber Cancer Institute, Boston, Massachusetts. william_hahn@dfci.harvard.edu.
#
Contributed equally

Abstract

Focal amplification of chromosome 1q23.3 in patients with advanced primary or relapsed urothelial carcinomas is associated with poor survival. We interrogated chromosome 1q23.3 and the nearby focal amplicon 1q21.3, as both are associated with increased lymph node disease in patients with urothelial carcinoma. Specifically, we assessed whether the oncogene MCL1 that resides in 1q21.3 and the genes that reside in the 1q23.3 amplicon were required for the proliferation or survival of urothelial carcinoma. We observed that suppressing MCL1 or the death effector domain-containing protein (DEDD) in the cells that harbor amplifications of 1q21.3 or 1q23.3, respectively, inhibited cell proliferation. We also found that overexpression of MCL1 or DEDD increased anchorage independence growth in vitro and increased experimental metastasis in vivo in the nonamplified urothelial carcinoma cell line, RT112. The expression of MCL1 confers resistance to a range of apoptosis inducers, while the expression of DEDD led to resistance to TNFα-induced apoptosis. These observations identify MCL1 and DEDD as genes that contribute to aggressive urothelial carcinoma. IMPLICATIONS: These studies identify MCL1 and DEDD as genes that contribute to aggressive urothelial carcinomas.

PMID:
30777879
PMCID:
PMC6548646
[Available on 2020-06-01]
DOI:
10.1158/1541-7786.MCR-18-0963

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