RNA-seq Identification of RACGAP1 as a Metastatic Driver in Uterine Carcinosarcoma.
OBJECTIVE
Uterine carcinosarcoma is a rare aggressive malignancy frequently presenting at advanced stage of disease with extrauterine metastases. Median survival is less than 2 years due to high relapse rates after surgery and poor response to chemotherapy or radiotherapy. The goal of this study was to identify novel therapeutic targets.


METHODS
We applied RNA-seq analysis to prospectively collected uterine carcinosarcoma tumor samples from patients undergoing primary surgical resection and for comparison, normal endometrial tissues from postmenopausal women undergoing hysterectomy for benign indications. Functional assays were done in primary carcinosarcoma cell lines developed from patients and in established cell lines, as well as a cell line-derived xenograft model. Validation was done by analysis of an independent cohort of patients with uterine carcinosarcoma from The Cancer Genome Atlas (TCGA).


RESULTS
Rac GTPase-activating protein 1 (RACGAP1) was identified to be highly upregulated in uterine carcinosarcoma. Functional assays showed that RACGAP1 mediates motility and invasion via regulation of STAT3 phosphorylation and survivin expression. RACGAP1 depletion or survivin inhibition abrogated motility and invasiveness of carcinosarcoma cells, while RACGAP1 overexpression conferred invasiveness to endometrial adenocarcinoma cells. In the TCGA cohort, RACGAP1 expression correlated with survivin expression and extrauterine spread of disease.


CONCLUSIONS
The RACGAP1-STAT3-survivin signaling pathway is required for the invasive phenotype of uterine carcinosarcoma and is a newly identified therapeutic target in this lethal disease. Clin Cancer Res; 22(18); 4676-86. ©2016 AACR.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York.
Shijun
S
Mi
Department of Genetics, Albert Einstein College of Medicine, Bronx, New York.
Mingyan
M
Lin
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York.
Jurriaan
J
Brouwer-Visser
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York.
Jennifer
J
Heim
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York.
David
D
Smotkin
Department of Pathology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York.
Tiffany
T
Hebert
Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France.
Marc J
MJ
Gunter
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York. Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, New York.
Gary L
GL
Goldberg
Department of Genetics, Albert Einstein College of Medicine, Bronx, New York. Departments of Neurology and Neuroscience, Albert Einstein College of Medicine, Bronx, New York.
Deyou
D
Zheng
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York. Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, New York. Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York. ghuang@montefiore.org.
Gloria S
GS
Huang
D000368:Aged; D000369:Aged, 80 and over; D002296:Carcinosarcoma / Q000235:genetics* / Q000473:pathology* / Q000628:therapy; D016022:Case-Control Studies; D002465:Cell Movement; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics*; D015870:Gene Expression; D020869:Gene Expression Profiling; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000077022:Survivin; D059467:Transcriptome; D014594:Uterine Neoplasms / Q000235:genetics* / Q000473:pathology* / Q000628:therapy
C107489:BIRC5 protein, human; D020690:GTPase-Activating Proteins; D051034:Inhibitor of Apoptosis Proteins; D050796:STAT3 Transcription Factor; D000077022:Survivin; C115995:mgcRacGAP