RNA-seq Identification of RACGAP1 as a Metastatic Driver in Uterine Carcinosarcoma

Mi, Shijun; Lin, Mingyan; Brouwer‐Visser, Jurriaan; Heim, Jennifer; Smotkin, David; Hébert, Tiffany; Gunter, Marc J.; Goldberg, Gary L.; Zheng, Deyou; Huang, Gloria S.

doi:10.1158/1078-0432.ccr-15-2116

Cited by 37 publications

(37 citation statements)

References 36 publications

(38 reference statements)

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“…The remarkable complexity of Rac-GAP function is also well illustrated by studies showing a pro-tumorigenic function for RacGAP1 (MgcRacGAP), whose elevated expression has been linked with aggressiveness in several human cancers and has been recently identified as a metastatic driver in uterine carcinosarcoma (53). Similarly, high expression of the Rac/Cdc42 GAP CdGAP correlates with poor prognosis in breast cancer patients, and its expression is particularly elevated in the basal breast cancer subtype.…”

Section: Emerging Paradigms In Rho Gtpase Hyperactivation In Cancermentioning

confidence: 99%

The Rac GTPase in Cancer: From Old Concepts to New Paradigms

2017

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Rho family GTPases are critical regulators of cellular functions that play important roles in cancer progression. Aberrant activity of Rho small G-proteins, particularly Rac1 and their regulators, is a hallmark of cancer, and contributes to the tumorigenic and metastatic phenotypes of cancer cells. This review examines the multiple mechanisms leading to Rac1 hyperactivation, particularly focusing on emerging paradigms that involve gain-of-function mutations in Rac and guanine nucleotide exchange factors (GEFs), defects in Rac1 degradation, and mislocalization of Rac signaling components. The unexpected pro-oncogenic functions of Rac GTPase activating proteins (GAPs) also challenged the dogma that these negative Rac regulators solely act as tumor suppressors. The potential contribution of Rac hyperactivation to resistance to anti-cancer agents, including targeted therapies, as well as to the suppression of anti-tumor immune response, highlights the critical need to develop therapeutic strategies to target the Rac pathway in a clinical setting.

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Section: Emerging Paradigms In Rho Gtpase Hyperactivation In Cancermentioning

confidence: 99%

The Rac GTPase in Cancer: From Old Concepts to New Paradigms

2017

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“…In fact, several studies have reported the importance of analyzing tissues at relapse,88, 89 and clinical trials such as MAPPYACTS (molecular profiling for pediatric and young adult cancer treatment stratification) conducted in our institute will contribute to this investigation (NCT02613962). The study of patients’ genomic patterns at relapse could lead to better knowledge of cancer-driving and resistance mechanisms but could also allow better classification of patients.…”

Section: Main Textmentioning

confidence: 99%

Relevance of Fusion Genes in Pediatric Cancers: Toward Precision Medicine

Dupain

Harttrampf

Urbinati

et al. 2017

Molecular Therapy - Nucleic Acids

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Pediatric cancers differ from adult tumors, especially by their very low mutational rate. Therefore, their etiology could be explained in part by other oncogenic mechanisms such as chromosomal rearrangements, supporting the possible implication of fusion genes in the development of pediatric cancers. Fusion genes result from chromosomal rearrangements leading to the juxtaposition of two genes. Consequently, an abnormal activation of one or both genes is observed. The detection of fusion genes has generated great interest in basic cancer research and in the clinical setting, since these genes can lead to better comprehension of the biological mechanisms of tumorigenesis and they can also be used as therapeutic targets and diagnostic or prognostic biomarkers. In this review, we discuss the molecular mechanisms of fusion genes and their particularities in pediatric cancers, as well as their relevance in murine models and in the clinical setting. We also point out the difficulties encountered in the discovery of fusion genes. Finally, we discuss future perspectives and priorities for finding new innovative therapies in childhood cancer.

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“…Mechanistically, Rac GTPase activating protein 1 ( RACGAP1 ) was identified as a direct target gene of miR‐4324. As a GTPase activating protein, RACGAP1 was originally identified in testis and male germ cells . RACGAP1 has been reported to be an essential regulator in several cancers, including uterine carcinosarcoma, hepatocellular carcinoma, and breast cancer, and it is linked to aggressive clinical behavior.…”

Section: Introductionmentioning

confidence: 99%

“…As a GTPase activating protein, RACGAP1 was originally identified in testis and male germ cells. 9,10 RACGAP1 has been reported to be an essential regulator in several cancers, including uterine carcinosarcoma, 9 hepatocellular carcinoma, 11 and breast cancer, 12 and it is linked to aggressive clinical behavior. However, the involvement of RACGAP1 in BCa has not yet been investigated.…”

Section: Introductionmentioning

confidence: 99%

miR‐4324‐RACGAP1‐STAT3‐ESR1 feedback loop inhibits proliferation and metastasis of bladder cancer

Lü

et al. 2019

Intl Journal of Cancer

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Considering the importance of microRNAs (miRNAs) in regulating cellular processes, we performed microarray analysis and revealed miR‐4324 as one of the most differentially expressed miRNAs in bladder cancer (BCa). Then, we discovered that miR‐4324 was a negative regulator of Rac GTPase activating protein 1 (RACGAP1) and that RACGAP1 functioned as an oncogenic protein in BCa. Our studies indicated that ectopic overexpression of miR‐4324 in BCa cells significantly suppressed cell proliferation and metastasis and enhanced chemotherapy sensitivity to doxorubicin by repressing RACGAP1 expression. Further studies showed that estrogen receptor 1 (ESR1) increased the expression of miR‐4324 by binding to its promoter, while the downregulation of ESR1 in BCa was caused by hypermethylation of its promoter. p‐STAT3 induced the enrichment of DNMT3B by binding to the ESR1 promoter and then induced methylation of the ESR1 promoter. In turn, RACGAP1 induced STAT3 phosphorylation, increasing p‐STAT3 expression and promoting its translocation to the nucleus. Therefore, the miR‐4324‐RACGAP1‐STAT3‐ESR1 feedback loop could be a critical regulator of BCa progression.

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RNA-seq Identification of RACGAP1 as a Metastatic Driver in Uterine Carcinosarcoma

Abstract: 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.

Cited by 37 publications

References 36 publications

The Rac GTPase in Cancer: From Old Concepts to New Paradigms

The Rac GTPase in Cancer: From Old Concepts to New Paradigms

Relevance of Fusion Genes in Pediatric Cancers: Toward Precision Medicine

miR‐4324‐RACGAP1‐STAT3‐ESR1 feedback loop inhibits proliferation and metastasis of bladder cancer

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