FGFR4 promotes nuclear localization of GABP to inhibit cell apoptosis in uterine leiomyosarcoma
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REGULAR ARTICLE
FGFR4 promotes nuclear localization of GABP to inhibit cell apoptosis in uterine leiomyosarcoma Pei Zhang1 · Hengliang Zhang2 · Yan Wang1 Received: 18 December 2019 / Accepted: 14 September 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Fibroblast growth factor receptor 4 (FGFR4) has been indicated as a potential “oncogene” in various types of cancer. However, the effects and underlying mechanisms of FGFR4 on uterine leiomyosarcoma (ULMS) progression remain unclear. In this study, we firstly discovered that FGFR4 was upregulated in ULMS specimens and cell lines and closely associated with poor prognosis of ULMS patients. Cell viability and apoptosis assays showed that FGFR4 deletion inhibited cell proliferation and promoted cell apoptosis. Moreover, FGFR4 silence increased cytoplasmic GABP (GA binding protein) expression, while it decreased the nuclear GABP level to inhibit nuclear localization of GABP. Mechanistically, the inhibition ability of FGFR4 silence on nuclear localization of GABP was mediated via mammalian Ste20-like kinases 1 (MST1) activation, which could promote phosphorylation of large tumor suppressor 1 (LATS1) to reduce nuclear localization of GABP. Gain- and loss-of-functional assays indicated that FGFR4 promoted nuclear localization of GABP to inhibit cell apoptosis in ULMS. In conclusion, our findings indicated that FGFR4 inhibited cell apoptosis in ULMS via the promotion of MST1/LATS1mediated GABP nuclear localization, shedding light on the underlying mechanism of FGFR4-induced ULMS progression. Keywords FGFR4 · MST1 · LATS1 · GABP · Nuclear localization · Uterine leiomyosarcoma
Introduction Uterine cancer ranks as the fourth most common tumor in women (Kuehn 2019; Tse and Ngan 2018). Uterine sarcomas, a rare type of female reproductive system malignant tumor, accounts for 5% of uterine cancer incidence (D’Angelo and Prat 2010). Among uterine sarcomas, ULMS (uterine leiomyosarcoma), a smooth muscle tumor, accounts for 30% of uterine sarcomas and 1% of all uterine malignancies (Valzacchi et al. 2019). Unfortunately, as radiotherapy and chemotherapy exhibited little effects on ULMS, surgical resection become a preferable treatment method (Reichardt
* Pei Zhang [email protected] 1
Department of Gynaecology, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, No. 24, Jinghua Road, Henan Province 471000 Luoyang City, China
Department of Cardiology, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Henan Province 471000 Luoyang City, China
2
2012). However, the 5-year overall survival rate is lower than 25% (Yasutake et al. 2018) due high to metastasis in lungs (Eskander et al. 2012). Therefore, it is urgent to identify novel targets and develop effective therapeutic strategies, which have been considered as prioritized tasks in current ULMS research. Tumor cells rely on receptor tyrosine kinases (RTKs) to send carcinogeni
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