Amplification of FRS2 and activation of FGFR/FRS2 signaling pathway in high-grade liposarcoma

Keqiang Zhang, Kevin Chu, Xiwei Wu, Hanlin Gao, Jinhui Wang, Yate Ching Yuan, Sofia Loera, Kimberley Ho, Yafan Wang, Warren Chow, Frank Un, Peiguo Chu, Yun Yen

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Abstract

Fibroblast growth factor (FGF) receptor (FGFR) substrate 2 (FRS2) is an adaptor protein that plays a critical role in FGFR signaling. FRS2 is located on chromosome 12q13-15 that is frequently amplified in liposarcomas. The significance of FRS2 and FGFR signaling in high-grade liposarcomas is unknown. Herein, we first comparatively examined the amplification and expression of FRS2 with CDK4 andMDM2in dedifferentiated liposarcoma (DDLS) and undifferentiated high-grade pleomorphic sarcoma (UHGPS). Amplification and expression of the three genes were identified in 90% to 100% (9-11 of 11) of DDLS, whereas that of FRS2, CDK4, andMDM2were observed in 55% (41 of 75), 48% (36 of 75), and 44% (33/75) of clinically diagnosed UHGPS, suggesting that these UHGPS may represent DDLS despite lacking histologic evidence of lipoblasts. Immunohistochemical analysis of phosphorylated FRS2 protein indicated that the FGFR/FRS2 signaling axis was generally activated in about 75% of FRS2- positive high-grade liposarcomas. Moreover, we found that FRS2 and FGFRs proteins are highly expressed and functional in three high-grade liposarcoma cell lines: FU-DDLS-1, LiSa-2, and SW872. Importantly, the FGFR selective inhibitor NVP-BGJ-398 significantly inhibited the growth of FU-DDLS-1 and LiSa-2 cells with a concomitant suppression of FGFR signal transduction. Attenuation of FRS2 protein in FU-DDLS-1 and LiSa-2 cell lines decreased the phosphorylated extracellular signal-regulated kinase 1/2 and AKT and repressed cell proliferation. These findings indicate that analysis of FRS2 in combination with CDK4 and MDM2 will more accurately characterize pathologic features of high-grade liposarcomas. Activated FGFR/FRS2 signaling may play a functional role in the development of high-grade liposarcomas, therefore, serve as a potential therapeutic target.

Original languageEnglish
Pages (from-to)1298-1307
Number of pages10
JournalCancer Research
Volume73
Issue number4
DOIs
Publication statusPublished - Jan 15 2013

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Fibroblast Growth Factor Receptors
Liposarcoma
Sarcoma
Proteins
Receptor, Fibroblast Growth Factor, Type 2
Chromosomes, Human, Pair 15
Cell Line
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Signal Transduction

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Amplification of FRS2 and activation of FGFR/FRS2 signaling pathway in high-grade liposarcoma. / Zhang, Keqiang; Chu, Kevin; Wu, Xiwei; Gao, Hanlin; Wang, Jinhui; Yuan, Yate Ching; Loera, Sofia; Ho, Kimberley; Wang, Yafan; Chow, Warren; Un, Frank; Chu, Peiguo; Yen, Yun.

In: Cancer Research, Vol. 73, No. 4, 15.01.2013, p. 1298-1307.

Research output: Contribution to journalArticle

Zhang, K, Chu, K, Wu, X, Gao, H, Wang, J, Yuan, YC, Loera, S, Ho, K, Wang, Y, Chow, W, Un, F, Chu, P & Yen, Y 2013, 'Amplification of FRS2 and activation of FGFR/FRS2 signaling pathway in high-grade liposarcoma', Cancer Research, vol. 73, no. 4, pp. 1298-1307. https://doi.org/10.1158/0008-5472.CAN-12-2086
Zhang, Keqiang ; Chu, Kevin ; Wu, Xiwei ; Gao, Hanlin ; Wang, Jinhui ; Yuan, Yate Ching ; Loera, Sofia ; Ho, Kimberley ; Wang, Yafan ; Chow, Warren ; Un, Frank ; Chu, Peiguo ; Yen, Yun. / Amplification of FRS2 and activation of FGFR/FRS2 signaling pathway in high-grade liposarcoma. In: Cancer Research. 2013 ; Vol. 73, No. 4. pp. 1298-1307.
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abstract = "Fibroblast growth factor (FGF) receptor (FGFR) substrate 2 (FRS2) is an adaptor protein that plays a critical role in FGFR signaling. FRS2 is located on chromosome 12q13-15 that is frequently amplified in liposarcomas. The significance of FRS2 and FGFR signaling in high-grade liposarcomas is unknown. Herein, we first comparatively examined the amplification and expression of FRS2 with CDK4 andMDM2in dedifferentiated liposarcoma (DDLS) and undifferentiated high-grade pleomorphic sarcoma (UHGPS). Amplification and expression of the three genes were identified in 90{\%} to 100{\%} (9-11 of 11) of DDLS, whereas that of FRS2, CDK4, andMDM2were observed in 55{\%} (41 of 75), 48{\%} (36 of 75), and 44{\%} (33/75) of clinically diagnosed UHGPS, suggesting that these UHGPS may represent DDLS despite lacking histologic evidence of lipoblasts. Immunohistochemical analysis of phosphorylated FRS2 protein indicated that the FGFR/FRS2 signaling axis was generally activated in about 75{\%} of FRS2- positive high-grade liposarcomas. Moreover, we found that FRS2 and FGFRs proteins are highly expressed and functional in three high-grade liposarcoma cell lines: FU-DDLS-1, LiSa-2, and SW872. Importantly, the FGFR selective inhibitor NVP-BGJ-398 significantly inhibited the growth of FU-DDLS-1 and LiSa-2 cells with a concomitant suppression of FGFR signal transduction. Attenuation of FRS2 protein in FU-DDLS-1 and LiSa-2 cell lines decreased the phosphorylated extracellular signal-regulated kinase 1/2 and AKT and repressed cell proliferation. These findings indicate that analysis of FRS2 in combination with CDK4 and MDM2 will more accurately characterize pathologic features of high-grade liposarcomas. Activated FGFR/FRS2 signaling may play a functional role in the development of high-grade liposarcomas, therefore, serve as a potential therapeutic target.",
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AU - Zhang, Keqiang

AU - Chu, Kevin

AU - Wu, Xiwei

AU - Gao, Hanlin

AU - Wang, Jinhui

AU - Yuan, Yate Ching

AU - Loera, Sofia

AU - Ho, Kimberley

AU - Wang, Yafan

AU - Chow, Warren

AU - Un, Frank

AU - Chu, Peiguo

AU - Yen, Yun

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N2 - Fibroblast growth factor (FGF) receptor (FGFR) substrate 2 (FRS2) is an adaptor protein that plays a critical role in FGFR signaling. FRS2 is located on chromosome 12q13-15 that is frequently amplified in liposarcomas. The significance of FRS2 and FGFR signaling in high-grade liposarcomas is unknown. Herein, we first comparatively examined the amplification and expression of FRS2 with CDK4 andMDM2in dedifferentiated liposarcoma (DDLS) and undifferentiated high-grade pleomorphic sarcoma (UHGPS). Amplification and expression of the three genes were identified in 90% to 100% (9-11 of 11) of DDLS, whereas that of FRS2, CDK4, andMDM2were observed in 55% (41 of 75), 48% (36 of 75), and 44% (33/75) of clinically diagnosed UHGPS, suggesting that these UHGPS may represent DDLS despite lacking histologic evidence of lipoblasts. Immunohistochemical analysis of phosphorylated FRS2 protein indicated that the FGFR/FRS2 signaling axis was generally activated in about 75% of FRS2- positive high-grade liposarcomas. Moreover, we found that FRS2 and FGFRs proteins are highly expressed and functional in three high-grade liposarcoma cell lines: FU-DDLS-1, LiSa-2, and SW872. Importantly, the FGFR selective inhibitor NVP-BGJ-398 significantly inhibited the growth of FU-DDLS-1 and LiSa-2 cells with a concomitant suppression of FGFR signal transduction. Attenuation of FRS2 protein in FU-DDLS-1 and LiSa-2 cell lines decreased the phosphorylated extracellular signal-regulated kinase 1/2 and AKT and repressed cell proliferation. These findings indicate that analysis of FRS2 in combination with CDK4 and MDM2 will more accurately characterize pathologic features of high-grade liposarcomas. Activated FGFR/FRS2 signaling may play a functional role in the development of high-grade liposarcomas, therefore, serve as a potential therapeutic target.

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