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Int J Biol Sci 2023; 19(12):3920-3936. doi:10.7150/ijbs.83467 This issue Cite

Research Paper

PAK1 overexpression promotes myxofibrosarcoma angiogenesis through STAT5B-mediated CSF2 transactivation: clinical and therapeutic relevance of amplification and nuclear entry

Chien-Feng Li1,2,3, Ti-Chun Chan1,2, Fu-Min Fang4, Shih-Chen Yu5, Hsuan-Ying Huang5✉

1. Department of Medical Research, Chi-Mei Medical Center, Tainan, Taiwan.
2. National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.
3. Institute of Precision Medicine, National Sun Yat-sen University, Kaohsiung, Taiwan.
4. Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
5. Department of Anatomic Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.

✉ Corresponding author: Hsuan-Ying Huang, M.D, Department of Anatomic Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123, Ta-Pei Rd., Niao-Sung District, Kaohsiung City, Taiwan. e-mail: a120600310com, Tel: 011-886-7-7317123-2537, Fax: 011-886-7-7333198. More

Citation:
Li CF, Chan TC, Fang FM, Yu SC, Huang HY. PAK1 overexpression promotes myxofibrosarcoma angiogenesis through STAT5B-mediated CSF2 transactivation: clinical and therapeutic relevance of amplification and nuclear entry. Int J Biol Sci 2023; 19(12):3920-3936. doi:10.7150/ijbs.83467. https://www.ijbs.com/v19p3920.htm
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Abstract

Graphic abstract

Myxofibrosarcoma is genetically complex without established nonsurgical therapies. In public datasets, PAK1 was recurrently gained with mRNA upregulation. Using myxofibrosarcoma cells, we explored the oncogenic underpinning of PAK1 with genetic manipulation and a pan-PAK inhibitor (PF3758309). Myxofibrosarcoma specimens were analyzed for the levels of PAK1, phospho-PAKT423, CSF2 and microvascular density (MVD) and those of PAK1 gene and mRNA. PAK1-expressing xenografts were assessed for the effects of PF3758309 and CSF2 silencing. Besides pro-proliferative and pro-migrator/pro-invasive attributes, PAK1 strongly enhanced angiogenesis in vitro, which, not phenocopied by PAK2-4, was identified as CSF2-mediated using antibody arrays. PAK1 underwent phosphorylation at tyrosines153,201,285 and threonine423 to facilitate nuclear entry, whereby nuclear PAK1 bound STAT5B to co-transactivate the CSF2 promoter, increasing CSF2 secretion needed for angiogenesis. Angiogenesis driven by PAK1-upregulated CSF2 was negated by CSF2 silencing, anti-CSF2, and PF3758309. Clinically, overexpressed whole-cell phospho-PAKT423, related to PAK1 amplification, was associated with increased grades, stages, and PAK1 mRNA, higher MVD, and CSF2 overexpression. Overexpressed whole-cell phospho-PAKT423 and CSF2 independently portended shorter metastasis-free survival and disease-specific survival, respectively. In vivo, both CSF2 silencing and PF3758309 suppressed PAK1-driven tumor proliferation and angiogenesis. Conclusively, the nuclear entry of overexpressed/activated PAK1 endows myxofibrosarcomas with pro-angiogenic function, highlighting the vulnerable PAK1/STAT5B/CSF2 regulatory axis.

Keywords: myxofibrosarcoma, PAK1, nuclear entry, STAT5B, CSF2, angiogenesis

Citation styles

APA
Li, C.F., Chan, T.C., Fang, F.M., Yu, S.C., Huang, H.Y. (2023). PAK1 overexpression promotes myxofibrosarcoma angiogenesis through STAT5B-mediated CSF2 transactivation: clinical and therapeutic relevance of amplification and nuclear entry. International Journal of Biological Sciences, 19(12), 3920-3936. https://doi.org/10.7150/ijbs.83467.

ACS
Li, C.F.; Chan, T.C.; Fang, F.M.; Yu, S.C.; Huang, H.Y. PAK1 overexpression promotes myxofibrosarcoma angiogenesis through STAT5B-mediated CSF2 transactivation: clinical and therapeutic relevance of amplification and nuclear entry. Int. J. Biol. Sci. 2023, 19 (12), 3920-3936. DOI: 10.7150/ijbs.83467.

NLM
Li CF, Chan TC, Fang FM, Yu SC, Huang HY. PAK1 overexpression promotes myxofibrosarcoma angiogenesis through STAT5B-mediated CSF2 transactivation: clinical and therapeutic relevance of amplification and nuclear entry. Int J Biol Sci 2023; 19(12):3920-3936. doi:10.7150/ijbs.83467. https://www.ijbs.com/v19p3920.htm

CSE
Li CF, Chan TC, Fang FM, Yu SC, Huang HY. 2023. PAK1 overexpression promotes myxofibrosarcoma angiogenesis through STAT5B-mediated CSF2 transactivation: clinical and therapeutic relevance of amplification and nuclear entry. Int J Biol Sci. 19(12):3920-3936.

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