STAT3 and HIF1 signaling drives oncogenic cellular phenotypes in malignant peripheral nerve sheath tumors

Rad, Ellie, Dodd, Kayleigh M., Thomas, Laura E. ORCID: https://orcid.org/0000-0002-8621-5285, Upadhyaya, Meena and Tee, Andrew ORCID: https://orcid.org/0000-0002-5577-4631 2015. STAT3 and HIF1 signaling drives oncogenic cellular phenotypes in malignant peripheral nerve sheath tumors. Molecular Cancer Research 13 (7) , p. 1149. 10.1158/1541-7786.MCR-14-0182

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Abstract

Therapeutic options are limited for neurofibromatosis type 1 (NF1)-associated malignant peripheral nerve sheath tumors (MPNST) and clinical trials using drug agents have so far been unsuccessful. This lack of clinical success is likely attributed to high levels of intratumoral molecular heterogeneity and variations in signal transduction within MPNSTs. To better explore the variance of malignant signaling properties within heterogeneous MPNSTs, four MPNST cell lines (ST8814, S462, S1844.1, and S1507.2) were used. The data demonstrate that small-molecule inhibition of the MET proto-oncogene and mTOR had variable outcome when preventing wound healing, cell migration, and invasion, with the S462 cells being highly resistant to both. Of interest, targeted inhibition of the STAT3 transcription factor suppressed wound healing, cell migration, invasion, and tumor formation in all four MPNST lines, which demonstrates that unlike MET and mTOR, STAT3 functions as a common driver of tumorigenesis in NF1-MPNSTs. Of clinical importance, STAT3 knockdown was sufficient to block the expression of hypoxia-inducible factor (HIF)1α, HIF2α, and VEGF-A in all four MPNST lines. Finally, the data demonstrate that wound healing, cell migration, invasion, and tumor formation through STAT3 are highly dependent on HIF signaling, where knockdown of HIF1α ablated these oncogenic facets of STAT3.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Publisher:	American Association for Cancer Research
ISSN:	1541-7786
Date of First Compliant Deposit:	7 April 2016
Last Modified:	16 Nov 2024 19:45
URI:	https://orca.cardiff.ac.uk/id/eprint/77300

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