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Cancer Med. 2019 Sep;8(11):5232-5241. doi: 10.1002/cam4.2386. Epub 2019 Jul 6.

TYK2 promotes malignant peripheral nerve sheath tumor progression through inhibition of cell death.

Author information

1
Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.
2
School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China.
3
Siteman Cancer Center, Washington University School of Medicine, Saint Louis, Missouri.
4
Cancer Center Biostatistics Shared Resource, Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.

Abstract

BACKGROUND:

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas that arise most commonly in the setting of the Neurofibromatosis Type 1 (NF1) cancer predisposition syndrome. Despite aggressive multimodality therapy, outcomes are dismal and most patients die within 5 years of diagnosis. Prior genomic studies in our laboratory identified tyrosine kinase 2 (TYK2) as a frequently mutated gene in MPNST. Herein, we explored the function of TYK2 in MPNST pathogenesis.

METHODS:

Immunohistochemistry was utilized to examine expression of TYK2 in MPNSTs and other sarcomas. To establish a role for TYK2 in MPNST pathogenesis, murine and human TYK2 knockdown and knockout cells were established using shRNA and CRISPR/Cas9 systems, respectively.

RESULTS:

We have demonstrated that TYK2 was highly expressed in the majority of human MPNSTs examined. Additionally, we demonstrated that knockdown of Tyk2/TYK2 in murine and human MPNST cells significantly increased cell death in vitro. These effects were accompanied by a decrease in the levels of activated Stats and Bcl-2 as well as an increase in the levels of Cleaved Caspase-3. In addition, Tyk2-KD cells demonstrated impaired growth in subcutaneous and metastasis models in vivo.

CONCLUSION:

Taken together, these data illustrate the importance of TYK2 in MPNST pathogenesis and suggest that the TYK2 pathway may be a potential therapeutic target for these deadly cancers.

KEYWORDS:

MPNST; TYK2; cancer; sarcoma

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