SHARPIN overexpression promotes TAK1 expression and activates JNKs and NF-κB pathway in Mycosis Fungoides.

Abstract

Mycosis Fungoides (MF) is the most common subtype of cutaneous T-cell lymphomas (CTCL). Shank-associated RH domain-interacting protein (SHARPIN) participates in the initiation and development of multiple tumors. However, the clinical significance of SHARPIN in MF hasn't been investigated. The c-Jun N-terminal kinases (JNKs) pathway is a member of mitogen-activated protein kinases (MAPKs). Its dysregulation is observed in various tumors including CTCL, whereas the roles of JNKs pathway in MF remain largely unknown, the relationship between SHARPIN and JNKs pathway remains elusive. Herein, we showed that upregulated expression of SHARPIN was related to poor prognosis of MF patients. In vitro experiments found increased SHARPIN expression and activation of JNKs pathway in MF cell line MyLa2059. SHARPIN induced transforming growth factor β activated kinase-1 (TAK1) transcription, which is an upstream kinase of JNKs, NF-κB and p38 pathway, leading to activation of JNKs and NF-κB pathway. SHARPIN also promoted p38 signalling independent of TAK1 expression, by which overexpression of SHARPIN induced cell proliferation, inhibited apoptosis, enhanced migration and invasion of MyLa2059. Our work provided direct evidences for effects of SHARPIN on JNKs and NF-κB pathway, and the contributing roles of JNKs, NF-κB and p38 pathway regulated by SHARPIN in the development of MF.