SHARPIN is an important component of the linear ubiquitin chain assembly complex (LUBAC). Loss of function of SHARPIN results in eosinophilic inflammation in multiple organs including skin with Th -dominant cytokines and dysregulated development of lymphoid tissues in mice. The clinicopathological features are similar to atopic dermatitis (AD) in humans. In order to investigate the potential role of SHARPIN in the pathogenesis of AD, we performed genetic association study of the genotypes and haplotypes as well as SHARPIN's expression between AD cases and controls. We found three mutations (g.480G>A, g.4576A>G and g.5070C>T) in patient group, and significantly decreased expression in AD lesions, suggesting a primary role of SHARPIN during AD development. Lentivirus-mediated in vitro assays identified that knockdown of SHARPIN can induce elevated expression of IL-33 and its orphan receptor ST2, FLG and STAT3 and NF-κB inactivation in HaCaT keratinocytes, which has been widely evidenced in regulating AD development. ST2 expression was highly induced in SHARPIN-silenced HaCaT keratinocytes after the combined stimulation of IL-4 and IL-13. Our in vivo and in vitro findings implicated that SHARPIN may be a novel participant in the pathogenesis and/or new therapeutic target of AD.

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.

SHanK-associated rH domain-interacting protein (SHarPin) is a component of the linear ubiquitin chain assembly complex that can enhance the nF-κB and JnK signaling pathways, acting as a tumor-associated protein in a variety of cancer types. The present study investigated the role of SHarPin in cutaneous basal cell carcinoma (Bcc). Human Bcc (n=26) and normal skin (n=5) tissues, and Bcc (Te354.T) and normal skin (HacaT) cell lines were used to evaluate SHarPin expression level using immunohistochemistry and western blotting, respectively. a lentivirus carrying SHarPin-targeting or negative control short hairpin rna was infected into Te354.T cells, and the infected stable cells were assayed to analyze tumor cell proliferation, cell cycle, apoptosis, migration and invasion by cell counting Kit-8 and 5-ethynyl-2'-deoxyuridine incorporation assays, flow cytometry and Transwell assays. Western blotting was performed to assess the protein expression levels of gene signaling in SHarPin-silenced Bcc cells. SHarPin protein expression levels were downregulated or absent in Bcc cancer nests and precancerous lesions compared with normal skin samples. in addition, SHarPin expression levels were lower in Te354.T cells compared with HacaT cells. SHarPin shrna enhanced tumor cell proliferation and the S phase of the cell cycle, whereas Bcc cell apoptotic rates, and migratory and invasive abilities were not significantly altered. The expression levels of cyclin d1, cyclin-dependent kinase 4, phosphorylated-c-Jun and GLI family zinc finger 2 proteins were increased, whereas Patched 1 (PTcH1) and PTcH2 were decreased in the SHarPin-shrna-infected Bcc cells. Therefore, the present results suggested that SHarPin may act as a tumor suppressor during Bcc development. SHARPIN regulates cell proliferation of cutaneous basal cell carcinoma via inactivation of the transcriptional factors GLI2 and c-JUN

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