SHARPIN, as a tumor-associated gene, is involved in the metastatic process of many kinds of tumors. Herein, we studied the function of Shank-associated RH domain interacting protein (SHARPIN) in melanoma metastasis and the relevant molecular mechanisms. We found that SHARPIN expression was increased in melanoma tissues and activated the process of proliferation, migration, and invasion in vitro and in vivo, resulting in a poor prognosis of the disease. Functional analysis demonstrated that SHARPIN promoted melanoma migration and invasion by regulating Ras-associated protein-1(Rap1) and its downstream pathways, including p38 and JNK/c-Jun. Rap1 activator (8-pCPT-2'-O-Me-cAMP) and inhibitor (ESI-09 and farnesylthiosalicylic acid-amide) treatments could partially rescue invasion and migration of tumor cells. Additionally, SHARPIN expression in cell lines and public datasets also indicated that molecules other than BRAF and N-RAS may contribute to SHARPIN activation. In conclusion, our broad-in-depth work suggests that SHARPIN promotes melanoma development via p38 and JNK/c-Jun pathways through upregulation of Rap1 expression.
Summary Background Atopic dermatitis (AD) is a chronic inflammatory skin disease in which T‐helper type 2 (Th2) immune responses are dominant. SH3 and multiple ankyrin repeat domains (SHANK)‐associated RH domain‐interacting protein (SHARPIN) is expressed at low levels in AD, resulting in the upregulation of the signal transducer and activator of transcription (STAT)3 protein and the Th2 cytokine, interleukin (IL)‐33. However, the roles of SHARPIN in AD are not yet fully elucidated. Aim To evaluate the signalling interactions of SHARPIN and IL‐33 in order to improve understanding of AD pathogenesis. Methods Western blotting was used to detect the Janus kinase (JAK)/STAT signalling proteins and IL‐33 protein in HaCaT cells to determine the key proteins mediating the interaction between SHARPIN and IL‐33. The findings were validated by immunofluorescence and immunohistochemical staining. Chromatin immunoprecipitation assays were used to evaluate the activity of STAT3 at the IL‐33 promoter. Results We found that phosphorylated (p)JAK2 and pSTAT3 were upregulated in SHARPIN‐knockdown HaCaT cells. Subsequent chromatin immunoprecipitation assays revealed that STAT3 binds to the IL‐33 promoter to mediate IL‐33 expression. Moreover, SHARPIN‐mediated expression of IL‐33 was reduced after treatment of HaCaT cells with the JAK/STAT inhibitor ruxolitinib. STAT3 and IL‐33 expression levels were higher in AD skin lesion tissues than in normal skin tissues. Conclusion These findings suggest that SHARPIN modulates inflammation in HaCaT cells by inhibiting JAK/STAT signalling, supporting the application of SHARPIN as a potential therapeutic target for AD.
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