SHARPIN Promotes Melanoma Progression via Rap1 Signaling Pathway

J Invest Dermatol. 2020 Feb;140(2):395-403.e6. doi: 10.1016/j.jid.2019.07.696. Epub 2019 Aug 8.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged, 80 and over
  • Animals
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Datasets as Topic
  • Disease Progression
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Humans
  • Kaplan-Meier Estimate
  • MAP Kinase Signaling System / drug effects
  • Male
  • Melanoma / mortality
  • Melanoma / pathology*
  • Mice
  • Middle Aged
  • Neoplasm Invasiveness / pathology
  • Prognosis
  • Shelterin Complex
  • Skin / pathology
  • Skin Neoplasms / mortality
  • Skin Neoplasms / pathology*
  • Telomere-Binding Proteins / agonists
  • Telomere-Binding Proteins / antagonists & inhibitors
  • Telomere-Binding Proteins / metabolism*
  • Ubiquitins / genetics
  • Ubiquitins / metabolism*
  • Up-Regulation
  • Xenograft Model Antitumor Assays

Substances

  • SHARPIN protein, human
  • Shelterin Complex
  • TERF2IP protein, human
  • Telomere-Binding Proteins
  • Ubiquitins