Immunohistochemical analysis of T-type calcium channels in acquired melanocytic naevi and melanoma

Br J Dermatol. 2017 May;176(5):1247-1258. doi: 10.1111/bjd.15121. Epub 2017 Mar 20.

Abstract

Background: Cutaneous malignant melanoma arises from transformed melanocytes de novo or from congenital or acquired melanocytic naevi. We have recently reported that T-type Ca2+ channels (TT-Cs) are upregulated in human melanoma and play an important role in cell proliferation.

Objectives: To describe for the first time in formalin-fixed paraffin-embedded tissue the immunoexpression of TT-Cs in biopsies of normal skin, acquired melanocytic naevi and melanoma, in order to evaluate their role in melanomagenesis and/or tumour progression, their utility as prognostic markers and their possible use in targeted therapies.

Methods: Tissue samples from normal skin, melanocytic naevi and melanoma were subjected to immunohistochemistry for two TT-Cs (Cav3.1, Cav3.2); markers of proliferation (Ki67), the cell cycle (cyclin D1), hypoxia (Glut1), vascularization (CD31) and autophagy (LC3); BRAF V600E mutation (VE1) and phosphatase and tensin homologue (PTEN). Immunostaining was evaluated by histoscore. In silico analysis was used to assess the prognostic value of TT-C overexpression.

Results: TT-C immunoexpression increased gradually from normal skin to common naevi, dysplastic naevi and melanoma samples, but with differences in the distribution of both isoforms. Particularly, Cav3.2 expression was significantly higher in metastatic melanoma than in primary melanoma. Statistical correlation showed a linear interaction between PTEN loss/BRAF V600E/Cav3.1/LC3/ Ki67/cyclin D1/Cav3.2/Glut1. Disease-free survival (DFS) and overall survival correlated inversely with overexpression of Cav3.2. DFS also correlated inversely with overexpression of Cav3.1.

Conclusions: TT-C immunoexpression on melanocytic neoplasms is consistent with our previous in vitro studies and appears to be related to tumour progression. TT-C upregulation can be considered as a prognostic marker using The Cancer Genome Atlas database. The high expression of Cav3.2 in metastatic melanoma encourages the investigation of the use of TT-C blockers in targeted therapies.

MeSH terms

  • Biomarkers, Tumor / metabolism*
  • Calcium Channels, T-Type / metabolism*
  • Cell Proliferation / physiology
  • Disease Progression
  • Disease-Free Survival
  • Humans
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • Melanoma / diagnosis*
  • Melanoma / mortality
  • Neoplasm Recurrence, Local / etiology
  • Nevus, Pigmented / diagnosis*
  • Nevus, Pigmented / mortality
  • Prognosis
  • Skin Neoplasms / diagnosis*
  • Skin Neoplasms / mortality
  • Up-Regulation

Substances

  • Biomarkers, Tumor
  • CACNA1G protein, human
  • CACNA1H protein, human
  • Calcium Channels, T-Type