Complex multipathways alterations and oxidative stress are associated with Hailey-Hailey disease

Abstract

Our attempt to explore the molecular mechanism underlying HHD indicates a complex puzzle in which multi-hit combinations of altered signal pathways may explain the wide spectrum of defects in HHD.

Two Patients With Hailey-Hailey Disease, Multiple Primary Melanomas, and Other Cancers

“…Cialfi et al demonstrated that HHD keratinocytes undergo oxidative stress, which may contribute to DNA damage. 18 They also found downregulation of Notch1 and Itch in HHD keratinocytes. 18 It has been reported that Notch1 may act as a transforming oncogene in human melanocytes, therefore, in terms of Notch 1 levels, HHD patients should, in theory, be at decreased risk for advanced melanomas.…”

Population-Specific Association between a Polymorphic Variant in ST18, Encoding a Pro-Apoptotic Molecule, and Pemphigus Vulgaris

“…HLA-DQA1, HLA-DQB1, and HLA-DRBs loci have been described in association with PV in previous studies in both Jewish and non-Jewish populations (Ahmed et al, 1993;Bordenave et al, 2001;Miyagawa et al, 2002;Slomov et al, 2003;Gazit and Loewenthal, 2004;Tron et al, 2005;Brick et al, 2007;Shams et al, 2009). The other three gene loci have not yet been reported in association with PV but harbor variants predisposing to other inflammatory and/or skin disorders (Simmonds et al, 2006;Fernandez-Morera et al, 2008;Okuyama et al, 2008;Barcellos et al, 2009;Cialfi et al, 2010;Clancy et al, 2010;Hsueh et al, 2010;Jin et al, 2011;Juyal et al, 2011). A number of additional loci outside the MHC region and not previously known to be related to PV also showed significant association with PV.…”

Loss of Notch1-dependent p21Waf1/Cip1expression influences the Notch1 outcome in tumorigenesis

“…We have recently reported that the clinical manifestation of Hailey-Hailey disease, a hereditary skin disease, is associated with Notch1 down modulation as a consequence of increased oxidative stress. [5][6][7] Much recent interest has focused on the role of ROS in normal and malignant cell biology. 8,9 Organisms living in aerobic conditions are continuously subjected to ROS, and the response to ROS influences central cellular processes such as proliferation, apoptosis, and senescence, and elevated levels of ROS are associated with various human diseases including various cancers.…”

“…13 Additionally we previously observed that in Hailey-Hailey disease increased oxidative stress is accompanied by reduced expression of both Nrf2 and Notch1. 5,6 Thus, to elucidate whether the effect of As 2 O 3 on Notch1 expression occurred by a reduced function of Nrf2, Nrf2 expression levels were measured in As 2 O 3 -treated cells. However, assessment of Nrf2 expression refuted this notion.…”