RHBDF2-Regulated Growth Factor Signaling in a Rare Human Disease, Tylosis With Esophageal Cancer: What Can We Learn From Murine Models?

Abstract

Tylosis with esophageal cancer syndrome (TOC) is a rare autosomal dominant proliferative skin disease caused by missense mutations in the rhomboid 5 homolog 2 (RHBDF2) gene. TOC is characterized by thickening of the skin in the palms and feet and is strongly linked with the development of esophageal squamous cell carcinoma. Murine models of human diseases have been valuable tools for investigating the underlying genetic and molecular mechanisms of a broad range of diseases. Although current mouse models do not fully recapitulate all aspects of human TOC, and the molecular mechanisms underlying TOC are still emerging, the available mouse models exhibit several key aspects of the disease, including a proliferative skin phenotype, a rapid wound healing phenotype, susceptibility to epithelial cancer, and aberrant epidermal growth factor receptor (EGFR) signaling. Furthermore, we and other investigators have used these models to generate new insights into the causes and progression of TOC, including findings suggesting a tissue-specific role of the RHBDF2-EGFR pathway, rather than a role of the immune system, in mediating TOC; and indicating that amphiregulin, an EGFR ligand, is a functional driver of the disease. This review highlights the mouse models of TOC available to researchers for use in investigating the disease mechanisms and possible therapies, and the significance of genetic modifiers of the disease identified in these models in delineating the underlying molecular mechanisms.

Whole Exome Sequencing Identified a Novel Mutation of the RHBDF2 Gene in a Chinese Family of Tylosis with Esophageal Cancer

“…Substantial evidence suggests that RHBDF2 regulates the EGFR signaling pathway and its downstream signaling events, including development of tylosis and epithelial tumorigenesis, through an enhanced secretion of the EGFR ligand amphiregulin (AREG) (9,10,11). It indicates a tissue-specific role of the RHBDF2-AREG-ADAM17-EGFR pathway in TOC, using mouse models (9,11).…”

The complex life of rhomboid pseudoproteases

“…A connection to most of the known hallmarks of cancer can be established for rhomboid pseudoproteases, most notably iRhom2 [69,89–96] and iRhom1 [47,71,97–99] but also RHBDD2 [100–102] and Derlin 1 [103–106] (Fig. 6).…”

“…In cancer cell lines, iRhom1 has been reported to activate important and diverse cancer signaling pathways, such as WNT [98], HIF‐1 [71], and EGFR signaling [99] as well as tumor xenograft growth [97]. However, only for iRhom2 there is enough supportive evidence from mouse genetics and human disease to implicate it in cancer [89–93,107]. Mutations in iRhom2, which were identified by the Kelsell Lab to affect a conserved region within the cytoplasmic tail of iRhom2, are the cause of a rare autosomal dominant disease called ‘Tylosis with esophageal cancer’ (TOC).…”

“…Mutations in iRhom2, which were identified by the Kelsell Lab to affect a conserved region within the cytoplasmic tail of iRhom2, are the cause of a rare autosomal dominant disease called ‘Tylosis with esophageal cancer’ (TOC). Affected individuals have palmoplantar hyperkeratosis (skin thickening) and a higher risk of developing esophageal cancer [89,90,92]. Mutant TOC iRhom2 is proposed to confer a ADAM17/TACE gain‐of‐function phenotype to keratinocytes, resulting in increased EGFR‐ligand shedding, migration, and proliferation [89–93].…”

From Interconnection between Genes and Microenvironment to Novel Immunotherapeutic Approaches in Upper Gastro-Intestinal Cancers—A Multidisciplinary Perspective

“…Interestingly inactivating mutations clustered in defined geographic areas, being more frequent in those ECSSs which affect North American patients than in those aroused in Chinese population. Moreover, germline mutations in the RHBDF2 gene (17q25) which cause tylosis (focal non-epidermolytic palmoplantar keratoderma) have been reported to be markers of genetic familial susceptibility for the early onset of ESSC [ 49 , 50 , 51 ].…”