Abstract
Over the last few decades, the number of cases of non‐melanoma skin cancer (NMSC) has risen to over 3 million cases every year worldwide. Members of the ERBB receptor family are important regulators of skin development and homeostasis and, when dysregulated, contribute to skin pathogenesis. In this study, we investigated leucine‐rich repeats and immunoglobulin‐like domains 2 (LRIG2), a transmembrane protein involved in feedback loop regulation of the ERBB receptor family during NMSC. LRIG2 was identified to be up‐regulated in various types of squamous cell carcinoma (SCC), but little is known about LRIG2 in cutaneous SCC (cSCC). To investigate the function of LRIG2 in cSCC in vivo, we generated a skin‐specific LRIG2 overexpressing transgenic mouse line (LRIG2‐TG) using the Tet‐Off system. We employed the 7,12‐dimethylbenz(a)anthracene/12‐O‐tetra‐decanoylphorbol‐13‐acetate (DMBA/TPA) two‐stage chemical carcinogenesis model and analyzed the skin during homeostasis and tumorigenesis. LRIG2‐TG mice did not exhibit alterations in skin development or homeostasis but showed an interaction between LRIG2 and thrombospondin‐1, which is often involved in angiogenesis and tumorigenesis. However, during carcinogenesis, transgenic animals showed significantly increased tumor progression and a more rapid development of cSCC. This was accompanied by changes in the ERBB system. After a single TPA application, inflammation of the epidermis was enhanced during LRIG2 overexpression. In human skin samples, LRIG2 expression was identified in the basal layer of the epidermis and in hair follicles of normal skin, but also in cSCC samples. In conclusion, epidermal LRIG2 excess is associated with activated EGFR/ERBB4‐MAPK signaling and accelerated tumor progression in experimentally induced NMSC, suggesting LRIG2 as a potential oncoprotein in skin.
Highlights
Excessive exposure to the sun and a history of sunburns are often linked to an increased incidence of malignant skin lesions (Kim and He, 2014; Rosso et al, 1996)
It has been shown that LRIG1 promotes EGF receptor (EGFR), ERBB2, and ERBB3 degradation from the cell surface in a negative feedback loop (Gur et al, 2004; Laederich et al, 2004; Rubin et al, 2005) and that the extracellular domain of LRIG1 decreases EGFR signaling in a paracrine manner (Yi et al, 2011)
Western blot analysis revealed that LRIG2 expression was significantly increased in human cutaneous squamous cell carcinoma (cSCC) (A431) and melanoma (A375) cell lines compared to human keratinocytes (HaCaT) (Fig. 1A)
Summary
Excessive exposure to the sun and a history of sunburns are often linked to an increased incidence of malignant skin lesions (Kim and He, 2014; Rosso et al, 1996). It has been shown that LRIG1 promotes EGFR, ERBB2, and ERBB3 degradation from the cell surface in a negative feedback loop (Gur et al, 2004; Laederich et al, 2004; Rubin et al, 2005) and that the extracellular domain of LRIG1 decreases EGFR signaling in a paracrine manner (Yi et al, 2011). It is known that LRIG proteins can promote and suppress tumor growth in a tissue-specific manner (Hedman and Henriksson, 2007), the molecular mechanisms and their impact on tumorigenesis in the skin are mostly unknown. The overexpression of LRIG2, resulted in increased inflammation, angiogenesis, tumor progression, and an early onset of cSCC, which affected the ERBB signaling and components of the extracellular matrix (ECM)
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call