The transmembrane protein LRIG2 increases tumor progression in skin carcinogenesis

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.

MiR-193b-3p–ERBB4 axis regulates psoriasis pathogenesis via modulating cellular proliferation and inflammatory-mediator production of keratinocytes

“…The ERBB4 gene is a member of the ERBB family and plays an important role in the occurrence and development of various tumors [ 28 , 29 ]. Accumulating evidence has shown that ERBB4 plays a critical role in regulating cellular growth, as ERBB4 overexpression promotes proliferation and cellular survival, whereas ERBB4-null cells demonstrate decreased proliferation and cellular survival [ 40 ].…”

The transmembrane protein LRIG1 triggers melanocytic tumor development following chemically induced skin carcinogenesis

“…While LRIG1 and LRIG3 are thought to be tumor suppressors, LRIG2 expression is mostly related to poor prognosis [38]. Previously, we have shown that LRIG2 acts as an oncogene in skin cancer affecting ERBB signaling [32]. In this study, we used a LRIG1-TG gain-of-function mouse model to investigate the influence of LRIG1 overexpression on skin tumorigenesis.…”

“…As previously described [32], total RNA was isolated from all investigated cell lines (HaCaT, A431, A375, SK‐MEL2, SK‐MEL28) using TRIZOL reagent (Invitrogen, Darmstadt, Germany). According to the manufacturer's instructions, 3 µg RNA was reverse‐transcribed in a final volume of 30 µL using RevertAid reverse transcriptase (Thermo Scientific, Schwerte, Germany).…”

“…Mass spectrometry analysis was done as described previously [32]. Briefly, for mass spectrometry analysis, nonreduced protein samples of DMBA/TPA-treated back skin of LRIG1-TG mice and controls as well as of untreated LRIG1-TG skin were separated by SDS/ PAGE.…”

Concomitant using of topical carrageenan-kappa and oral vitamin D against 7, 12-dimethylbenz[a]anthracene induced-oral cancer in rats: A synergism or an antagonism effects

“…Activation of epidermal growth factor receptor (EDFR) leads to activation of metabolic pathways that cause progression of the oral cancer, suggesting that EGFR plays a role in the development of the cancer stem cells [10]. In animal skin cancer model using DMBA, the activity of EGFR pathways are significantly increased compared with control animals [11].…”