Abstract
Basal Cell Carcinoma (BCC) is one of the most diagnosed cancers worldwide. It develops due to an unrestrained Sonic Hedgehog (SHH) signaling activity in basal cells of the skin. Certain subtypes of BCC are more aggressive than others, although the molecular basis of this phenomenon remains unknown. We have previously reported that Neogenin-1 (NEO1) is a downstream target gene of the SHH/GLI pathway in neural tissue. Given that SHH participates in epidermal homeostasis, here we analyzed the epidermal expression of NEO1 in order to identify whether it plays a role in adult epidermis or BCC. We describe the mRNA and protein expression profile of NEO1 and its ligands (Netrin-1 and RGMA) in human and mouse control epidermis and in a broad range of human BCCs. We identify in human BCC a significant positive correlation in the levels of NEO1 receptor, NTN-1 and RGMA ligands with respect to GLI1, the main target gene of the canonical SHH pathway. Moreover, we show via cyclopamine inhibition of the SHH/GLI pathway of ex vivo cultures that NEO1 likely functions as a downstream target of SHH/GLI signaling in the skin. We also show how Neo1 expression decreases throughout BCC progression in the K14-Cre:Ptch1lox/lox mouse model and that aggressive subtypes of human BCC exhibit lower levels of NEO1 than non-aggressive BCC samples. Taken together, these data suggest that NEO1 is a SHH/GLI target in epidermis. We propose that NEO1 may be important in tumor onset and is then down-regulated in advanced BCC or aggressive subtypes.
Highlights
According to the International Agency for Research on Cancer (IARC, WHO) basal cell carcinoma of the skin (BCC) is one of the most common neoplasms worldwide, with a 10% increase in incidence every year
We have previously reported that Neogenin-1 (NEO1) is a downstream target gene of the Sonic Hedgehog (SHH)/GLI pathway in neural tissue
We identify in human Basal Cell Carcinoma (BCC) a significant positive correlation in the levels of NEO1 receptor, NTN-1 and RGMA ligands with respect to GLI1, the main target gene of the canonical SHH pathway
Summary
According to the International Agency for Research on Cancer (IARC, WHO) basal cell carcinoma of the skin (BCC) is one of the most common neoplasms worldwide, with a 10% increase in incidence every year. UV radiation is one of the main risk factors for the acquisition of BCC, it develops most frequently in areas of the skin that are most exposed to the sun and its incidence increases with age [1, 2]. Nodular BCC (comprising 60–80% of BCCs) and superficial BCC (comprising 10% of BCCs) exhibit a slow growing and non-invasive growth pattern, these tumors form cellular nodules that do not infiltrate the dermis and are easier to resect [4,5,6]. SMO is subsequently phosphorylated which results in the accumulation of transcriptional GLI activators that drive the expression of hedgehog target genes such as PTCH1, GLI1, and BCL2, among others [7, 8]. SHH/GLI signaling regulates hair follicle growth and morphogenesis, allowing the initiation of anagen (growth) phase, where the expression of SHH and the ability of cells to respond to this signaling is temporally and spatially regulated during the hair follicle cycle [9, 10]
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