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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.

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Background: Parathyroid carcinoma accounts for 0.5-5% of primary hyperparathyroidism, and is exceptional in Chronic Kidney Disease. It usually presents with Hypercalcemia and increased PTH. Image studies with 99Tc-sestaMIBI scintigraphy and ultrasonography are first line. Histopathological features and negative immunohistochemistry staining for parafibromin provide the definitive diagnosis. Summary:A 49-year-old male with stage 5 CKD presented with Hypercalcemia and a rapid rise in PTH levels. Image studies showed signs of parathyroid hyperplasia. After subtotal parathyriodectomy, intraoperative PTH levels did not fall, and a fifth ectopic gland in the mediastinum was resected. Biopsies were consistent with parathyroid carcinoma. Conclusion:Parathyroid carcinoma is an infrequent pathology in CKD, and should be considered in patients with sudden rises in calcium and/or PTH levels. Image studies are highly sensitive, but false negatives exist. Unsatisfactory decreases in intraoperative PTH levels suggest an ectopic gland, and may provide the key to a successful surgery.