To Örebro University

Basal cell carcinoma is the most common type of cancer in fair-skinned individuals, and its incidence is rapidly increasing. The aim of the present study was to investigate the gene and protein expression of the mitochondrial solute carrier family 25 member 43 (SLC25A43) in basal cell carcinoma. SLC25A43 has previously been identified to be genetically altered and associated with cell proliferation in human epidermal growth factor receptor 2-positive breast cancer. However, the knowledge about SLC25A43 is limited, and its role in other cancers is unknown. The SLC25A43 gene and protein expression was analysed in 14 basal cell carcinomas and healthy skin samples from the same individuals by quantitative polymerase chain reaction and immunohistochemistry, respectively. The results demonstrated a significantly lower (>= 50%) SLC25A43 gene expression in all carcinomas compared with that in healthy skin. In addition, SLC25A43 protein expression was absent in >90% of all visual fields in the basal cell carcinomas, and the H-score was significantly lower in tumours compared with the adjacent epidermis. These results demonstrate that SLC25A43 expression is altered at the gene and protein levels in basal cell carcinoma. The underlying mechanisms and the clinical relevance of these data must be elucidated in additional experimental and clinical studies.

Background: The incidence of basal cell carcinoma (BCC) is increasing and the costs for care rising. Therefore, the need for simplified and cost-effective treatment choices is substantial. Aberrant signalling in several pathways, induced by ultraviolet radiation, is of importance in the development of BCC. Alterations in tumour metabolic activity are part of general carcinogenesis; however, these alterations are only partially recognized in skin cancer.

Objectives: To study expression profiles in BCCs compared with individually matched nontumour skin, with a focus on finding differences associated with tumour metabolism.

Materials and methods: Gene expression in biopsies from BCCs (n = 14) compared with biopsies from nontumour gluteal skin was analysed with microarrays (n = 4 + 4) and/or quantitative real-time polymerase chain reaction (qPCR, n = 14 + 14). Protein expression and localization was assessed using immunohistochemistry (IHC) in formalin-fixed and paraffin-embedded BCC samples.

Results: Microarray analysis revealed increased expression of the amino acid transporters SLC7A5, SLC7A7 and SLC7A8 as well as the cytosolic enzyme tryptophan 2,3-dioxygenase (TDO) 2 in BCC. Higher expression of SLC7A5 (P < 0.001), SLC7A8 (P < 0.001) and TDO2 (P = 0.002), but not SLC7A7 (P = 0.50), was confirmed by qPCR, and IHC demonstrated correlating tumour cell protein expression of SLC7A5 and SLC7A8. Protein expression of SLC7A7 was observed in the stratum granulosum, and TDO2 in immune cells.

Conclusions: This study highlights the upregulation of SLC7A5, SLC7A8 and TDO2 in BCC compared with nontumour skin. Our findings imply that amino acid transporters may be further explored as potential targets for future medical treatment.

BACKGROUND: Basal cell carcinoma (BCC) is the most common type of cancer in fair-skinned individuals worldwide. Altered metabolism is a hallmark of cancer, and a growing body of evidence has shown increased expression of the large neutral amino acid transporter (LAT) small subunit 1 in several types of cancers, including BCC. However, the mechanisms behind changed LAT1 expression in BCC are largely unknown.

OBJECTIVES: To describe the protein expression of LAT1 and its co-localisation with LAT2, and to examine LAT1 in association with BCC tumour biology characteristics such as cell proliferation, apoptosis, and hypoxia.

METHODS: Formalin-fixed and paraffin-embedded tissue samples (n=14) from excised BCCs were stained with immunofluorescence and examined regarding protein-staining patterns.

RESULTS: There was no correlation between expression of LAT1 and LAT2, and the co-localisation was low. The proliferation markers topoisomerase IIα and Ki-67 both showed a significantly higher expression in the BCC tissue than in the normal epidermis (p=0.0063 and p=0.010, respectively). The fraction of LAT1-expressing cells in the BCC was inversely correlated to the fraction of proliferative active tumour cells (p=0.0013). Cleaved caspase-3 was significantly increased in tumour areas with high LAT1 expression (p=0.016).

CONCLUSIONS: The findings of the present study show that LAT1 is not usually expressed by proliferating BCC cells. The morphological localisation suggests that tumour cells use LAT1 in adaption to environmental changes such as starvation and/or hypoxia. These findings could have implications for future development of LAT1-inhibitory BCC treatments.