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Increased expression of LAT1 in basal cell carcinoma: implications for tumour cell survival
Örebro University, School of Medical Sciences. Department of Dermatology, Örebro University Hospital, Faculty of Medicine and Health, Örebro, Sweden.ORCID iD: 0000-0003-1662-0020
Örebro University, School of Medical Sciences. Department of Clinical Research Laboratory.
School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
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2022 (English)In: Clincal and Experimental Dermatology, ISSN 0307-6938, E-ISSN 1365-2230, Vol. 47, no 5, p. 910-917Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Wiley-Blackwell Publishing Inc., 2022. Vol. 47, no 5, p. 910-917
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:oru:diva-95746DOI: 10.1111/ced.15038ISI: 000740940600001PubMedID: 34856000Scopus ID: 2-s2.0-85122458539OAI: oai:DiVA.org:oru-95746DiVA, id: diva2:1616589
Available from: 2021-12-03 Created: 2021-12-03 Last updated: 2025-02-12Bibliographically approved
In thesis
1. Studies on expression profiles in keratinocyte cancers with focus on basal cell carcinoma
Open this publication in new window or tab >>Studies on expression profiles in keratinocyte cancers with focus on basal cell carcinoma
2025 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Aims: This thesis aimed to investigate metabolic changes in keratinocyte carcinoma with a focus on basal cell carcinoma (BCC), to find potential treatment targets.

Material and Methods: Patients diagnosed with BCC (n=55) or cutaneous squamous cell carcinoma (cSCC, n=4) were included. Snap-frozen tumour tissue from BCC tumours, formalin-fixed paraffin-embeddedt issue from BCC and cSCC tumours, and donor skin were investigated with quantitative real-time polymerase chain reaction (qPCR), microarray analysis, immunohistochemistry, and immunofluorescence. Cell lines from BCC, cSCC, and non-neoplastic keratinocytes were used to examine LAT1 inhibition with JPH203 in terms of decreased viability and changed gene expression in genes important for cell metabolism and carcinogenesis.

Results: SLC25A43 gene- and protein expression were significantly decreased in the BCC tumour samples (n=14) compared to the surrounding epidermis. Microarray examination of the tumour material (n=4+4) revealed increased expression of the amino acid transporters SLC7A5/LAT1 and SLC7A8/LAT2, which was confirmed with qPCR(n=14) and immunohisto chemistry (n=14). The LAT1 expression was mainly in the centre of the tumours, and the fraction of LAT1-positive cells were significantly (p<0.01) inversely correlated to the proliferative active cells. Cleaved caspase 3 was significantly (p=0.02) increased in tumour areas with high LAT1 expression. In the patient cohort (n=57), the H-score for LAT1 was significantly higher (p<0.001) than for GLUT1 or GLI1. A sub-analysis of the BCC tumours also revealed a statistically significant correlation (p<0.01) between LAT1 and GLUT1 protein expression. The keratinocyte cell line (HEK001) showed significantly decreased viability when exposed to the LAT1 inhibitor JPH203 at concentration of 100 μM, and a low but significant upregulation of SLC7A5, SLC3A2, CCND1, ATF4 and GLI1 when exposed to a concentration of 10 μM JPH203.

Conclusions: Both SLC25A43 and LAT1 are altered in BCC tumoursc ompared to normal skin suggesting metabolic changes in the tumours. The changed LAT1 expression might be explained by the harsh tumour environment. LAT1 could be a drug target for keratinocyte cancer, but needs further investigations in more advanced models.

Place, publisher, year, edition, pages
Örebro: Örebro University, 2025. p. 85
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 312
Keywords
keratinocyte cancer, non-melanoma skin cancer, basal cell carcinoma, cutaneous squamous cell carcinoma, SLC25A43, LAT1
National Category
General Practice Dermatology and Venereal Diseases
Identifiers
urn:nbn:se:oru:diva-117803 (URN)9789175296241 (ISBN)9789175296258 (ISBN)
Public defence
2025-03-07, Örebro universitet, Campus USÖ, Tidefeltsalen (X2502), X-huset, Södra Grev Rosengatan 32, Örebro, 13:00 (English)
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Available from: 2024-12-13 Created: 2024-12-13 Last updated: 2025-02-13Bibliographically approved

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Prosén, SaraTina, ElisabetLindberg, MagnusGöthlin Eremo, Anna

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