Abstract
TWIK-related acid-sensitive potassium channels TASK1 and TASK3, as well as the G-protein-coupled receptors GPR31 and GPR151, are proton-sensitive membrane proteins. They can be activated or inhibited by low extracellular pH (pHe), which is a hallmark of the tumor microenvironment in solid tumors. However, the role of these channels in the development of skin tumors is still unclear. In this study, we investigated the expression profiles of TASK1, TASK3, GPR31 and GPR151 in squamous cell carcinomas (SCCs), basal cell carcinomas (BCCs), nevus cell nevi (NCN), and malignant melanomas (MMs). We performed immunohistochemistry using paraffin-embedded tissue samples from patients and found that most skin tumors express TASK1/3 and GPR31/151. The results show that BCCs are often negative for GPR31/151 as well as for TASK1/3, while nearly all SCCs express these markers. MMs and NCN show similar expression patterns. However, some tumors show a decreasing TASK1/3 expression in deeper dermal tumor tissue, while GPCRs were expressed more evenly. The lower frequency of GPR31/151 and TSAK1/3 expression in BCCs when compared to SCCs is a novel histological feature distinguishing these two entities. Moreover, BCCs also show lower expression of GPR31/151 and TASK1/3 as compared to NCN and MMs.
Highlights
Published: 23 December 2021The inverse pH gradient is a hallmark of solid tumor cells [1]
One of the most striking results found was the lower frequency of GPR31/151 and TASK1/3 expression in basal cell carcinomas (BCCs) when compared to squamous cell carcinomas (SCCs)
Our findings need to be verified by a larger sample size and by the study of different patient collectives to investigate the different roles of G-protein coupled receptors (GPCRs)/TASKs more precisely
Summary
The inverse pH gradient (extracellular pHe < intracellular pHi) is a hallmark of solid tumor cells [1]. Acidic metabolic waste products in the tumor microenvironment (TME). Result from poor blood perfusion with subsequent hypoxia as well as from inflammation and high metabolic activity [1,2]. H+ ions and lactate accumulate in the TME due to metabolic changes in tumors as well as the altered activity/expression of membrane-bound transporters. The decrease in pHe activates proton-sensitive receptors, such as certain. G-protein coupled receptors (GPCRs), transient receptor potential channels (TRPCs), acidsensing ion channels (ASICs) as well as TWIK-related acid-sensitive potassium channels (TASKs) [3]. Tumor cells exhibit complex pH regulation via sodium hydrogen exchanger-1 (NHE1), monocarboxylate transporters (MCT1-4), bicarbonate transporters, vacuolar ATPases (VATPase) and carboanhydrases (CAII, CAIX, CAXII) [1,4–6]. Cancer cells exhibit a more alkaline pHi > 7.2 and correspondingly a lower pHe of
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