A subgroup of these channels are the Ca2+-permeable, nonselective thermo-TRPs TRPV1 and TRPV4 . Dermal portions of MM show strong expression of TRPV1 more frequently than dermal NCN portions. Some NCN show a decreasing ASIC1/2 expression in deeper dermal tumor tissue, while MM seem to not lose ASIC1/2 in deeper dermal portions. ASIC1, ASIC2, TRPV1 and TRPV4 in skin tumors might be involved in tumor progression, Calcitetrol thus being potential diagnostic and therapeutic targets. strong class=”kwd-title” Keywords: melanoma, squamous cell carcinoma, basal cell carcinoma, proton-sensitive ion channels 1. Introduction Melanoma and non-melanoma skin cancers (NMSCs) are the most prevalent cancers among the white population, exhibiting an increasing incidence rate worldwide . The WHO counts between 2 to 3 3 million new cases of NMSC per year, being 18C20 times higher than melanoma. However, due to its risk of metastasis, the malignant melanoma (MM) is responsible for 90% of deaths among skin cancers, with a yearly increasing incidence rate between 4 and 6% . The group of NMSC includes basal cell carcinomas (BCCs), which account for around 80% of NMSC, and squamous cell carcinomas (SCCs), with around 20% of NMSC. Only 1% can be classified as other skin tumors . Nevus cell nevi (NCN) are benign neoplasms, but about 10C30% of melanomas arise from NCN . Even if the mortality rate and metastatic potential of NMSCs are low, those tumors lead to enormous morbidity and extensive costs for our health system . Therefore, it is important to find new therapeutic targets in MM and NMSC for future treatments. Tumor formation changes the physical microenvironment in the tissue. Little vascular perfusion, regional hypoxia and the subsequent anaerobic glucose metabolism lead to lactic acid and, hence, to extracellular acidosis in tumors with extracellular pH (pHe) as low as 6.5 . Furthermore, membrane-bound transporters (monocarboxylate transporters MCTs 1C4, carboanhydrases CA2/9/12, sodium hydrogen exchanger 1 NHE, vacuolar type ATPases VATPases, sodium bicarbonate symporters) contribute to the acidified tumor microenvironment (TME) . In physiological conditions, the pHe is higher (7.2C7.4) than the intracellular pHi (6.9C7.2), whereas in a tumor environment, the so-called reversed pH gradient (pHe pHi) develops . This reversed pH gradient (or Calcitetrol inside-out pH gradient) is harmful to normal cells, as cellular acidification in general leads to apoptosis. In tumor cells, however, it causes migration and invasion and, hence, benefits tumor growth . In contrast to normal cells, tumor cells can adjust to survive in low pH by increasing glycolytic activity and Calcitetrol expression of proton transporters, which stabilize intracellular pH . Several of these transporters and pumps have already been detected to play a role in the maintenance of TME, such as carbonic anhydrases (CA2,CA9, CA12), V-ATPases (vacuolar-type H+ ATPases), Na+/HCO? 3-Co-transporters, the monocarboxylate transporters MCT 1C4 or Na+/H+ exchanger 1 (NHE1) . Through changes in their expression or activity, these plasma membrane proteins promote H+ efflux, thus leading to the typical alkaline pHi and the acidic pHe in tumor cells . Cancer cells need to detect the dysregulated pH by sensors to mediate adequate cellular response. Acid-sensing proteins transmit signals to the cytoplasm and nucleus, hence influencing intracellular signal transduction pathways and gene expression . One group of these sensors is the proton-sensitive G-protein coupled receptors (pH-GPCRs) . We recently published first data on the expression profiles of pH-GPCRs in various skin tumors [8,12]. Other proton-sensing sensors in the plasma membrane are the transient receptor potential vanilloid channels (TRPVs) as well as the acid-sensitive ion channels (ASICs). Little is, however, known on their expression and role in skin tumors. Transient receptor vanilloid potential ion channels (TRPVs) are a group of subfamilies numerously and diversely expressed in several tissues and organs, where they perform pleiotropic physiological and pathological functions. These nonselective cation channels were originally characterized as polymodal cellular sensors in neurons, being activated by chemical, Rabbit polyclonal to VWF physical and thermal stimuli . A subgroup Calcitetrol of these channels are the Ca2+-permeable, nonselective thermo-TRPs TRPV1 and TRPV4 . These proton-sensing proteins are both activated by extracellular acidity . Furthermore, TRPV1 is stimulated by vanilloid compounds (capsaicin and resiniferatoxin), injurious heat (43 C) and some eicosanoids . TRPV4 is activated by lower temperature ( 24 C) and by hypoosmotic stimulation . Apart from neuronal cells, the expression of TRPV1 and TRPV4 has been proven in a wide range of tissues, amongst others in epidermal keratinocytes . Moreover, they play a role in the regulation of cell apoptosis and survival by regulating calcium signaling, which is essential for the apoptosis-driven differentiation program of keratinocytes . TRPV1 has been found within the skin in.