Abstract
The P2X7 receptor for extracellular ATP is a well-established mediator of tumoral development and progression both in solid cancers and hematological malignancies. The human P2X7 gene is highly polymorphic, and several splice variants of the receptor have been identified in time. P2X7 single-nucleotide polymorphisms (SNPs) have been broadly analyzed by studies relating them to pathologies as different as infectious, inflammatory, nervous, and bone diseases, among which cancer is included. Moreover, in the last years, an increasing number of reports concentrated on P2X7 splice variants’ different roles and their implications in pathological conditions, including oncogenesis. Here, we give an overview of established and recent literature demonstrating a role for human P2X7 gene products in oncological conditions, mainly focusing on current data emerging on P2X7 isoform B and nfP2X7. We explored the role of these and other genetic variants of P2X7 in cancer insurgence, dissemination, and progression, as well as the effect of chemotherapy on isoforms expression. The described literature strongly suggests that P2X7 variants are potential new biomarkers and therapeutical targets in oncological conditions and that their study in carcinogenesis deserves to be further pursued.
Highlights
P2 purinergic receptors are plasma membrane proteins activated by nucleotides and subdivided into metabotropic P2Y and ionotropic P2X receptors
We give an overview of established and recent literature demonstrating a role for human P2X7 gene products in oncological conditions, mainly focusing on current data emerging on P2X7 isoform B and nfP2X7
NfP2X7 was the object of numerous tumor-related studies due to its widespread expression in cancer specimens [45,90,91,92] and to the efficacy of antibodies targeting it in basal cell carcinoma [83] (Table 1). This conformational variant of the P2X7 receptor seems to be more expressed than P2X7A on tumor cells and biopsies, promoting cell viability [45]. These features are highly reminiscent of P2X7B, which was demonstrated to be overexpressed compared to P2X7A in both solid cancer and leukemia, where it increased survival in serum starvation and even protected cells from chemotherapy-dependent cell death [37,42]
Summary
P2 purinergic receptors are plasma membrane proteins activated by nucleotides and subdivided into metabotropic P2Y and ionotropic P2X receptors. Different domains form the P2X7 structure, including a short intracellular Nterminal tail (26 aa), a large extracellular loop (282 aa) containing the ATP binding site, two transmembrane helices (24 aa each), and a long cytoplasmic carboxy-terminal tail (239 aa) [2,3] Among these domains, the C terminal tail is unique at P2X7, as it is not present in any other member of the P2X family, and it confers to the receptor the ability to interact with several intra-cytoplasmic and transmembrane proteins [4,5,6]. The authors reported the presence of a C-cys anchor domain that, if palmitoylated, causes the typical non-desensitizing current associated with P2X7 Based on this molecular structure, a following study proposed that the P2X7 C terminal domain was acquired by genomic rearrangement from a P2X4-like gene in ancient jawed vertebrates generating the actual mammalian P2X7 [17]. We wish to give an overview on established and recent literature reporting the involvement of human splice and polymorphic variants of the P2X7 receptor in oncological conditions
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