P2X7 Variants in Oncogenesis

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.

Keywords: P2X7; P2X7 SNPs; P2X7 splice variants; P2X7B; cancer; leukemia.

Figure 1

Depiction of human P2X7 receptor splicing variants described in this overview as involved in carcinogenesis and for which a published sequence is available. Different colors identify each region: transmembrane domain 1 (TM1) is in blue, transmembrane domain 2 (TM2) is in red, altered carboxy-terminal tails of P2X7B and P2X7J are respectively in green and in purple. (a) Schematic representation of the human P2X7 gene and its splice variants. The boxes represent the 13 exons, while the black lines between exons represent new introns. The full-length P2X7A variant derives from the original sequence formed by 13 exons. The P2X7B isoform is a truncated variant as it retains an intron between exons 10 and 11, which includes a new stop codon altering the carboxy-terminal tail. P2X7J is a truncated isoform that lacks exon 8 and carries a modified carboxy-terminal tail. P2X7-V3 gains an extra exon called N3 (yellow) and a stop codon; it does not give rise to a protein but instead acts as a short non-coding RNA. (b) Schematic representation of the full-length P2X7A and the truncated isoforms P2X7B and P2X7J expressed on the cell membrane.

Figure 2

P2X7A (full length) and P2X7B and J amino acids sequence alignment. TM1 is in blue, while TM2 is in red. The ten aminoacids unique to the P2X7J isoform are in purple, while the 18 extra amino acids characterizing P2X7B and located after TM2 are in green.

Figure 3

Schematic representation of the position of P2X7 receptor single-nucleotide polymorphisms (SNP) studied in cancer and covered by this overview. The gain of function SNPs are in blue, while the loss of function SNPs are in green.