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.

The P2X7 Receptor Stimulates IL-6 Release from Pancreatic Stellate Cells and Tocilizumab Prevents Activation of STAT3 in Pancreatic Cancer Cells

“…One of the relevant purinergic receptors is the P2X7 receptor (P2X7R), as it is involved in several patho-/physiological processes, such as pancreatic cancer [22,23], inflammation [24] and pain [25]. The P2X7R belongs to the P2X ion channel/receptor family and is encoded by a highly polymorphic gene [26][27][28][29] with some single nucleotide polymorphisms correlating with human diseases (chronic lymphocytic leukemia, osteoporosis and pain) [27,30,31]. Moreover, there are also different splice isoforms of the P2X7R, A-J in humans and A and K in rodents, where A are regarded as the common full-length variants [26,32].…”

Antagonism of the ATP-gated P2X7 receptor: a potential therapeutic strategy for cancer

“…Whilst P2X7R functionality is not fully assessed in every cancer type, some cancers studies have demonstrated that the receptor retains its functionality and is able to drive processes such as increased tumour cell survival via several different mechanisms [14,16,18,40]. Several other splice variants of P2X7R have also been identified in recent years, such as P2X7 isoform B and nfP2X7 with studies increasingly indicating them as potential biomarkers and therapeutic targets [41].…”

Cancer Metabostemness and Metabolic Reprogramming via P2X7 Receptor

“…The P2X7 receptor can be assembled by just one of them or by a composition of two or three different isoforms [ 42 ]. P2X7 receptor-related functions in physiological or oncological processes are associated with the expression levels of its genetic variants [ 43 , 44 ]. Among them, P2X7A and B isoforms are the most studied in humans.…”

“…Among them, P2X7A and B isoforms are the most studied in humans. P2X7A has a C-terminal crucial for opening membrane large pores causing apoptosis, while P2X7B has a reduced C-terminal, being incapable of inducing cell death [ 11 ], while it is able to promote proliferation of stem and tumor cells [ 43 , 44 ] and participates in the cell differentiation process [ 44 ]. Although the role of isoforms for cancer metabolism reprogramming and metabostemness has been clarified yet, we hypothesize that a differential contribution of these isoforms account for cancer cell survival and self-renewal, metastasis and chemoresistance.…”