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Depletion of P2X4 receptors alleviates prostate cancer bone metastasis through reducing cancer cell invasiveness and enhancing cell adhesion activities

ABSTRACT: The P2X4 receptor (P2X4R) is a receptor for ATP that is highly expressed in many cancer types including prostate cancer and is positively associated with tumourigenesis. To understand the role of P2X4R in prostate cancer bone metastasis gene P2RX4 was knocked out in human prostate cancer PC3 cells using the CRISPR/Cas9 system. Animal studies demonstrated that targeting P2X4R suppresses the process of tumour bone metastasis. RNA-seq was performed to understand the further mechanism for P2X4R deficiency correlated reduction in prostate cancer tumourigenicity. The results demonstrated that P2X4R deficiency in PC3 cells caused dramatically up-regulate the anti-tumour genes (CLDN18, ADAMTS12 and PRB2), and it also significantly increased cell adhesion function and characteristic of the epithelia gene (CLDN18), which may inhibit cancer cell invasion and delay the process of PCa bone metastasis. These findings provide important insights into the underlying biology of P2X4R and prostate cancer progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE245125 | GEO | 2025/12/04

REPOSITORIES: GEO

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Project description:The estrogen receptor (ER)M-NM-21 is successively lost during cancer progression, whereas its splice variant, ERM-NM-22, is expressed in advanced prostate cancer. The latter form of cancer often metastasizes to bone, and we wanted to investigate whether the loss of ERM-NM-21 and/or the expression of ERM-NM-22 affect such signaling pathways in prostate cancer. Using PC3 and 22Rv1 prostate cancer cell lines that stably express ERM-NM-21 or ERM-NM-22, we found that the ERM-NM-2 variants differentially regulate genes known to affect tumor behavior. We found that ERM-NM-21 repressed the expression of the bone metastasis regulator Runx2 in PC3 cells. By contrast, RUNX2 expression was up-regulated at the mRNA level by ERM-NM-22 in PC3 cells, whereas Slug was up-regulated by ERM-NM-22 in both PC3 and 22Rv1 cells. In addition, the expression of Twist1, a factor whose expression strongly correlates with high Gleason grade prostate carcinoma, was increased by ERM-NM-22. In agreement with the increased Twist1 expression, we found increased expression of Dickkopf homolog 1; Dickkopf homolog 1 is a factor that has been shown to increase the RANK ligand/osteoprotegerin ratio and enhance osteoclastogenesis, indicating that the expression of ERM-NM-22 can cause osteolytic cancer. Furthermore, we found that only ERM-NM-21 inhibited proliferation, whereas ERM-NM-22 increased proliferation. The expression of the proliferation markers Cyclin E, c-Myc, and p45(Skp2) was differentially affected by ERM-NM-21 and ERM-NM-22 expression. In addition, nuclear M-NM-2-catenin protein and its mRNA levels were reduced by ERM-NM-21 expression. In conclusion, we found that ERM-NM-21 inhibited proliferation and factors known to be involved in bone metastasis, whereas ERM-NM-22 increased proliferation and up-regulated factors involved in bone metastasis. Thus, in prostate cancer cells, ERM-NM-22 has oncogenic abilities that are in strong contrast to the tumor-suppressing effects of ERM-NM-21. The GFP vs. ERbeta1 comparison was carried out with three replicate dye-swaps, six arrays total. The GFP vs. ERbeta2 comparison was carried out with two replicate dye-swaps, four arrays total.

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Depletion of P2X4 receptors alleviates prostate cancer bone metastasis through reducing cancer cell invasiveness and enhancing cell adhesion activities

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