Calcium overload via PVT1 reprograms neutrophil fate and constrains gastric cancer progression
Abstract Background The aberrant upregulation of PVT1 in gastric cancer (GC) has emerged as a critical molecular marker, while its mechanism of remodeling the tumor microenvironment (TME) through metabolic regulation remains unclear. This study aims to unveil the novel mechanism by which PVT1 regula...
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BMC
2025-08-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-025-06912-6 |
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| author | Dong Wang Yunlong Li Xiaoyu Peng Lulu Zhang Ying Zhang Xue Guan Xiao Liang Songbin Fu Jingcui Yu |
| author_facet | Dong Wang Yunlong Li Xiaoyu Peng Lulu Zhang Ying Zhang Xue Guan Xiao Liang Songbin Fu Jingcui Yu |
| author_sort | Dong Wang |
| collection | DOAJ |
| description | Abstract Background The aberrant upregulation of PVT1 in gastric cancer (GC) has emerged as a critical molecular marker, while its mechanism of remodeling the tumor microenvironment (TME) through metabolic regulation remains unclear. This study aims to unveil the novel mechanism by which PVT1 regulates the fate determination of tumor-associated neutrophils (TANs) via the calcium signaling pathway. Methods Clinical analysis of 90 GC cases revealed a correlation between PVT1 expression and neutrophil infiltration in tumor tissues. Mechanistically, multi-omics integration of transcriptomics and 4D-label-free quantitative proteomics identified PVT1-associated pathways driving GC progression. Functional validation through in vitro and in vivo models demonstrated PVT1’s oncogenic role, while transcriptomic profiling further decoded neutrophil activation mechanisms regulated by PVT1. Results The expression of PVT1 was significantly elevated in GC tissues compared to adjacent non-tumor tissues (p < 0.001), with 73.3% of cases showing an increased proportion of PVT1-positive cells. High PVT1 expression negatively correlated with the infiltration of neutrophils (r = − 0.3554, p = 0.0012), and patients in the PVT1 + CD66b- subgroup exhibited the poorest prognosis, characterized by a median survival of 20.5 months and a mortality rate of 72.5%. Silencing PVT1 upregulated calcium signaling pathway-related genes (RYR2 and RYR3) in GC cells, accompanied by a marked increase in intracellular Ca2⁺ concentration (p < 0.01). Proteomic analysis revealed that PVT1 knockdown significantly enhanced the secretion of synaptopodin (SYNPO), which demonstrated co-expression and physical interactions with calcium channel proteins RYR2/RYR3. PVT1 knockdown markedly suppressed GC cell proliferation, migration, and invasion (p < 0.05) while elevating the expression of γ-H2AX (p < 0.05). In xenograft models, tumors with PVT1 knockdown displayed reduced volume and decreased Ki67 expression (p < 0.01). Conditioned medium from PVT1-knockdown GC cells promoted neutrophil activation, delayed apoptosis, and amplified intracellular Ca2⁺ signaling. Exogenous SYNPO supplementation mimicked these effects and attenuated neutrophil replicative senescence by modulating p53 pathway-associated genes (TP53, CHEK1, and SERPINE1). Conclusions Overall, this study provides the first evidence that PVT1 establishes a metabolic checkpoint by inducing calcium overload, thereby regulating both the senescence process and functional phenotype of neutrophils, which provides a novel metabolic intervention target for GC immunotherapy. |
| format | Article |
| id | doaj-art-e0fded641c2a4424acb9262c4754f15c |
| institution | DOAJ |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | BMC |
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| series | Journal of Translational Medicine |
| spelling | doaj-art-e0fded641c2a4424acb9262c4754f15c2025-08-20T03:05:57ZengBMCJournal of Translational Medicine1479-58762025-08-0123111810.1186/s12967-025-06912-6Calcium overload via PVT1 reprograms neutrophil fate and constrains gastric cancer progressionDong Wang0Yunlong Li1Xiaoyu Peng2Lulu Zhang3Ying Zhang4Xue Guan5Xiao Liang6Songbin Fu7Jingcui Yu8Scientific Research Centre, the Second Affiliated Hospital of Harbin Medical UniversityDepartment of General Surgery, the Second Affiliated Hospital of Harbin Medical UniversityScientific Research Centre, the Second Affiliated Hospital of Harbin Medical UniversityScientific Research Centre, the Second Affiliated Hospital of Harbin Medical UniversityMinistry of Education, Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (Harbin Medical University)Animal Laboratory Center, the Second Affiliated Hospital of Harbin Medical UniversityMinistry of Education, Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (Harbin Medical University)Ministry of Education, Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (Harbin Medical University)Scientific Research Centre, the Second Affiliated Hospital of Harbin Medical UniversityAbstract Background The aberrant upregulation of PVT1 in gastric cancer (GC) has emerged as a critical molecular marker, while its mechanism of remodeling the tumor microenvironment (TME) through metabolic regulation remains unclear. This study aims to unveil the novel mechanism by which PVT1 regulates the fate determination of tumor-associated neutrophils (TANs) via the calcium signaling pathway. Methods Clinical analysis of 90 GC cases revealed a correlation between PVT1 expression and neutrophil infiltration in tumor tissues. Mechanistically, multi-omics integration of transcriptomics and 4D-label-free quantitative proteomics identified PVT1-associated pathways driving GC progression. Functional validation through in vitro and in vivo models demonstrated PVT1’s oncogenic role, while transcriptomic profiling further decoded neutrophil activation mechanisms regulated by PVT1. Results The expression of PVT1 was significantly elevated in GC tissues compared to adjacent non-tumor tissues (p < 0.001), with 73.3% of cases showing an increased proportion of PVT1-positive cells. High PVT1 expression negatively correlated with the infiltration of neutrophils (r = − 0.3554, p = 0.0012), and patients in the PVT1 + CD66b- subgroup exhibited the poorest prognosis, characterized by a median survival of 20.5 months and a mortality rate of 72.5%. Silencing PVT1 upregulated calcium signaling pathway-related genes (RYR2 and RYR3) in GC cells, accompanied by a marked increase in intracellular Ca2⁺ concentration (p < 0.01). Proteomic analysis revealed that PVT1 knockdown significantly enhanced the secretion of synaptopodin (SYNPO), which demonstrated co-expression and physical interactions with calcium channel proteins RYR2/RYR3. PVT1 knockdown markedly suppressed GC cell proliferation, migration, and invasion (p < 0.05) while elevating the expression of γ-H2AX (p < 0.05). In xenograft models, tumors with PVT1 knockdown displayed reduced volume and decreased Ki67 expression (p < 0.01). Conditioned medium from PVT1-knockdown GC cells promoted neutrophil activation, delayed apoptosis, and amplified intracellular Ca2⁺ signaling. Exogenous SYNPO supplementation mimicked these effects and attenuated neutrophil replicative senescence by modulating p53 pathway-associated genes (TP53, CHEK1, and SERPINE1). Conclusions Overall, this study provides the first evidence that PVT1 establishes a metabolic checkpoint by inducing calcium overload, thereby regulating both the senescence process and functional phenotype of neutrophils, which provides a novel metabolic intervention target for GC immunotherapy.https://doi.org/10.1186/s12967-025-06912-6Gastric cancerPVT1Tumor-associated neutrophilsCalcium signaling pathwayReplicative senescence |
| spellingShingle | Dong Wang Yunlong Li Xiaoyu Peng Lulu Zhang Ying Zhang Xue Guan Xiao Liang Songbin Fu Jingcui Yu Calcium overload via PVT1 reprograms neutrophil fate and constrains gastric cancer progression Journal of Translational Medicine Gastric cancer PVT1 Tumor-associated neutrophils Calcium signaling pathway Replicative senescence |
| title | Calcium overload via PVT1 reprograms neutrophil fate and constrains gastric cancer progression |
| title_full | Calcium overload via PVT1 reprograms neutrophil fate and constrains gastric cancer progression |
| title_fullStr | Calcium overload via PVT1 reprograms neutrophil fate and constrains gastric cancer progression |
| title_full_unstemmed | Calcium overload via PVT1 reprograms neutrophil fate and constrains gastric cancer progression |
| title_short | Calcium overload via PVT1 reprograms neutrophil fate and constrains gastric cancer progression |
| title_sort | calcium overload via pvt1 reprograms neutrophil fate and constrains gastric cancer progression |
| topic | Gastric cancer PVT1 Tumor-associated neutrophils Calcium signaling pathway Replicative senescence |
| url | https://doi.org/10.1186/s12967-025-06912-6 |
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