PAQR5 drives the malignant progression and shapes the immunosuppressive microenvironment of hepatocellular carcinoma by activating the NF-κB signaling
Abstract Background Progesterone and adipose Q receptor 5 (PAQR5), a membrane receptor characterized by seven transmembrane domains, has been indirectly implicated in pro-carcinogenic activities, though its specific role in hepatocellular carcinoma (HCC) remains to be defined. Methods This study aim...
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2025-05-01
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| Online Access: | https://doi.org/10.1186/s40364-025-00785-z |
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| author | Ruida Yang Huanhuan Wang Cong Wu Yu Shi Hanqi Li Xinyue Bao Yuqian Yang Shaoshan Han Xue Yang Jie Tao Hao Sun Shaobo Wu Liankang Sun |
| author_facet | Ruida Yang Huanhuan Wang Cong Wu Yu Shi Hanqi Li Xinyue Bao Yuqian Yang Shaoshan Han Xue Yang Jie Tao Hao Sun Shaobo Wu Liankang Sun |
| author_sort | Ruida Yang |
| collection | DOAJ |
| description | Abstract Background Progesterone and adipose Q receptor 5 (PAQR5), a membrane receptor characterized by seven transmembrane domains, has been indirectly implicated in pro-carcinogenic activities, though its specific role in hepatocellular carcinoma (HCC) remains to be defined. Methods This study aimed to elucidate the molecular mechanisms by which PAQR5 facilitates HCC progression and contributes to the immunosuppressive microenvironment through an integrative approach combining multi-omics analysis and experimental validation. Utilizing data from bulk, single-cell, and spatial transcriptomics cohorts, this study systematically assessed the expression patterns, immune landscape, and functional characteristics of PAQR5 across different levels of resolution in HCC. Results PAQR5 expression was significantly upregulated in tumor tissues and correlated with poor clinical outcomes. Enrichment analysis revealed that PAQR5 activated the NF-κB signaling pathway in HCC. Single-cell transcriptomics identified PAQR5 as predominantly localized within malignant cell clusters, with significant association with NF-κB pathway activation. Spatial transcriptomics further corroborated the alignment of PAQR5 expression with tumor cell distribution. In vitro assays showed elevated PAQR5 levels in HCC cell lines, and silencing PAQR5 significantly suppressed cell proliferation, invasion, epithelial-mesenchymal transition (EMT), and prevented the formation of immunosuppressive microenvironment. In vivo studies demonstrated that targeting PAQR5 attenuated tumorigenic potential, disrupted the invasion-metastasis cascade and inhibited the tumor immune escape. Mechanistically, PAQR5 was found to activate NF-κB signaling by inducing ERK phosphorylation, thereby driving proliferation, invasion, EMT, and immune escape in HCC through the pathway. |
| format | Article |
| id | doaj-art-73fd3b4eac584cfeb9bc70cebc07132c |
| institution | DOAJ |
| issn | 2050-7771 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
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| series | Biomarker Research |
| spelling | doaj-art-73fd3b4eac584cfeb9bc70cebc07132c2025-08-20T03:09:20ZengBMCBiomarker Research2050-77712025-05-0113112410.1186/s40364-025-00785-zPAQR5 drives the malignant progression and shapes the immunosuppressive microenvironment of hepatocellular carcinoma by activating the NF-κB signalingRuida Yang0Huanhuan Wang1Cong Wu2Yu Shi3Hanqi Li4Xinyue Bao5Yuqian Yang6Shaoshan Han7Xue Yang8Jie Tao9Hao Sun10Shaobo Wu11Liankang Sun12Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Oncology, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Medical Oncology, Xi’an No.3 Hospital, The Affiliated Hospital of Northwest UniversityDepartment of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong UniversityHonghui Hospital, Xi’an Jiaotong UniversityDepartment of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong UniversityAbstract Background Progesterone and adipose Q receptor 5 (PAQR5), a membrane receptor characterized by seven transmembrane domains, has been indirectly implicated in pro-carcinogenic activities, though its specific role in hepatocellular carcinoma (HCC) remains to be defined. Methods This study aimed to elucidate the molecular mechanisms by which PAQR5 facilitates HCC progression and contributes to the immunosuppressive microenvironment through an integrative approach combining multi-omics analysis and experimental validation. Utilizing data from bulk, single-cell, and spatial transcriptomics cohorts, this study systematically assessed the expression patterns, immune landscape, and functional characteristics of PAQR5 across different levels of resolution in HCC. Results PAQR5 expression was significantly upregulated in tumor tissues and correlated with poor clinical outcomes. Enrichment analysis revealed that PAQR5 activated the NF-κB signaling pathway in HCC. Single-cell transcriptomics identified PAQR5 as predominantly localized within malignant cell clusters, with significant association with NF-κB pathway activation. Spatial transcriptomics further corroborated the alignment of PAQR5 expression with tumor cell distribution. In vitro assays showed elevated PAQR5 levels in HCC cell lines, and silencing PAQR5 significantly suppressed cell proliferation, invasion, epithelial-mesenchymal transition (EMT), and prevented the formation of immunosuppressive microenvironment. In vivo studies demonstrated that targeting PAQR5 attenuated tumorigenic potential, disrupted the invasion-metastasis cascade and inhibited the tumor immune escape. Mechanistically, PAQR5 was found to activate NF-κB signaling by inducing ERK phosphorylation, thereby driving proliferation, invasion, EMT, and immune escape in HCC through the pathway.https://doi.org/10.1186/s40364-025-00785-zPAQR5Hepatocellular carcinomaNF-κBSingle cell-RNA seqSpatial transcriptomic |
| spellingShingle | Ruida Yang Huanhuan Wang Cong Wu Yu Shi Hanqi Li Xinyue Bao Yuqian Yang Shaoshan Han Xue Yang Jie Tao Hao Sun Shaobo Wu Liankang Sun PAQR5 drives the malignant progression and shapes the immunosuppressive microenvironment of hepatocellular carcinoma by activating the NF-κB signaling Biomarker Research PAQR5 Hepatocellular carcinoma NF-κB Single cell-RNA seq Spatial transcriptomic |
| title | PAQR5 drives the malignant progression and shapes the immunosuppressive microenvironment of hepatocellular carcinoma by activating the NF-κB signaling |
| title_full | PAQR5 drives the malignant progression and shapes the immunosuppressive microenvironment of hepatocellular carcinoma by activating the NF-κB signaling |
| title_fullStr | PAQR5 drives the malignant progression and shapes the immunosuppressive microenvironment of hepatocellular carcinoma by activating the NF-κB signaling |
| title_full_unstemmed | PAQR5 drives the malignant progression and shapes the immunosuppressive microenvironment of hepatocellular carcinoma by activating the NF-κB signaling |
| title_short | PAQR5 drives the malignant progression and shapes the immunosuppressive microenvironment of hepatocellular carcinoma by activating the NF-κB signaling |
| title_sort | paqr5 drives the malignant progression and shapes the immunosuppressive microenvironment of hepatocellular carcinoma by activating the nf κb signaling |
| topic | PAQR5 Hepatocellular carcinoma NF-κB Single cell-RNA seq Spatial transcriptomic |
| url | https://doi.org/10.1186/s40364-025-00785-z |
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