REG3A secreted by peritumoral acinar cells enhances pancreatic ductal adenocarcinoma progression via activation of EGFR signaling
Abstract Background Regenerating family member 3A (REG3A) is involved in the development of multiple malignant tumors, including pancreatic ductal adenocarcinoma (PDAC). However, any role of REG3A in PDAC remains controversial due to its unclear tissue localization or direct receptors, and complex d...
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BMC
2025-02-01
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| Series: | Cell Communication and Signaling |
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| Online Access: | https://doi.org/10.1186/s12964-025-02103-4 |
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| author | Xiaojing Ren Yunfei Teng Kunxin Xie Xiao He Gang Chen Kaini Zhang Qingyi Liao Jia Zhang Xiaohang Zhou Yating Zhu Wenyu Song Yuege Lin Yi Zhang Zhijian Xu Noriaki Maeshige Xiubin Liang Dongming Su Peng Sun Ying Ding |
| author_facet | Xiaojing Ren Yunfei Teng Kunxin Xie Xiao He Gang Chen Kaini Zhang Qingyi Liao Jia Zhang Xiaohang Zhou Yating Zhu Wenyu Song Yuege Lin Yi Zhang Zhijian Xu Noriaki Maeshige Xiubin Liang Dongming Su Peng Sun Ying Ding |
| author_sort | Xiaojing Ren |
| collection | DOAJ |
| description | Abstract Background Regenerating family member 3A (REG3A) is involved in the development of multiple malignant tumors, including pancreatic ductal adenocarcinoma (PDAC). However, any role of REG3A in PDAC remains controversial due to its unclear tissue localization or direct receptors, and complex downstream signal transductions. Methods Morphological analysis and public multi-omics data retrieval were was utilized to elucidate the tissue localization of REG3A in PDAC. To ascertain the pro-oncogenic role of secreted REG3A, experiments were conducted using in vitro PDAC cell lines and in vivo tumor formation assays in nude mice. A battery of investigative techniques, including RNA sequencing, phospho-kinase arrays, western blot analyses, in silico docking simulations, gene truncation strategies, and co-immunoprecipitation, were employed to delve into the downstream signaling transduction pathways induced by REG3A. Results In this study, we confirmed an association between increased serum levels of REG3A and poor prognosis in patients with PDAC. Morphological staining and bioinformatic analysis showed that REG3A was mainly expressed in peritumoral acinar cells that were spatially close to tumor region, while it was almost negative in PDAC tumor cells. Peritumoral REG3A expression levels, but not tumoral REG3A, were highly correlated with PDAC progression. Further in vitro experiments including RNA sequencing and molecular biological assays revealed that secreted REG3A could directly bind to the epidermal growth factor receptor (EGFR), an important pro-oncogene involved in cellular proliferation, and subsequently activate the downstream mitogen-activated protein kinase (MAPK) signals to promote PDAC tumor cell growth. Conclusion Taken together, our data indicated that increased expression of REG3A in peritumoral acinar cells acts as a specific event to indicate PDAC progression, and verified EGFR as a possible target of REG3A, providing mechanistic insights into the role of REG3A, the diagnostic method and therapeutic strategy of PDAC. |
| format | Article |
| id | doaj-art-81a1084ca6374d7a9be04ddcb03eb949 |
| institution | DOAJ |
| issn | 1478-811X |
| language | English |
| publishDate | 2025-02-01 |
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| series | Cell Communication and Signaling |
| spelling | doaj-art-81a1084ca6374d7a9be04ddcb03eb9492025-08-20T03:13:15ZengBMCCell Communication and Signaling1478-811X2025-02-0123111910.1186/s12964-025-02103-4REG3A secreted by peritumoral acinar cells enhances pancreatic ductal adenocarcinoma progression via activation of EGFR signalingXiaojing Ren0Yunfei Teng1Kunxin Xie2Xiao He3Gang Chen4Kaini Zhang5Qingyi Liao6Jia Zhang7Xiaohang Zhou8Yating Zhu9Wenyu Song10Yuege Lin11Yi Zhang12Zhijian Xu13Noriaki Maeshige14Xiubin Liang15Dongming Su16Peng Sun17Ying Ding18Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi HospitalDepartment of Pathology, Nanjing Medical UniversityKey Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical UniversityDepartment of Pathology, Nanjing Medical UniversityDepartment of Pathology, Nanjing Medical UniversityDepartment of Pathophysiology, Nanjing Medical UniversityState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesKey Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical UniversityKey Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical UniversityKey Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical UniversityKey Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical UniversityDepartment of Pathology, Nanjing Medical UniversityDepartment of Pathology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer HospitalState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesDepartment of Rehabilitation Science, Kobe University Graduate School of Health SciencesDepartment of Pathophysiology, Nanjing Medical UniversityDepartment of Pathology, Nanjing Medical UniversityKey Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical UniversityDepartment of Pathology, the First Affiliated Hospital of Nanjing Medical UniversityAbstract Background Regenerating family member 3A (REG3A) is involved in the development of multiple malignant tumors, including pancreatic ductal adenocarcinoma (PDAC). However, any role of REG3A in PDAC remains controversial due to its unclear tissue localization or direct receptors, and complex downstream signal transductions. Methods Morphological analysis and public multi-omics data retrieval were was utilized to elucidate the tissue localization of REG3A in PDAC. To ascertain the pro-oncogenic role of secreted REG3A, experiments were conducted using in vitro PDAC cell lines and in vivo tumor formation assays in nude mice. A battery of investigative techniques, including RNA sequencing, phospho-kinase arrays, western blot analyses, in silico docking simulations, gene truncation strategies, and co-immunoprecipitation, were employed to delve into the downstream signaling transduction pathways induced by REG3A. Results In this study, we confirmed an association between increased serum levels of REG3A and poor prognosis in patients with PDAC. Morphological staining and bioinformatic analysis showed that REG3A was mainly expressed in peritumoral acinar cells that were spatially close to tumor region, while it was almost negative in PDAC tumor cells. Peritumoral REG3A expression levels, but not tumoral REG3A, were highly correlated with PDAC progression. Further in vitro experiments including RNA sequencing and molecular biological assays revealed that secreted REG3A could directly bind to the epidermal growth factor receptor (EGFR), an important pro-oncogene involved in cellular proliferation, and subsequently activate the downstream mitogen-activated protein kinase (MAPK) signals to promote PDAC tumor cell growth. Conclusion Taken together, our data indicated that increased expression of REG3A in peritumoral acinar cells acts as a specific event to indicate PDAC progression, and verified EGFR as a possible target of REG3A, providing mechanistic insights into the role of REG3A, the diagnostic method and therapeutic strategy of PDAC.https://doi.org/10.1186/s12964-025-02103-4REG3APancreatic ductal adenocarcinomaPeritumoral acinar cellEpidermal growth factor receptor (EGFR)Paracrine |
| spellingShingle | Xiaojing Ren Yunfei Teng Kunxin Xie Xiao He Gang Chen Kaini Zhang Qingyi Liao Jia Zhang Xiaohang Zhou Yating Zhu Wenyu Song Yuege Lin Yi Zhang Zhijian Xu Noriaki Maeshige Xiubin Liang Dongming Su Peng Sun Ying Ding REG3A secreted by peritumoral acinar cells enhances pancreatic ductal adenocarcinoma progression via activation of EGFR signaling Cell Communication and Signaling REG3A Pancreatic ductal adenocarcinoma Peritumoral acinar cell Epidermal growth factor receptor (EGFR) Paracrine |
| title | REG3A secreted by peritumoral acinar cells enhances pancreatic ductal adenocarcinoma progression via activation of EGFR signaling |
| title_full | REG3A secreted by peritumoral acinar cells enhances pancreatic ductal adenocarcinoma progression via activation of EGFR signaling |
| title_fullStr | REG3A secreted by peritumoral acinar cells enhances pancreatic ductal adenocarcinoma progression via activation of EGFR signaling |
| title_full_unstemmed | REG3A secreted by peritumoral acinar cells enhances pancreatic ductal adenocarcinoma progression via activation of EGFR signaling |
| title_short | REG3A secreted by peritumoral acinar cells enhances pancreatic ductal adenocarcinoma progression via activation of EGFR signaling |
| title_sort | reg3a secreted by peritumoral acinar cells enhances pancreatic ductal adenocarcinoma progression via activation of egfr signaling |
| topic | REG3A Pancreatic ductal adenocarcinoma Peritumoral acinar cell Epidermal growth factor receptor (EGFR) Paracrine |
| url | https://doi.org/10.1186/s12964-025-02103-4 |
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