Over-expressed Phospholamban in Cancer-associated Fibroblasts Is a Driver for CMS4 Subtype Colorectal Cancer FormationSummary
Background & Aims: Heterogeneity is the malignancy feature of colorectal cancer (CRC), which augments the difficulty of CRC treatment. Consensus molecular subtypes (CMSs) classified CRC into 4 subtypes. CMS4 is the most aggressive subtype, characterized with epithelial mesenchymal transition...
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Elsevier
2025-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X25000657 |
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| author | Tao Li Yuxiang Fei Xu Sun Jun Zhu Xin Fang Fanjun Meng Danyi Wang Xu Zhang Chao Liu Qianming Du |
| author_facet | Tao Li Yuxiang Fei Xu Sun Jun Zhu Xin Fang Fanjun Meng Danyi Wang Xu Zhang Chao Liu Qianming Du |
| author_sort | Tao Li |
| collection | DOAJ |
| description | Background & Aims: Heterogeneity is the malignancy feature of colorectal cancer (CRC), which augments the difficulty of CRC treatment. Consensus molecular subtypes (CMSs) classified CRC into 4 subtypes. CMS4 is the most aggressive subtype, characterized with epithelial mesenchymal transition (EMT) and angiogenesis activation. However, the mechanism of CMS4 formation still remains unclear. We aimed to investigate the role of phospholamban (PLN) on CMS4 formation. Methods: Immunohistochemistry and Western blotting were used to detected PLN expressions. Transwell and wound-healing assays were used to evaluate migration and invasion of HCT116 and HT29. Tube formation assay was used to evaluate angiogenesis of HUVECs. GST pull-down was used to detected the interaction between PLN and AXIN2. The CAF-CT26 spleen co-transplantation mouse model was built to evaluate PLN’s effects on CRC metastasis. Results: PLN knockdown reversed CAFs’ conditional medium (CM)-induced EMT, cell migration, and angiogenesis (P < .01). PLN strongly bound to AXIN2, the main component of β-catenin degradation complex, and PLN knockdown increased β-catenin ubiquitination in CAFs (P < .01). PLN knockdown blocked GREM1 secretion (P < .01), and PLN overexpression-induced EMT, cell migration, and angiogenesis were blocked by anti-GREM1 neutralizing antibody (P < .01). Knockdown of BMP2 and VEGFR2 reversed CAFs’ CM induced EMT and angiogenesis effects, respectively (P < .01). PLN knockdown attenuated CAFs mediated tumor promoting effects in vivo (P < .01). Conclusions: PLN competitively binds with AXIN2 to increase β-catenin activity in CAFs. β-catenin signal induces GREM1 secretion, driving EMT and angiogenesis via BMP2 and VEGFR2, respectively. These findings demonstrate that PLN is a driver for CMS4 formation. |
| format | Article |
| id | doaj-art-54d221cd3b694d13b377fd1bf6fcc8c8 |
| institution | OA Journals |
| issn | 2352-345X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj-art-54d221cd3b694d13b377fd1bf6fcc8c82025-08-20T02:37:09ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2025-01-0119910152410.1016/j.jcmgh.2025.101524Over-expressed Phospholamban in Cancer-associated Fibroblasts Is a Driver for CMS4 Subtype Colorectal Cancer FormationSummaryTao Li0Yuxiang Fei1Xu Sun2Jun Zhu3Xin Fang4Fanjun Meng5Danyi Wang6Xu Zhang7Chao Liu8Qianming Du9General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, P.R. China; School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, P.R. China; Nanjing First Hospital, Nanjing University of Chinese Medicine, Nanjing, P.R. ChinaSchool of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, P.R. China; Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing, P.R. China; Nanjing First Hospital, Nanjing University of Chinese Medicine, Nanjing, P.R. ChinaDepartment of Pharmacy, Nanjing Luhe People’s Hospital, Nanjing, China; Department of Pharmacy, Nanjing Luhe People’s Hospital, Yangzhou University, Nanjing, P.R. ChinaDepartment of Pharmacy, Nanjing Luhe People’s Hospital, Nanjing, China; Department of Pharmacy, Nanjing Luhe People’s Hospital, Yangzhou University, Nanjing, P.R. ChinaSchool of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, P.R. ChinaSchool of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, P.R. ChinaSchool of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, P.R. ChinaDepartment of Pharmacy, Chengdu Integrated TCM & Western Medicine Hospital, Chengdu University of TCM, Chengdu, P. R. China; Xu Zhang, PhD, Department of Pharmacy, Chengdu Integrated TCM & Western Medicine Hospital, Chengdu University of TCM, 18# Wanxiang East Road, Chengdu, 610041, P. R.China.School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, P.R. China; Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing, P.R. China; Nanjing First Hospital, Nanjing University of Chinese Medicine, Nanjing, P.R. China; Chao Liu, PhD, Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing 210029, P.R. China.General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, P.R. China; School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, P.R. China; Nanjing First Hospital, Nanjing University of Chinese Medicine, Nanjing, P.R. China; Correspondence Address correspondence to: Qianming Du, PhD, General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, P.R. China.Background & Aims: Heterogeneity is the malignancy feature of colorectal cancer (CRC), which augments the difficulty of CRC treatment. Consensus molecular subtypes (CMSs) classified CRC into 4 subtypes. CMS4 is the most aggressive subtype, characterized with epithelial mesenchymal transition (EMT) and angiogenesis activation. However, the mechanism of CMS4 formation still remains unclear. We aimed to investigate the role of phospholamban (PLN) on CMS4 formation. Methods: Immunohistochemistry and Western blotting were used to detected PLN expressions. Transwell and wound-healing assays were used to evaluate migration and invasion of HCT116 and HT29. Tube formation assay was used to evaluate angiogenesis of HUVECs. GST pull-down was used to detected the interaction between PLN and AXIN2. The CAF-CT26 spleen co-transplantation mouse model was built to evaluate PLN’s effects on CRC metastasis. Results: PLN knockdown reversed CAFs’ conditional medium (CM)-induced EMT, cell migration, and angiogenesis (P < .01). PLN strongly bound to AXIN2, the main component of β-catenin degradation complex, and PLN knockdown increased β-catenin ubiquitination in CAFs (P < .01). PLN knockdown blocked GREM1 secretion (P < .01), and PLN overexpression-induced EMT, cell migration, and angiogenesis were blocked by anti-GREM1 neutralizing antibody (P < .01). Knockdown of BMP2 and VEGFR2 reversed CAFs’ CM induced EMT and angiogenesis effects, respectively (P < .01). PLN knockdown attenuated CAFs mediated tumor promoting effects in vivo (P < .01). Conclusions: PLN competitively binds with AXIN2 to increase β-catenin activity in CAFs. β-catenin signal induces GREM1 secretion, driving EMT and angiogenesis via BMP2 and VEGFR2, respectively. These findings demonstrate that PLN is a driver for CMS4 formation.http://www.sciencedirect.com/science/article/pii/S2352345X25000657AngiogenesisCancer-associated FibroblastsColorectal CancerEpithelial Mesenchymal TransitionPhospholamban |
| spellingShingle | Tao Li Yuxiang Fei Xu Sun Jun Zhu Xin Fang Fanjun Meng Danyi Wang Xu Zhang Chao Liu Qianming Du Over-expressed Phospholamban in Cancer-associated Fibroblasts Is a Driver for CMS4 Subtype Colorectal Cancer FormationSummary Cellular and Molecular Gastroenterology and Hepatology Angiogenesis Cancer-associated Fibroblasts Colorectal Cancer Epithelial Mesenchymal Transition Phospholamban |
| title | Over-expressed Phospholamban in Cancer-associated Fibroblasts Is a Driver for CMS4 Subtype Colorectal Cancer FormationSummary |
| title_full | Over-expressed Phospholamban in Cancer-associated Fibroblasts Is a Driver for CMS4 Subtype Colorectal Cancer FormationSummary |
| title_fullStr | Over-expressed Phospholamban in Cancer-associated Fibroblasts Is a Driver for CMS4 Subtype Colorectal Cancer FormationSummary |
| title_full_unstemmed | Over-expressed Phospholamban in Cancer-associated Fibroblasts Is a Driver for CMS4 Subtype Colorectal Cancer FormationSummary |
| title_short | Over-expressed Phospholamban in Cancer-associated Fibroblasts Is a Driver for CMS4 Subtype Colorectal Cancer FormationSummary |
| title_sort | over expressed phospholamban in cancer associated fibroblasts is a driver for cms4 subtype colorectal cancer formationsummary |
| topic | Angiogenesis Cancer-associated Fibroblasts Colorectal Cancer Epithelial Mesenchymal Transition Phospholamban |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X25000657 |
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