Cancer-associated fibroblast-derived COL17A1 promotes gemcitabine resistance and tumorigenesis in pancreatic cancer cells by interacting with ACTN4
Abstract Background Cancer-associated fibroblasts (CAFs) are key components of tumor microenvironment and have been identified to be involved in modulating drug resistance in cancers by secreting molecules. Pancreatic cancer (PC) is a leading cause of cancer mortality with high aggressiveness. Gemci...
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| Format: | Article |
| Language: | English |
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Springer
2025-02-01
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| Series: | Discover Oncology |
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| Online Access: | https://doi.org/10.1007/s12672-025-01825-8 |
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| author | Rongyu Shi Ning Zhang Han Li Hu Zhong Chengcheng Zhong Wei Du Xi Yang |
| author_facet | Rongyu Shi Ning Zhang Han Li Hu Zhong Chengcheng Zhong Wei Du Xi Yang |
| author_sort | Rongyu Shi |
| collection | DOAJ |
| description | Abstract Background Cancer-associated fibroblasts (CAFs) are key components of tumor microenvironment and have been identified to be involved in modulating drug resistance in cancers by secreting molecules. Pancreatic cancer (PC) is a leading cause of cancer mortality with high aggressiveness. Gemcitabine (GEM) is one of primary antineoplastic drugs for PC. Collagen XVII (COL17A1) expression was found to be upregulated in GEM-resistant CAFs. Here, this study focused on investigating whether CAFs affected GEM resistance in PC by secreting COL17A1 and its associated mechanisms. Methods In total, 60 newly diagnosed PC patients only with GEM-based chemotherapy were recruited. Normal fibroblasts (NFs) and CAFs were isolated using fresh normal and resistant PC tissues. Human pancreatic duct epithelial (HPDE) cells were used for functional analyses. Levels of COL17A1 and Actinin Alpha 4 (ACTN4) were measured by using qRT-PCR and western blotting. Functional analyses were conducted using MTT, 5-ethynyl-2ʹ-deoxyuridine, transwell, and sphere formation assays, respectively. The interaction between COL17A1 and ACTN4 was analyzed by Co-immunoprecipitation and immunofluorescence assays. Animal models were established for in vivo analysis. Results CAF incubation promoted GEM resistance and enhanced the proliferation, invasion and stemness in GEM-resistant PC cells. COL17A1 was highly expressed in resistant CAFs and GEM-resistant PC cells, and CAF incubation could increase COL17A1 expression in resistant PC cells. Moreover, COL17A1 silencing in GEM-resistant PC cells or the incubation of COL17A1-decreased CAF with GEM-resistant PC cells could suppress GEM resistance and cell oncogenic phenotype progression. Mechanistically, COL17A1 interacted with ACTN4 protein, and the anticancer effects mediated by COL17A1-decreased CAFs in resistant PC cells were reversed by ACTN4 overexpression. In vivo assay also showed that COL17A1-decreased CAFs suppressed the growth and GEM resistance in PC by ACTN4. Conclusion CAFs-derived COL17A1 promoted GEM resistance and tumorigenesis in PC by interacting with ACTN4, suggesting a new method for overcoming GEM resistance in PC. |
| format | Article |
| id | doaj-art-9f1b57c4e798445abb672cbb5f08c89c |
| institution | Kabale University |
| issn | 2730-6011 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Springer |
| record_format | Article |
| series | Discover Oncology |
| spelling | doaj-art-9f1b57c4e798445abb672cbb5f08c89c2025-02-09T12:43:39ZengSpringerDiscover Oncology2730-60112025-02-0116111310.1007/s12672-025-01825-8Cancer-associated fibroblast-derived COL17A1 promotes gemcitabine resistance and tumorigenesis in pancreatic cancer cells by interacting with ACTN4Rongyu Shi0Ning Zhang1Han Li2Hu Zhong3Chengcheng Zhong4Wei Du5Xi Yang6Department of Hepatobiliary and Pancreatic Surgery, First People’s Hospital of Jiashan CountyDepartment of Hepatobiliary and Pancreatic Surgery, First People’s Hospital of Jiashan CountyDepartment of Hepatobiliary and Pancreatic Surgery, First People’s Hospital of Jiashan CountyDepartment of General Surgery, The Affiliated Shuyang Hospital of Xuzhou Medical UniversityDepartment of General Surgery, The Affiliated Shuyang Hospital of Xuzhou Medical UniversityDepartment of Hepatobiliary and Pancreatic Surgery, First People’s Hospital of Jiashan CountyDepartment of General Surgery, The Affiliated Shuyang Hospital of Xuzhou Medical UniversityAbstract Background Cancer-associated fibroblasts (CAFs) are key components of tumor microenvironment and have been identified to be involved in modulating drug resistance in cancers by secreting molecules. Pancreatic cancer (PC) is a leading cause of cancer mortality with high aggressiveness. Gemcitabine (GEM) is one of primary antineoplastic drugs for PC. Collagen XVII (COL17A1) expression was found to be upregulated in GEM-resistant CAFs. Here, this study focused on investigating whether CAFs affected GEM resistance in PC by secreting COL17A1 and its associated mechanisms. Methods In total, 60 newly diagnosed PC patients only with GEM-based chemotherapy were recruited. Normal fibroblasts (NFs) and CAFs were isolated using fresh normal and resistant PC tissues. Human pancreatic duct epithelial (HPDE) cells were used for functional analyses. Levels of COL17A1 and Actinin Alpha 4 (ACTN4) were measured by using qRT-PCR and western blotting. Functional analyses were conducted using MTT, 5-ethynyl-2ʹ-deoxyuridine, transwell, and sphere formation assays, respectively. The interaction between COL17A1 and ACTN4 was analyzed by Co-immunoprecipitation and immunofluorescence assays. Animal models were established for in vivo analysis. Results CAF incubation promoted GEM resistance and enhanced the proliferation, invasion and stemness in GEM-resistant PC cells. COL17A1 was highly expressed in resistant CAFs and GEM-resistant PC cells, and CAF incubation could increase COL17A1 expression in resistant PC cells. Moreover, COL17A1 silencing in GEM-resistant PC cells or the incubation of COL17A1-decreased CAF with GEM-resistant PC cells could suppress GEM resistance and cell oncogenic phenotype progression. Mechanistically, COL17A1 interacted with ACTN4 protein, and the anticancer effects mediated by COL17A1-decreased CAFs in resistant PC cells were reversed by ACTN4 overexpression. In vivo assay also showed that COL17A1-decreased CAFs suppressed the growth and GEM resistance in PC by ACTN4. Conclusion CAFs-derived COL17A1 promoted GEM resistance and tumorigenesis in PC by interacting with ACTN4, suggesting a new method for overcoming GEM resistance in PC.https://doi.org/10.1007/s12672-025-01825-8GemcitabineChemoresistanceStemnessCAFsCOL17A1ACTN4 |
| spellingShingle | Rongyu Shi Ning Zhang Han Li Hu Zhong Chengcheng Zhong Wei Du Xi Yang Cancer-associated fibroblast-derived COL17A1 promotes gemcitabine resistance and tumorigenesis in pancreatic cancer cells by interacting with ACTN4 Discover Oncology Gemcitabine Chemoresistance Stemness CAFs COL17A1 ACTN4 |
| title | Cancer-associated fibroblast-derived COL17A1 promotes gemcitabine resistance and tumorigenesis in pancreatic cancer cells by interacting with ACTN4 |
| title_full | Cancer-associated fibroblast-derived COL17A1 promotes gemcitabine resistance and tumorigenesis in pancreatic cancer cells by interacting with ACTN4 |
| title_fullStr | Cancer-associated fibroblast-derived COL17A1 promotes gemcitabine resistance and tumorigenesis in pancreatic cancer cells by interacting with ACTN4 |
| title_full_unstemmed | Cancer-associated fibroblast-derived COL17A1 promotes gemcitabine resistance and tumorigenesis in pancreatic cancer cells by interacting with ACTN4 |
| title_short | Cancer-associated fibroblast-derived COL17A1 promotes gemcitabine resistance and tumorigenesis in pancreatic cancer cells by interacting with ACTN4 |
| title_sort | cancer associated fibroblast derived col17a1 promotes gemcitabine resistance and tumorigenesis in pancreatic cancer cells by interacting with actn4 |
| topic | Gemcitabine Chemoresistance Stemness CAFs COL17A1 ACTN4 |
| url | https://doi.org/10.1007/s12672-025-01825-8 |
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