Cancer-associated fibroblasts induce sorafenib resistance of hepatocellular carcinoma cells through CXCL12/FOLR1
Abstract Background Due to the high drug resistance of hepatocellular carcinoma (HCC), sorafenib has limited efficacy in the treatment of advanced HCC. Cancer-associated fibroblasts (CAFs) play an important regulatory role in the induction of chemoresistance. This study aimed to clarify the mechanis...
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BMC
2023-12-01
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| Series: | BMC Cancer |
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| Online Access: | https://doi.org/10.1186/s12885-023-11613-8 |
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| author | Jiali Zhao En Lin Zirui Bai Yingbin Jia Bo Wang Yihua Dai Wenfeng Zhuo Guifang Zeng Xialei Liu Chaonong Cai Peiping Li Baojia Zou Jian Li |
| author_facet | Jiali Zhao En Lin Zirui Bai Yingbin Jia Bo Wang Yihua Dai Wenfeng Zhuo Guifang Zeng Xialei Liu Chaonong Cai Peiping Li Baojia Zou Jian Li |
| author_sort | Jiali Zhao |
| collection | DOAJ |
| description | Abstract Background Due to the high drug resistance of hepatocellular carcinoma (HCC), sorafenib has limited efficacy in the treatment of advanced HCC. Cancer-associated fibroblasts (CAFs) play an important regulatory role in the induction of chemoresistance. This study aimed to clarify the mechanism underlying CAF-mediated resistance to sorafenib in HCC. Methods Immunohistochemistry and immunofluorescence showed that the activation of CAFs was enhanced in HCC tissues. CAFs and paracancerous normal fibroblasts (NFs) were isolated from the cancer and paracancerous tissues of HCC, respectively. Cell cloning assays, ELISAs, and flow cytometry were used to detect whether CAFs induced sorafenib resistance in HCC cells via CXCL12. Western blotting and qPCR showed that CXCL12 induces sorafenib resistance in HCC cells by upregulating FOLR1. We investigated whether FOLR1 was the target molecule of CAFs regulating sorafenib resistance in HCC cells by querying gene expression data for human HCC specimens from the GEO database. Results High levels of activated CAFs were present in HCC tissues but not in paracancerous tissues. CAFs decreased the sensitivity of HCC cells to sorafenib. We found that CAFs secrete CXCL12, which upregulates FOLR1 in HCC cells to induce sorafenib resistance. Conclusions CAFs induce sorafenib resistance in HCC cells through CXCL12/FOLR1. |
| format | Article |
| id | doaj-art-d62a3c6659d6470eba4631389bdadecc |
| institution | DOAJ |
| issn | 1471-2407 |
| language | English |
| publishDate | 2023-12-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj-art-d62a3c6659d6470eba4631389bdadecc2025-08-20T03:06:01ZengBMCBMC Cancer1471-24072023-12-0123111110.1186/s12885-023-11613-8Cancer-associated fibroblasts induce sorafenib resistance of hepatocellular carcinoma cells through CXCL12/FOLR1Jiali Zhao0En Lin1Zirui Bai2Yingbin Jia3Bo Wang4Yihua Dai5Wenfeng Zhuo6Guifang Zeng7Xialei Liu8Chaonong Cai9Peiping Li10Baojia Zou11Jian Li12Department of Hepatobiliary Surgery, Fifth Affiliated Hospital of Sun Yat-Sen UniversityDepartment of Hepatobiliary Surgery, Fifth Affiliated Hospital of Sun Yat-Sen UniversityDepartment of Hepatobiliary Surgery, Fifth Affiliated Hospital of Sun Yat-Sen UniversityDepartment of Urology Surgery, Fifth Affiliated Hospital of Sun Yat-Sen UniversityDepartment of Hepatobiliary Surgery, Fifth Affiliated Hospital of Sun Yat-Sen UniversityDepartment of Anesthesiology, Fifth Affiliated Hospital of Sun Yat-Sen UniversityDepartment of Hepatobiliary Surgery, Fifth Affiliated Hospital of Sun Yat-Sen UniversityDepartment of Hepatobiliary Surgery, Fifth Affiliated Hospital of Sun Yat-Sen UniversityDepartment of Hepatobiliary Surgery, Fifth Affiliated Hospital of Sun Yat-Sen UniversityDepartment of Hepatobiliary Surgery, Fifth Affiliated Hospital of Sun Yat-Sen UniversityDepartment of Hepatobiliary Surgery, Fifth Affiliated Hospital of Sun Yat-Sen UniversityDepartment of Hepatobiliary Surgery, Fifth Affiliated Hospital of Sun Yat-Sen UniversityDepartment of Hepatobiliary Surgery, Fifth Affiliated Hospital of Sun Yat-Sen UniversityAbstract Background Due to the high drug resistance of hepatocellular carcinoma (HCC), sorafenib has limited efficacy in the treatment of advanced HCC. Cancer-associated fibroblasts (CAFs) play an important regulatory role in the induction of chemoresistance. This study aimed to clarify the mechanism underlying CAF-mediated resistance to sorafenib in HCC. Methods Immunohistochemistry and immunofluorescence showed that the activation of CAFs was enhanced in HCC tissues. CAFs and paracancerous normal fibroblasts (NFs) were isolated from the cancer and paracancerous tissues of HCC, respectively. Cell cloning assays, ELISAs, and flow cytometry were used to detect whether CAFs induced sorafenib resistance in HCC cells via CXCL12. Western blotting and qPCR showed that CXCL12 induces sorafenib resistance in HCC cells by upregulating FOLR1. We investigated whether FOLR1 was the target molecule of CAFs regulating sorafenib resistance in HCC cells by querying gene expression data for human HCC specimens from the GEO database. Results High levels of activated CAFs were present in HCC tissues but not in paracancerous tissues. CAFs decreased the sensitivity of HCC cells to sorafenib. We found that CAFs secrete CXCL12, which upregulates FOLR1 in HCC cells to induce sorafenib resistance. Conclusions CAFs induce sorafenib resistance in HCC cells through CXCL12/FOLR1.https://doi.org/10.1186/s12885-023-11613-8Cancer-associated fibroblastsHepatocellular carcinomaSorafenibResistance |
| spellingShingle | Jiali Zhao En Lin Zirui Bai Yingbin Jia Bo Wang Yihua Dai Wenfeng Zhuo Guifang Zeng Xialei Liu Chaonong Cai Peiping Li Baojia Zou Jian Li Cancer-associated fibroblasts induce sorafenib resistance of hepatocellular carcinoma cells through CXCL12/FOLR1 BMC Cancer Cancer-associated fibroblasts Hepatocellular carcinoma Sorafenib Resistance |
| title | Cancer-associated fibroblasts induce sorafenib resistance of hepatocellular carcinoma cells through CXCL12/FOLR1 |
| title_full | Cancer-associated fibroblasts induce sorafenib resistance of hepatocellular carcinoma cells through CXCL12/FOLR1 |
| title_fullStr | Cancer-associated fibroblasts induce sorafenib resistance of hepatocellular carcinoma cells through CXCL12/FOLR1 |
| title_full_unstemmed | Cancer-associated fibroblasts induce sorafenib resistance of hepatocellular carcinoma cells through CXCL12/FOLR1 |
| title_short | Cancer-associated fibroblasts induce sorafenib resistance of hepatocellular carcinoma cells through CXCL12/FOLR1 |
| title_sort | cancer associated fibroblasts induce sorafenib resistance of hepatocellular carcinoma cells through cxcl12 folr1 |
| topic | Cancer-associated fibroblasts Hepatocellular carcinoma Sorafenib Resistance |
| url | https://doi.org/10.1186/s12885-023-11613-8 |
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