N6-methyladenosine-modified circSLCO1B3 promotes intrahepatic cholangiocarcinoma progression via regulating HOXC8 and PD-L1
Abstract Background Refractoriness to surgical resection and chemotherapy makes intrahepatic cholangiocarcinoma (ICC) a fatal cancer of the digestive system with high mortality and poor prognosis. Important function invests circRNAs with tremendous potential in biomarkers and therapeutic targets. Ne...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-04-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13046-024-03006-x |
| _version_ | 1827276855734960128 |
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| author | Jing Li Xiaohong Xu Kaihao Xu Xueliang Zhou Kunpeng Wu Yuan Yao Zaoqu Liu Chen Chen Ling Wang Zhenqiang Sun Dechao Jiao Xinwei Han |
| author_facet | Jing Li Xiaohong Xu Kaihao Xu Xueliang Zhou Kunpeng Wu Yuan Yao Zaoqu Liu Chen Chen Ling Wang Zhenqiang Sun Dechao Jiao Xinwei Han |
| author_sort | Jing Li |
| collection | DOAJ |
| description | Abstract Background Refractoriness to surgical resection and chemotherapy makes intrahepatic cholangiocarcinoma (ICC) a fatal cancer of the digestive system with high mortality and poor prognosis. Important function invests circRNAs with tremendous potential in biomarkers and therapeutic targets. Nevertheless, it is still unknown how circRNAs contribute to the evolution of ICC. Methods CircRNAs in paired ICC and adjacent tissues were screened by circRNAs sequencing. To explore the impact of circRNAs on ICC development, experiments involving gain and loss of function were conducted. Various experimental techniques, including quantitative real-time PCR (qPCR), western blotting, RNA immunoprecipitation (RIP), luciferase reporter assays, RNA pull-down, chromatin immunoprecipitation (ChIP), ubiquitination assays and so on were employed to identify the molecular regulatory role of circRNAs. Results Herein, we reported a new circRNA, which originates from exon 9 to exon 15 of the SLCO1B3 gene (named circSLCO1B3), orchestrated ICC progression by promoting tumor proliferation, metastasis and immune evasion. We found that the circSLCO1B3 gene was highly overexpressed in ICC tissues and related to lymphatic metastasis, tumor sizes, and tumor differentiation. Mechanically, circSLCO1B3 not only promoted ICC proliferation and metastasis via miR-502-5p/HOXC8/SMAD3 axis, but also eradicated anti-tumor immunity via suppressing ubiquitin-proteasome-dependent degradation of PD-L1 by E3 ubiquitin ligase SPOP. We further found that methyltransferase like 3 (METTL3) mediated the m6A methylation of circSLCO1B3 and stabilizes its expression. Our findings indicate that circSLCO1B3 is a potential prognostic marker and therapeutic target in ICC patients. Conclusions Taken together, m6A-modified circSLCO1B3 was correlated with poor prognosis in ICC and promoted ICC progression not only by enhancing proliferation and metastasis via potentiating HOXC8 expression, but also by inducing immune evasion via antagonizing PD-L1 degradation. These results suggest that circSLCO1B3 is a potential prognostic marker and therapeutic target for ICC. |
| first_indexed | 2024-04-24T07:11:05Z |
| format | Article |
| id | doaj.art-ac6dfdd7a0064e519a03666cf202fd5a |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-04-24T07:11:05Z |
| publishDate | 2024-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-ac6dfdd7a0064e519a03666cf202fd5a2024-04-21T11:33:58ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662024-04-0143112310.1186/s13046-024-03006-xN6-methyladenosine-modified circSLCO1B3 promotes intrahepatic cholangiocarcinoma progression via regulating HOXC8 and PD-L1Jing Li0Xiaohong Xu1Kaihao Xu2Xueliang Zhou3Kunpeng Wu4Yuan Yao5Zaoqu Liu6Chen Chen7Ling Wang8Zhenqiang Sun9Dechao Jiao10Xinwei Han11Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Interventional Radiology, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Interventional Radiology, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Interventional Radiology, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Interventional Radiology, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Interventional Radiology, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Interventional Radiology, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Interventional Radiology, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Interventional Radiology, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Interventional Radiology, The First Affiliated Hospital of Zhengzhou UniversityAbstract Background Refractoriness to surgical resection and chemotherapy makes intrahepatic cholangiocarcinoma (ICC) a fatal cancer of the digestive system with high mortality and poor prognosis. Important function invests circRNAs with tremendous potential in biomarkers and therapeutic targets. Nevertheless, it is still unknown how circRNAs contribute to the evolution of ICC. Methods CircRNAs in paired ICC and adjacent tissues were screened by circRNAs sequencing. To explore the impact of circRNAs on ICC development, experiments involving gain and loss of function were conducted. Various experimental techniques, including quantitative real-time PCR (qPCR), western blotting, RNA immunoprecipitation (RIP), luciferase reporter assays, RNA pull-down, chromatin immunoprecipitation (ChIP), ubiquitination assays and so on were employed to identify the molecular regulatory role of circRNAs. Results Herein, we reported a new circRNA, which originates from exon 9 to exon 15 of the SLCO1B3 gene (named circSLCO1B3), orchestrated ICC progression by promoting tumor proliferation, metastasis and immune evasion. We found that the circSLCO1B3 gene was highly overexpressed in ICC tissues and related to lymphatic metastasis, tumor sizes, and tumor differentiation. Mechanically, circSLCO1B3 not only promoted ICC proliferation and metastasis via miR-502-5p/HOXC8/SMAD3 axis, but also eradicated anti-tumor immunity via suppressing ubiquitin-proteasome-dependent degradation of PD-L1 by E3 ubiquitin ligase SPOP. We further found that methyltransferase like 3 (METTL3) mediated the m6A methylation of circSLCO1B3 and stabilizes its expression. Our findings indicate that circSLCO1B3 is a potential prognostic marker and therapeutic target in ICC patients. Conclusions Taken together, m6A-modified circSLCO1B3 was correlated with poor prognosis in ICC and promoted ICC progression not only by enhancing proliferation and metastasis via potentiating HOXC8 expression, but also by inducing immune evasion via antagonizing PD-L1 degradation. These results suggest that circSLCO1B3 is a potential prognostic marker and therapeutic target for ICC.https://doi.org/10.1186/s13046-024-03006-xCholangiocarcinomacircRNAsImmune evasionN6-methyladenosineTumor progression |
| spellingShingle | Jing Li Xiaohong Xu Kaihao Xu Xueliang Zhou Kunpeng Wu Yuan Yao Zaoqu Liu Chen Chen Ling Wang Zhenqiang Sun Dechao Jiao Xinwei Han N6-methyladenosine-modified circSLCO1B3 promotes intrahepatic cholangiocarcinoma progression via regulating HOXC8 and PD-L1 Journal of Experimental & Clinical Cancer Research Cholangiocarcinoma circRNAs Immune evasion N6-methyladenosine Tumor progression |
| title | N6-methyladenosine-modified circSLCO1B3 promotes intrahepatic cholangiocarcinoma progression via regulating HOXC8 and PD-L1 |
| title_full | N6-methyladenosine-modified circSLCO1B3 promotes intrahepatic cholangiocarcinoma progression via regulating HOXC8 and PD-L1 |
| title_fullStr | N6-methyladenosine-modified circSLCO1B3 promotes intrahepatic cholangiocarcinoma progression via regulating HOXC8 and PD-L1 |
| title_full_unstemmed | N6-methyladenosine-modified circSLCO1B3 promotes intrahepatic cholangiocarcinoma progression via regulating HOXC8 and PD-L1 |
| title_short | N6-methyladenosine-modified circSLCO1B3 promotes intrahepatic cholangiocarcinoma progression via regulating HOXC8 and PD-L1 |
| title_sort | n6 methyladenosine modified circslco1b3 promotes intrahepatic cholangiocarcinoma progression via regulating hoxc8 and pd l1 |
| topic | Cholangiocarcinoma circRNAs Immune evasion N6-methyladenosine Tumor progression |
| url | https://doi.org/10.1186/s13046-024-03006-x |
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