Circular RNA circPHLPP2 promotes tumor growth and anti-PD-1 resistance through binding ILF3 to regulate IL36γ transcription in colorectal cancer
Abstract Background Most Colorectal Cancer (CRC) patients exhibit limited responsiveness to anti-programmed cell death protein 1 (PD-1) therapy, with the underlying mechanisms remaining elusive. Circular RNAs (circRNAs) play a significant role in tumorigenesis and development, with potential applica...
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BMC
2024-12-01
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| Series: | Molecular Cancer |
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| Online Access: | https://doi.org/10.1186/s12943-024-02192-8 |
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| author | Yan Hu Ze-Rong Cai Ren-Ze Huang De-Shen Wang Huai-Qiang Ju Dong-Liang Chen |
| author_facet | Yan Hu Ze-Rong Cai Ren-Ze Huang De-Shen Wang Huai-Qiang Ju Dong-Liang Chen |
| author_sort | Yan Hu |
| collection | DOAJ |
| description | Abstract Background Most Colorectal Cancer (CRC) patients exhibit limited responsiveness to anti-programmed cell death protein 1 (PD-1) therapy, with the underlying mechanisms remaining elusive. Circular RNAs (circRNAs) play a significant role in tumorigenesis and development, with potential applications in tumor screening and predicting treatment efficacy. However, there are few studies exploring the role of circRNAs in CRC immune evasion. Methods circRNA microarrays were used to identify circPHLPP2. RT-qPCR was used to examine the associations between the expression level of circPHLPP2 and the clinical characteristics of CRC patients. MTS assay, clone formation experiment, subcutaneous tumor implantation and multicolor flow cytometry were used to confirm the biological function of circPHLPP2. RAN-seq, RT-qPCR, and WB experiments were performed to investigate the downstream signaling pathways involved in circPHLPP2. RNA pull-down, RNA immunoprecipitation (RIP) and immunofluorescence staining were performed to identify the proteins associated with circPHLPP2. Results circPHLPP2 is up-regulated in CRC patients who exhibit resistance to anti-PD-1 based therapy. circPHLPP2 significantly promotes the proliferation and tumor growth of CRC cells. Knockdown of circPhlpp2 enhances the efficacy of anti-PD-1 in vivo. Mechanistically, the specific interaction between circPHLPP2 and ILF3 facilitates the nuclear accumulation of ILF3, which subsequently enhances the transcription of IL36γ. This process reduces NK cell infiltration and impairs NK cells’ granzyme B and IFN-γ production, thereby promoting tumor progression. Conclusions Overall, our findings reveal a novel mechanism by which circRNA regulates CRC immune evasion. circPHLPP2 may serve as a prognostic biomarker and potential therapeutic target for CRC patients. |
| format | Article |
| id | doaj-art-8dc2afeb1ccd4aa5ae99c75824595dae |
| institution | OA Journals |
| issn | 1476-4598 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj-art-8dc2afeb1ccd4aa5ae99c75824595dae2025-08-20T02:32:25ZengBMCMolecular Cancer1476-45982024-12-0123111810.1186/s12943-024-02192-8Circular RNA circPHLPP2 promotes tumor growth and anti-PD-1 resistance through binding ILF3 to regulate IL36γ transcription in colorectal cancerYan Hu0Ze-Rong Cai1Ren-Ze Huang2De-Shen Wang3Huai-Qiang Ju4Dong-Liang Chen5Department of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterDepartment of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterDepartment of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterDepartment of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterDepartment of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterDepartment of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer CenterAbstract Background Most Colorectal Cancer (CRC) patients exhibit limited responsiveness to anti-programmed cell death protein 1 (PD-1) therapy, with the underlying mechanisms remaining elusive. Circular RNAs (circRNAs) play a significant role in tumorigenesis and development, with potential applications in tumor screening and predicting treatment efficacy. However, there are few studies exploring the role of circRNAs in CRC immune evasion. Methods circRNA microarrays were used to identify circPHLPP2. RT-qPCR was used to examine the associations between the expression level of circPHLPP2 and the clinical characteristics of CRC patients. MTS assay, clone formation experiment, subcutaneous tumor implantation and multicolor flow cytometry were used to confirm the biological function of circPHLPP2. RAN-seq, RT-qPCR, and WB experiments were performed to investigate the downstream signaling pathways involved in circPHLPP2. RNA pull-down, RNA immunoprecipitation (RIP) and immunofluorescence staining were performed to identify the proteins associated with circPHLPP2. Results circPHLPP2 is up-regulated in CRC patients who exhibit resistance to anti-PD-1 based therapy. circPHLPP2 significantly promotes the proliferation and tumor growth of CRC cells. Knockdown of circPhlpp2 enhances the efficacy of anti-PD-1 in vivo. Mechanistically, the specific interaction between circPHLPP2 and ILF3 facilitates the nuclear accumulation of ILF3, which subsequently enhances the transcription of IL36γ. This process reduces NK cell infiltration and impairs NK cells’ granzyme B and IFN-γ production, thereby promoting tumor progression. Conclusions Overall, our findings reveal a novel mechanism by which circRNA regulates CRC immune evasion. circPHLPP2 may serve as a prognostic biomarker and potential therapeutic target for CRC patients.https://doi.org/10.1186/s12943-024-02192-8CircPHLPP2Colorectal cancerNK cellImmune evasion |
| spellingShingle | Yan Hu Ze-Rong Cai Ren-Ze Huang De-Shen Wang Huai-Qiang Ju Dong-Liang Chen Circular RNA circPHLPP2 promotes tumor growth and anti-PD-1 resistance through binding ILF3 to regulate IL36γ transcription in colorectal cancer Molecular Cancer CircPHLPP2 Colorectal cancer NK cell Immune evasion |
| title | Circular RNA circPHLPP2 promotes tumor growth and anti-PD-1 resistance through binding ILF3 to regulate IL36γ transcription in colorectal cancer |
| title_full | Circular RNA circPHLPP2 promotes tumor growth and anti-PD-1 resistance through binding ILF3 to regulate IL36γ transcription in colorectal cancer |
| title_fullStr | Circular RNA circPHLPP2 promotes tumor growth and anti-PD-1 resistance through binding ILF3 to regulate IL36γ transcription in colorectal cancer |
| title_full_unstemmed | Circular RNA circPHLPP2 promotes tumor growth and anti-PD-1 resistance through binding ILF3 to regulate IL36γ transcription in colorectal cancer |
| title_short | Circular RNA circPHLPP2 promotes tumor growth and anti-PD-1 resistance through binding ILF3 to regulate IL36γ transcription in colorectal cancer |
| title_sort | circular rna circphlpp2 promotes tumor growth and anti pd 1 resistance through binding ilf3 to regulate il36γ transcription in colorectal cancer |
| topic | CircPHLPP2 Colorectal cancer NK cell Immune evasion |
| url | https://doi.org/10.1186/s12943-024-02192-8 |
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