PREX2 contributes to radiation resistance by inhibiting radiotherapy-induced tumor immunogenicity via cGAS/STING/IFNs pathway in colorectal cancer
Abstract Background Colorectal cancer (CRC) lacks established biomarkers or molecular targets for predicting or enhancing radiation response. Phosphatidylinositol-3,4,5-triphosphate-dependent Rac exchange factor 2 (PREX2) exhibits intricate implications in tumorigenesis and progression. Nevertheless...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2024-04-01
|
| Series: | BMC Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12916-024-03375-2 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849343056593027072 |
|---|---|
| author | Mingzhou Li Jianbiao Xiao Shasha Song Fangyi Han Hongling Liu Yang Lin Yunfei Ni Sisi Zeng Xin Zou Jieqiong Wu Feifei Wang Shaowan Xu You Liang Peishuang Xu Huirong Hong Junfeng Qiu Jianing Cao Qin Zhu Li Liang |
| author_facet | Mingzhou Li Jianbiao Xiao Shasha Song Fangyi Han Hongling Liu Yang Lin Yunfei Ni Sisi Zeng Xin Zou Jieqiong Wu Feifei Wang Shaowan Xu You Liang Peishuang Xu Huirong Hong Junfeng Qiu Jianing Cao Qin Zhu Li Liang |
| author_sort | Mingzhou Li |
| collection | DOAJ |
| description | Abstract Background Colorectal cancer (CRC) lacks established biomarkers or molecular targets for predicting or enhancing radiation response. Phosphatidylinositol-3,4,5-triphosphate-dependent Rac exchange factor 2 (PREX2) exhibits intricate implications in tumorigenesis and progression. Nevertheless, the precise role and underlying mechanisms of PREX2 in CRC radioresistance remain unclear. Methods RNA-seq was employed to identify differentially expressed genes between radioresistant CRC cell lines and their parental counterparts. PREX2 expression was scrutinized using Western blotting, real-time PCR, and immunohistochemistry. The radioresistant role of PREX2 was assessed through in vitro colony formation assay, apoptosis assay, comet assay, and in vivo xenograft tumor models. The mechanism of PREX2 was elucidated using RNA-seq and Western blotting. Finally, a PREX2 small-molecule inhibitor, designated PREX-in1, was utilized to enhance the efficacy of ionizing radiation (IR) therapy in CRC mouse models. Results PREX2 emerged as the most significantly upregulated gene in radioresistant CRC cells. It augmented the radioresistant capacity of CRC cells and demonstrated potential as a marker for predicting radioresistance efficacy. Mechanistically, PREX2 facilitated DNA repair by upregulating DNA-PKcs, suppressing radiation-induced immunogenic cell death, and impeding CD8+ T cell infiltration through the cGAS/STING/IFNs pathway. In vivo, the blockade of PREX2 heightened the efficacy of IR therapy. Conclusions PREX2 assumes a pivotal role in CRC radiation resistance by inhibiting the cGAS/STING/IFNs pathway, presenting itself as a potential radioresistant biomarker and therapeutic target for effectively overcoming radioresistance in CRC. |
| format | Article |
| id | doaj-art-1cd153a0a0dc400b8b50dbba1aa25cfe |
| institution | Kabale University |
| issn | 1741-7015 |
| language | English |
| publishDate | 2024-04-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medicine |
| spelling | doaj-art-1cd153a0a0dc400b8b50dbba1aa25cfe2025-08-20T03:43:11ZengBMCBMC Medicine1741-70152024-04-0122112010.1186/s12916-024-03375-2PREX2 contributes to radiation resistance by inhibiting radiotherapy-induced tumor immunogenicity via cGAS/STING/IFNs pathway in colorectal cancerMingzhou Li0Jianbiao Xiao1Shasha Song2Fangyi Han3Hongling Liu4Yang Lin5Yunfei Ni6Sisi Zeng7Xin Zou8Jieqiong Wu9Feifei Wang10Shaowan Xu11You Liang12Peishuang Xu13Huirong Hong14Junfeng Qiu15Jianing Cao16Qin Zhu17Li Liang18Department of Pathology, Nanfang Hospital, Southern Medical UniversityDepartment of Pathology, Nanfang Hospital, Southern Medical UniversityDepartment of Pathology, Yantai Fushan People’s HospitalDepartment of Pathology, Nanfang Hospital, Southern Medical UniversityDepartment of Pathology, Nanfang Hospital, Southern Medical UniversityDepartment of Pathology, Nanfang Hospital, Southern Medical UniversityDepartment of Pathology, Nanfang Hospital, Southern Medical UniversityDepartment of Pathology, Nanfang Hospital, Southern Medical UniversityDepartment of Pathology, Nanfang Hospital, Southern Medical UniversityDepartment of Pathology, Nanfang Hospital, Southern Medical UniversityDepartment of Pathology, Nanfang Hospital, Southern Medical UniversityDepartment of Pathology, Nanfang Hospital, Southern Medical UniversityDepartment of Pathology, Nanfang Hospital, Southern Medical UniversityDepartment of Pathology, Nanfang Hospital, Southern Medical UniversityDepartment of Pathology, Nanfang Hospital, Southern Medical UniversityDepartment of Pathology, Nanfang Hospital, Southern Medical UniversityDepartment of Pathology, Nanfang Hospital, Southern Medical UniversityDepartment of Pathology, Nanfang Hospital, Southern Medical UniversityDepartment of Pathology, Nanfang Hospital, Southern Medical UniversityAbstract Background Colorectal cancer (CRC) lacks established biomarkers or molecular targets for predicting or enhancing radiation response. Phosphatidylinositol-3,4,5-triphosphate-dependent Rac exchange factor 2 (PREX2) exhibits intricate implications in tumorigenesis and progression. Nevertheless, the precise role and underlying mechanisms of PREX2 in CRC radioresistance remain unclear. Methods RNA-seq was employed to identify differentially expressed genes between radioresistant CRC cell lines and their parental counterparts. PREX2 expression was scrutinized using Western blotting, real-time PCR, and immunohistochemistry. The radioresistant role of PREX2 was assessed through in vitro colony formation assay, apoptosis assay, comet assay, and in vivo xenograft tumor models. The mechanism of PREX2 was elucidated using RNA-seq and Western blotting. Finally, a PREX2 small-molecule inhibitor, designated PREX-in1, was utilized to enhance the efficacy of ionizing radiation (IR) therapy in CRC mouse models. Results PREX2 emerged as the most significantly upregulated gene in radioresistant CRC cells. It augmented the radioresistant capacity of CRC cells and demonstrated potential as a marker for predicting radioresistance efficacy. Mechanistically, PREX2 facilitated DNA repair by upregulating DNA-PKcs, suppressing radiation-induced immunogenic cell death, and impeding CD8+ T cell infiltration through the cGAS/STING/IFNs pathway. In vivo, the blockade of PREX2 heightened the efficacy of IR therapy. Conclusions PREX2 assumes a pivotal role in CRC radiation resistance by inhibiting the cGAS/STING/IFNs pathway, presenting itself as a potential radioresistant biomarker and therapeutic target for effectively overcoming radioresistance in CRC.https://doi.org/10.1186/s12916-024-03375-2Colorectal cancerPREX2Immunogenic cell deathRadioresistancecGAS/STING/IFNs |
| spellingShingle | Mingzhou Li Jianbiao Xiao Shasha Song Fangyi Han Hongling Liu Yang Lin Yunfei Ni Sisi Zeng Xin Zou Jieqiong Wu Feifei Wang Shaowan Xu You Liang Peishuang Xu Huirong Hong Junfeng Qiu Jianing Cao Qin Zhu Li Liang PREX2 contributes to radiation resistance by inhibiting radiotherapy-induced tumor immunogenicity via cGAS/STING/IFNs pathway in colorectal cancer BMC Medicine Colorectal cancer PREX2 Immunogenic cell death Radioresistance cGAS/STING/IFNs |
| title | PREX2 contributes to radiation resistance by inhibiting radiotherapy-induced tumor immunogenicity via cGAS/STING/IFNs pathway in colorectal cancer |
| title_full | PREX2 contributes to radiation resistance by inhibiting radiotherapy-induced tumor immunogenicity via cGAS/STING/IFNs pathway in colorectal cancer |
| title_fullStr | PREX2 contributes to radiation resistance by inhibiting radiotherapy-induced tumor immunogenicity via cGAS/STING/IFNs pathway in colorectal cancer |
| title_full_unstemmed | PREX2 contributes to radiation resistance by inhibiting radiotherapy-induced tumor immunogenicity via cGAS/STING/IFNs pathway in colorectal cancer |
| title_short | PREX2 contributes to radiation resistance by inhibiting radiotherapy-induced tumor immunogenicity via cGAS/STING/IFNs pathway in colorectal cancer |
| title_sort | prex2 contributes to radiation resistance by inhibiting radiotherapy induced tumor immunogenicity via cgas sting ifns pathway in colorectal cancer |
| topic | Colorectal cancer PREX2 Immunogenic cell death Radioresistance cGAS/STING/IFNs |
| url | https://doi.org/10.1186/s12916-024-03375-2 |
| work_keys_str_mv | AT mingzhouli prex2contributestoradiationresistancebyinhibitingradiotherapyinducedtumorimmunogenicityviacgasstingifnspathwayincolorectalcancer AT jianbiaoxiao prex2contributestoradiationresistancebyinhibitingradiotherapyinducedtumorimmunogenicityviacgasstingifnspathwayincolorectalcancer AT shashasong prex2contributestoradiationresistancebyinhibitingradiotherapyinducedtumorimmunogenicityviacgasstingifnspathwayincolorectalcancer AT fangyihan prex2contributestoradiationresistancebyinhibitingradiotherapyinducedtumorimmunogenicityviacgasstingifnspathwayincolorectalcancer AT honglingliu prex2contributestoradiationresistancebyinhibitingradiotherapyinducedtumorimmunogenicityviacgasstingifnspathwayincolorectalcancer AT yanglin prex2contributestoradiationresistancebyinhibitingradiotherapyinducedtumorimmunogenicityviacgasstingifnspathwayincolorectalcancer AT yunfeini prex2contributestoradiationresistancebyinhibitingradiotherapyinducedtumorimmunogenicityviacgasstingifnspathwayincolorectalcancer AT sisizeng prex2contributestoradiationresistancebyinhibitingradiotherapyinducedtumorimmunogenicityviacgasstingifnspathwayincolorectalcancer AT xinzou prex2contributestoradiationresistancebyinhibitingradiotherapyinducedtumorimmunogenicityviacgasstingifnspathwayincolorectalcancer AT jieqiongwu prex2contributestoradiationresistancebyinhibitingradiotherapyinducedtumorimmunogenicityviacgasstingifnspathwayincolorectalcancer AT feifeiwang prex2contributestoradiationresistancebyinhibitingradiotherapyinducedtumorimmunogenicityviacgasstingifnspathwayincolorectalcancer AT shaowanxu prex2contributestoradiationresistancebyinhibitingradiotherapyinducedtumorimmunogenicityviacgasstingifnspathwayincolorectalcancer AT youliang prex2contributestoradiationresistancebyinhibitingradiotherapyinducedtumorimmunogenicityviacgasstingifnspathwayincolorectalcancer AT peishuangxu prex2contributestoradiationresistancebyinhibitingradiotherapyinducedtumorimmunogenicityviacgasstingifnspathwayincolorectalcancer AT huironghong prex2contributestoradiationresistancebyinhibitingradiotherapyinducedtumorimmunogenicityviacgasstingifnspathwayincolorectalcancer AT junfengqiu prex2contributestoradiationresistancebyinhibitingradiotherapyinducedtumorimmunogenicityviacgasstingifnspathwayincolorectalcancer AT jianingcao prex2contributestoradiationresistancebyinhibitingradiotherapyinducedtumorimmunogenicityviacgasstingifnspathwayincolorectalcancer AT qinzhu prex2contributestoradiationresistancebyinhibitingradiotherapyinducedtumorimmunogenicityviacgasstingifnspathwayincolorectalcancer AT liliang prex2contributestoradiationresistancebyinhibitingradiotherapyinducedtumorimmunogenicityviacgasstingifnspathwayincolorectalcancer |