m6A-modified circXPO1 accelerates colorectal cancer progression via interaction with FMRP to promote WWC2 mRNA decay
Abstract Background Recent evidence has demonstrated the vital roles of circular RNAs (circRNAs) in the progression of colorectal cancer (CRC); however, their functions and mechanisms in CRC need to be further explored. This study aimed to uncover the biological function of circXPO1 in CRC progressi...
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BMC
2024-10-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-024-05716-4 |
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| author | Xiaowen Zhu Pengxia Zhang |
| author_facet | Xiaowen Zhu Pengxia Zhang |
| author_sort | Xiaowen Zhu |
| collection | DOAJ |
| description | Abstract Background Recent evidence has demonstrated the vital roles of circular RNAs (circRNAs) in the progression of colorectal cancer (CRC); however, their functions and mechanisms in CRC need to be further explored. This study aimed to uncover the biological function of circXPO1 in CRC progression. Methods CircXPO1 was identified by Sanger sequencing, RNase R, and actinomycin D treatment assays. Colony formation, scratch, transwell assays, and mouse xenograft models were adopted to evaluate CRC cell growth and metastasis in vitro and in vivo. Subcellular expression of circXPO1 was detected by FISH and nuclear-cytoplasmic separation assays. Molecular mechanisms were investigated by MeRIP, RIP, and RNA pull-down assays. Target molecular expression was detected by RT-qPCR, Western blotting and immunohistochemical staining. Results circXPO1 was up-regulated in CRC tissues and cells, which indicated a poor prognosis of CRC patients. circXPO1 deficiency delayed the growth, EMT, and metastasis of CRC cells. Mechanistical experiments indicated that down-regulation of ALKBH5 enhanced IGF2BP2-mediated m6A modification of circXPO1 to increase circXPO1 expression. Furthermore, circXPO1 interacted with FMRP to reduce the mRNA stability of WWC2, which consequently resulted in Hippo-YAP pathway activation. Rescue experiments suggested that WWC2 overexpression abrogated circXPO1-mediated malignant capacities of CRC cells. The in vivo growth and liver metastasis of CRC cells were restrained by circXPO1 depletion or WWC2 overexpression. Conclusions m6A-modified circXPO1 by ALKBH5/IGF2BP2 axis destabilized WWC2 via interaction with FMRP to activate Hippo-YAP pathway, thereby facilitating CRC growth and metastasis. Targeting circXPO1 might be a potential therapeutic strategy for CRC. |
| format | Article |
| id | doaj-art-1f324f3bc2fb48db959e1be0e5f363b9 |
| institution | OA Journals |
| issn | 1479-5876 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | BMC |
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| series | Journal of Translational Medicine |
| spelling | doaj-art-1f324f3bc2fb48db959e1be0e5f363b92025-08-20T01:50:38ZengBMCJournal of Translational Medicine1479-58762024-10-0122111610.1186/s12967-024-05716-4m6A-modified circXPO1 accelerates colorectal cancer progression via interaction with FMRP to promote WWC2 mRNA decayXiaowen Zhu0Pengxia Zhang1Key laboratory of Microecology-immune Regulatory Network and Related Diseases, School of Basic Medicine, Jiamusi UniversityKey laboratory of Microecology-immune Regulatory Network and Related Diseases, School of Basic Medicine, Jiamusi UniversityAbstract Background Recent evidence has demonstrated the vital roles of circular RNAs (circRNAs) in the progression of colorectal cancer (CRC); however, their functions and mechanisms in CRC need to be further explored. This study aimed to uncover the biological function of circXPO1 in CRC progression. Methods CircXPO1 was identified by Sanger sequencing, RNase R, and actinomycin D treatment assays. Colony formation, scratch, transwell assays, and mouse xenograft models were adopted to evaluate CRC cell growth and metastasis in vitro and in vivo. Subcellular expression of circXPO1 was detected by FISH and nuclear-cytoplasmic separation assays. Molecular mechanisms were investigated by MeRIP, RIP, and RNA pull-down assays. Target molecular expression was detected by RT-qPCR, Western blotting and immunohistochemical staining. Results circXPO1 was up-regulated in CRC tissues and cells, which indicated a poor prognosis of CRC patients. circXPO1 deficiency delayed the growth, EMT, and metastasis of CRC cells. Mechanistical experiments indicated that down-regulation of ALKBH5 enhanced IGF2BP2-mediated m6A modification of circXPO1 to increase circXPO1 expression. Furthermore, circXPO1 interacted with FMRP to reduce the mRNA stability of WWC2, which consequently resulted in Hippo-YAP pathway activation. Rescue experiments suggested that WWC2 overexpression abrogated circXPO1-mediated malignant capacities of CRC cells. The in vivo growth and liver metastasis of CRC cells were restrained by circXPO1 depletion or WWC2 overexpression. Conclusions m6A-modified circXPO1 by ALKBH5/IGF2BP2 axis destabilized WWC2 via interaction with FMRP to activate Hippo-YAP pathway, thereby facilitating CRC growth and metastasis. Targeting circXPO1 might be a potential therapeutic strategy for CRC.https://doi.org/10.1186/s12967-024-05716-4Colorectal cancercircXPO1m6AWWC2Hippo-YAP pathway |
| spellingShingle | Xiaowen Zhu Pengxia Zhang m6A-modified circXPO1 accelerates colorectal cancer progression via interaction with FMRP to promote WWC2 mRNA decay Journal of Translational Medicine Colorectal cancer circXPO1 m6A WWC2 Hippo-YAP pathway |
| title | m6A-modified circXPO1 accelerates colorectal cancer progression via interaction with FMRP to promote WWC2 mRNA decay |
| title_full | m6A-modified circXPO1 accelerates colorectal cancer progression via interaction with FMRP to promote WWC2 mRNA decay |
| title_fullStr | m6A-modified circXPO1 accelerates colorectal cancer progression via interaction with FMRP to promote WWC2 mRNA decay |
| title_full_unstemmed | m6A-modified circXPO1 accelerates colorectal cancer progression via interaction with FMRP to promote WWC2 mRNA decay |
| title_short | m6A-modified circXPO1 accelerates colorectal cancer progression via interaction with FMRP to promote WWC2 mRNA decay |
| title_sort | m6a modified circxpo1 accelerates colorectal cancer progression via interaction with fmrp to promote wwc2 mrna decay |
| topic | Colorectal cancer circXPO1 m6A WWC2 Hippo-YAP pathway |
| url | https://doi.org/10.1186/s12967-024-05716-4 |
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