Exosomal circSHKBP1 promotes gastric cancer progression via regulating the miR-582-3p/HUR/VEGF axis and suppressing HSP90 degradation
Abstract Background Circular RNAs (circRNAs) play important regulatory roles in the development of various cancers. However, biological functions and the underlying molecular mechanism of circRNAs in gastric cancer (GC) remain obscure. Methods Differentially expressed circRNAs were identified by RNA...
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| Format: | Article |
| Language: | English |
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BMC
2020-06-01
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| Series: | Molecular Cancer |
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| Online Access: | http://link.springer.com/article/10.1186/s12943-020-01208-3 |
| _version_ | 1818302007335714816 |
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| author | Mengyan Xie Tao Yu Xinming Jing Ling Ma Yu Fan Fengming Yang Pei Ma Huning Jiang Xi Wu Yongqian Shu Tongpeng Xu |
| author_facet | Mengyan Xie Tao Yu Xinming Jing Ling Ma Yu Fan Fengming Yang Pei Ma Huning Jiang Xi Wu Yongqian Shu Tongpeng Xu |
| author_sort | Mengyan Xie |
| collection | DOAJ |
| description | Abstract Background Circular RNAs (circRNAs) play important regulatory roles in the development of various cancers. However, biological functions and the underlying molecular mechanism of circRNAs in gastric cancer (GC) remain obscure. Methods Differentially expressed circRNAs were identified by RNA sequencing. The biological functions of circSHKBP1 in GC were investigated by a series of in vitro and in vivo experiments. The expression of circSHKBP1 was evaluated using quantitative real-time PCR and RNA in situ hybridization, and the molecular mechanism of circSHKBP1 was demonstrated by western blot, RNA pulldown, RNA immunoprecipitation, luciferase assays and rescue experiments. Lastly, mouse xenograft and bioluminescence imaging were used to exam the clinical relevance of circSHKBP1 in vivo. Results Increased expression of circSHKBP1(hsa_circ_0000936) was revealed in GC tissues and serum and was related to advanced TNM stage and poor survival. The level of exosomal circSHKBP1 significantly decreased after gastrectomy. Overexpression of circSHKBP1 promoted GC cell proliferation, migration, invasion and angiogenesis in vitro and in vivo, while suppression of circSHKBP1 plays the opposite role. Exosomes with upregulated circSHKBP1 promoted cocultured cells growth. Mechanistically, circSHKBP1 sponged miR-582-3p to increase HUR expression, enhancing VEGF mRNA stability. Moreover, circSHKBP1 directly bound to HSP90 and obstructed the interaction of STUB1 with HSP90, inhibiting the ubiquitination of HSP90, resulting in accelerated GC development in vitro and in vivo. Conclusion Our findings demonstrate that exosomal circSHKBP1 regulates the miR-582-3p/HUR/VEGF pathway, suppresses HSP90 degradation, and promotes GC progression. circSHKBP1 is a promising circulating biomarker for GC diagnosis and prognosis and an exceptional candidate for further therapeutic exploration. |
| first_indexed | 2024-12-13T05:32:03Z |
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| institution | Directory Open Access Journal |
| issn | 1476-4598 |
| language | English |
| last_indexed | 2024-12-13T05:32:03Z |
| publishDate | 2020-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj.art-df8a210b34314d0cb034490f3cc496af2022-12-21T23:58:02ZengBMCMolecular Cancer1476-45982020-06-0119112210.1186/s12943-020-01208-3Exosomal circSHKBP1 promotes gastric cancer progression via regulating the miR-582-3p/HUR/VEGF axis and suppressing HSP90 degradationMengyan Xie0Tao Yu1Xinming Jing2Ling Ma3Yu Fan4Fengming Yang5Pei Ma6Huning Jiang7Xi Wu8Yongqian Shu9Tongpeng Xu10Department of Oncology, The First Affiliated Hospital of Nanjing Medical UniversityDepartment of Oncology, The First Affiliated Hospital of Nanjing Medical UniversityDepartment of Oncology, The First Affiliated Hospital of Nanjing Medical UniversityDepartment of Oncology, The First Affiliated Hospital of Nanjing Medical UniversityDepartment of Oncology, Zhenjiang First People’s HospitalDepartment of Oncology, The First Affiliated Hospital of Nanjing Medical UniversityDepartment of Oncology, The First Affiliated Hospital of Nanjing Medical UniversityDepartment of Oncology, The First Affiliated Hospital of Nanjing Medical UniversityDepartment of Oncology, The First Affiliated Hospital of Nanjing Medical UniversityDepartment of Oncology, The First Affiliated Hospital of Nanjing Medical UniversityDepartment of Oncology, The First Affiliated Hospital of Nanjing Medical UniversityAbstract Background Circular RNAs (circRNAs) play important regulatory roles in the development of various cancers. However, biological functions and the underlying molecular mechanism of circRNAs in gastric cancer (GC) remain obscure. Methods Differentially expressed circRNAs were identified by RNA sequencing. The biological functions of circSHKBP1 in GC were investigated by a series of in vitro and in vivo experiments. The expression of circSHKBP1 was evaluated using quantitative real-time PCR and RNA in situ hybridization, and the molecular mechanism of circSHKBP1 was demonstrated by western blot, RNA pulldown, RNA immunoprecipitation, luciferase assays and rescue experiments. Lastly, mouse xenograft and bioluminescence imaging were used to exam the clinical relevance of circSHKBP1 in vivo. Results Increased expression of circSHKBP1(hsa_circ_0000936) was revealed in GC tissues and serum and was related to advanced TNM stage and poor survival. The level of exosomal circSHKBP1 significantly decreased after gastrectomy. Overexpression of circSHKBP1 promoted GC cell proliferation, migration, invasion and angiogenesis in vitro and in vivo, while suppression of circSHKBP1 plays the opposite role. Exosomes with upregulated circSHKBP1 promoted cocultured cells growth. Mechanistically, circSHKBP1 sponged miR-582-3p to increase HUR expression, enhancing VEGF mRNA stability. Moreover, circSHKBP1 directly bound to HSP90 and obstructed the interaction of STUB1 with HSP90, inhibiting the ubiquitination of HSP90, resulting in accelerated GC development in vitro and in vivo. Conclusion Our findings demonstrate that exosomal circSHKBP1 regulates the miR-582-3p/HUR/VEGF pathway, suppresses HSP90 degradation, and promotes GC progression. circSHKBP1 is a promising circulating biomarker for GC diagnosis and prognosis and an exceptional candidate for further therapeutic exploration.http://link.springer.com/article/10.1186/s12943-020-01208-3CircSHKBP1Gastric cancerMiR-582-3pHURVEGFHSP90 |
| spellingShingle | Mengyan Xie Tao Yu Xinming Jing Ling Ma Yu Fan Fengming Yang Pei Ma Huning Jiang Xi Wu Yongqian Shu Tongpeng Xu Exosomal circSHKBP1 promotes gastric cancer progression via regulating the miR-582-3p/HUR/VEGF axis and suppressing HSP90 degradation Molecular Cancer CircSHKBP1 Gastric cancer MiR-582-3p HUR VEGF HSP90 |
| title | Exosomal circSHKBP1 promotes gastric cancer progression via regulating the miR-582-3p/HUR/VEGF axis and suppressing HSP90 degradation |
| title_full | Exosomal circSHKBP1 promotes gastric cancer progression via regulating the miR-582-3p/HUR/VEGF axis and suppressing HSP90 degradation |
| title_fullStr | Exosomal circSHKBP1 promotes gastric cancer progression via regulating the miR-582-3p/HUR/VEGF axis and suppressing HSP90 degradation |
| title_full_unstemmed | Exosomal circSHKBP1 promotes gastric cancer progression via regulating the miR-582-3p/HUR/VEGF axis and suppressing HSP90 degradation |
| title_short | Exosomal circSHKBP1 promotes gastric cancer progression via regulating the miR-582-3p/HUR/VEGF axis and suppressing HSP90 degradation |
| title_sort | exosomal circshkbp1 promotes gastric cancer progression via regulating the mir 582 3p hur vegf axis and suppressing hsp90 degradation |
| topic | CircSHKBP1 Gastric cancer MiR-582-3p HUR VEGF HSP90 |
| url | http://link.springer.com/article/10.1186/s12943-020-01208-3 |
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