Promoter hypomethylation mediated upregulation of MicroRNA-10b-3p targets FOXO3 to promote the progression of esophageal squamous cell carcinoma (ESCC)
Abstract Background Esophageal cancer is a high incident cancer worldwide with poor survival and limited therapeutic options. Alterations of microRNAs are common in cancers, and many of these micro RNAs are potential therapeutic and diagnostic targets to treat these cancers. miR-10b-3p located in ch...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2018-12-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13046-018-0966-1 |
| _version_ | 1818947943770619904 |
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| author | Yi-fang Lu Jia-rui Yu Zhao Yang Guan-xia Zhu Peng Gao Huan Wang Si-yuan Chen Jie Zhang Mei-yue Liu Yi Niu Xiao-mei Wei Wei Wang Feng-jin Ye Li-xin Zhang Yue Zhao Guo-gui Sun |
| author_facet | Yi-fang Lu Jia-rui Yu Zhao Yang Guan-xia Zhu Peng Gao Huan Wang Si-yuan Chen Jie Zhang Mei-yue Liu Yi Niu Xiao-mei Wei Wei Wang Feng-jin Ye Li-xin Zhang Yue Zhao Guo-gui Sun |
| author_sort | Yi-fang Lu |
| collection | DOAJ |
| description | Abstract Background Esophageal cancer is a high incident cancer worldwide with poor survival and limited therapeutic options. Alterations of microRNAs are common in cancers, and many of these micro RNAs are potential therapeutic and diagnostic targets to treat these cancers. miR-10b-3p located in chromosome region 2q31.1, and its expression is frequently increased in esophageal squamous cell carcinoma (ESCC). However, the biological functions, clinical significance and therapeutic implications of miR-10b-3p in ESCC remain unclear. Methods The expression levels of miR-10b-3p in ESCC specimens were analyzed by in situ hybridization (ISH) and quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays. Ectopic overexpression of miR-10b-3p in ESCC cells, mouse xenograft model, and metastasis model were used to evaluate the effects of miR-10b-3p on proliferation, and migration of cancer cells. Luciferase reporter assay and Western blot were performed to validate the potential targets of miR-10b-3p after the preliminary screening by computer-aided microarray analysis. Results We found that miR-10b-3p expression levels were significantly upregulated in the tumor tissues and serum samples of patients with ESCC. The expression levels of miR-10b-3p in both tumor tissues and serum samples were inversely associated with lymph node metastasis and clinical stages. We identified the expression level of miR-10b-3p in ESCC cancer samples as an independent prognostic marker of the overall survival rates of ESCC patients. We found more frequent hypomethylation of the CpG sites located upstream of the miR-10b-3p gene in the ESCC tissues compared with in the adjacent normal tissues, and the DNA methylation status of miR-10b-3p promoter region inversely correlated with the expression levels of miR-10b-3p. Ectopic overexpression of miR-10b-3p promoted cell proliferation, colony formation, migration and invasion in ESCC. While knockdown of miR-10b-3p had the opposite effects, particularly in promoting apoptosis. Mouse xenograft model confirmed that miR-10b-3p functions as a potent oncogenic miRNA in ESCC, which also promoting ESCC metastasis. Mechanistically, we found miR-10b-3p regulated FOXO3 expression by directly binding to the 3′-untranslated region. And systemic delivery of miR-10b-3p antagomir reduced tumor growth and inhibit FOXO3 protein expression in nude mice. Conclusions Collectively, our findings suggested upregulated expression of miR-10b-3p caused by promoter hypomethylation contributed to the progression of ESCC; Thus, miR-10b-3p is a potentially effective biomarker for ESCC that could have further therapeutic implications. |
| first_indexed | 2024-12-20T08:38:56Z |
| format | Article |
| id | doaj.art-8f766d428e5d4de3a8c6cffe232975c0 |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-12-20T08:38:56Z |
| publishDate | 2018-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-8f766d428e5d4de3a8c6cffe232975c02022-12-21T19:46:27ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662018-12-0137111910.1186/s13046-018-0966-1Promoter hypomethylation mediated upregulation of MicroRNA-10b-3p targets FOXO3 to promote the progression of esophageal squamous cell carcinoma (ESCC)Yi-fang Lu0Jia-rui Yu1Zhao Yang2Guan-xia Zhu3Peng Gao4Huan Wang5Si-yuan Chen6Jie Zhang7Mei-yue Liu8Yi Niu9Xiao-mei Wei10Wei Wang11Feng-jin Ye12Li-xin Zhang13Yue Zhao14Guo-gui Sun15Department of medicine, Tangshan gongren HospitalDepartment of Radiation Oncology, North China University of Science and Technology Affiliated People’s HospitalDepartment of Radiation Oncology, North China University of Science and Technology Affiliated People’s HospitalZhejiang Cancer Research Institute, Zhejiang Cancer HospitalDepartment of Radiation Oncology, North China University of Science and Technology Affiliated People’s HospitalDepartment of Radiation Oncology, North China University of Science and Technology Affiliated People’s HospitalDepartment of Radiation Oncology, North China University of Science and Technology Affiliated People’s HospitalDepartment of pathology, North China University of Science and Technology Affiliated People’s HospitalDepartment of Radiation Oncology, North China University of Science and Technology Affiliated People’s HospitalDepartment of Radiation Oncology, North China University of Science and Technology Affiliated People’s HospitalDepartment of Radiation Oncology, North China University of Science and Technology Affiliated People’s HospitalDepartment of Radiation Oncology, North China University of Science and Technology Affiliated People’s HospitalDepartment of Radiation Oncology, North China University of Science and Technology Affiliated People’s HospitalDepartment of Radiation Oncology, North China University of Science and Technology Affiliated People’s HospitalZhejiang Cancer Research Institute, Zhejiang Cancer HospitalDepartment of Radiation Oncology, North China University of Science and Technology Affiliated People’s HospitalAbstract Background Esophageal cancer is a high incident cancer worldwide with poor survival and limited therapeutic options. Alterations of microRNAs are common in cancers, and many of these micro RNAs are potential therapeutic and diagnostic targets to treat these cancers. miR-10b-3p located in chromosome region 2q31.1, and its expression is frequently increased in esophageal squamous cell carcinoma (ESCC). However, the biological functions, clinical significance and therapeutic implications of miR-10b-3p in ESCC remain unclear. Methods The expression levels of miR-10b-3p in ESCC specimens were analyzed by in situ hybridization (ISH) and quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays. Ectopic overexpression of miR-10b-3p in ESCC cells, mouse xenograft model, and metastasis model were used to evaluate the effects of miR-10b-3p on proliferation, and migration of cancer cells. Luciferase reporter assay and Western blot were performed to validate the potential targets of miR-10b-3p after the preliminary screening by computer-aided microarray analysis. Results We found that miR-10b-3p expression levels were significantly upregulated in the tumor tissues and serum samples of patients with ESCC. The expression levels of miR-10b-3p in both tumor tissues and serum samples were inversely associated with lymph node metastasis and clinical stages. We identified the expression level of miR-10b-3p in ESCC cancer samples as an independent prognostic marker of the overall survival rates of ESCC patients. We found more frequent hypomethylation of the CpG sites located upstream of the miR-10b-3p gene in the ESCC tissues compared with in the adjacent normal tissues, and the DNA methylation status of miR-10b-3p promoter region inversely correlated with the expression levels of miR-10b-3p. Ectopic overexpression of miR-10b-3p promoted cell proliferation, colony formation, migration and invasion in ESCC. While knockdown of miR-10b-3p had the opposite effects, particularly in promoting apoptosis. Mouse xenograft model confirmed that miR-10b-3p functions as a potent oncogenic miRNA in ESCC, which also promoting ESCC metastasis. Mechanistically, we found miR-10b-3p regulated FOXO3 expression by directly binding to the 3′-untranslated region. And systemic delivery of miR-10b-3p antagomir reduced tumor growth and inhibit FOXO3 protein expression in nude mice. Conclusions Collectively, our findings suggested upregulated expression of miR-10b-3p caused by promoter hypomethylation contributed to the progression of ESCC; Thus, miR-10b-3p is a potentially effective biomarker for ESCC that could have further therapeutic implications.http://link.springer.com/article/10.1186/s13046-018-0966-1microRNAsEsophageal squamous cell carcinomaHypomethylationBiomarkerTherapeutic target |
| spellingShingle | Yi-fang Lu Jia-rui Yu Zhao Yang Guan-xia Zhu Peng Gao Huan Wang Si-yuan Chen Jie Zhang Mei-yue Liu Yi Niu Xiao-mei Wei Wei Wang Feng-jin Ye Li-xin Zhang Yue Zhao Guo-gui Sun Promoter hypomethylation mediated upregulation of MicroRNA-10b-3p targets FOXO3 to promote the progression of esophageal squamous cell carcinoma (ESCC) Journal of Experimental & Clinical Cancer Research microRNAs Esophageal squamous cell carcinoma Hypomethylation Biomarker Therapeutic target |
| title | Promoter hypomethylation mediated upregulation of MicroRNA-10b-3p targets FOXO3 to promote the progression of esophageal squamous cell carcinoma (ESCC) |
| title_full | Promoter hypomethylation mediated upregulation of MicroRNA-10b-3p targets FOXO3 to promote the progression of esophageal squamous cell carcinoma (ESCC) |
| title_fullStr | Promoter hypomethylation mediated upregulation of MicroRNA-10b-3p targets FOXO3 to promote the progression of esophageal squamous cell carcinoma (ESCC) |
| title_full_unstemmed | Promoter hypomethylation mediated upregulation of MicroRNA-10b-3p targets FOXO3 to promote the progression of esophageal squamous cell carcinoma (ESCC) |
| title_short | Promoter hypomethylation mediated upregulation of MicroRNA-10b-3p targets FOXO3 to promote the progression of esophageal squamous cell carcinoma (ESCC) |
| title_sort | promoter hypomethylation mediated upregulation of microrna 10b 3p targets foxo3 to promote the progression of esophageal squamous cell carcinoma escc |
| topic | microRNAs Esophageal squamous cell carcinoma Hypomethylation Biomarker Therapeutic target |
| url | http://link.springer.com/article/10.1186/s13046-018-0966-1 |
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