Long non-coding RNA AGAP2-AS1, functioning as a competitive endogenous RNA, upregulates ANXA11 expression by sponging miR-16-5p and promotes proliferation and metastasis in hepatocellular carcinoma
Abstract Background Accumulating evidence has highlighted the potential role of long non-coding RNAs (lncRNAs) in the biological behaviors of hepatocellular carcinoma (HCC). Here, we elucidated the function and possible molecular mechanisms of the effect of lncRNA-AGAP2-AS1 on the biological behavio...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-05-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13046-019-1188-x |
| _version_ | 1818537151100354560 |
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| author | Zhikui Liu Yufeng Wang Liang Wang Bowen Yao Liankang Sun Runkun Liu Tianxiang Chen Yongshen Niu Kangsheng Tu Qingguang Liu |
| author_facet | Zhikui Liu Yufeng Wang Liang Wang Bowen Yao Liankang Sun Runkun Liu Tianxiang Chen Yongshen Niu Kangsheng Tu Qingguang Liu |
| author_sort | Zhikui Liu |
| collection | DOAJ |
| description | Abstract Background Accumulating evidence has highlighted the potential role of long non-coding RNAs (lncRNAs) in the biological behaviors of hepatocellular carcinoma (HCC). Here, we elucidated the function and possible molecular mechanisms of the effect of lncRNA-AGAP2-AS1 on the biological behaviors of HCC. Methods EdU, Transwell and flow cytometry were used to determine proliferation, migration, invasion and apoptosis of HCC cells in vitro. The subcutaneous tumor model and lung metastasis mouse model in nude mice was established to detect tumor growth and metastasis of HCC in vivo. The direct binding of miR-16-5p to 3’UTR of ANXA11 was confirmed by luciferase reporter assay. The expression of AGAP2-AS1 and miR-16-5p in HCC specimens and cell lines were detected by real-time PCR. The correlation among AGAP2-AS1 and miR-16-5p were disclosed by a dual-luciferase reporter assay, RIP assay and biotin pull-down assay. Results Here, we demonstrated that AGAP2-AS1 expression was up-regulated in HCC tissues and cell lines, especially in metastatic and recurrent cases. Gain- and loss-of-function experiments indicated that AGAP2-AS1 promoted cell proliferation, migration, invasion, EMT progression and inhibited apoptosis of HCC cells in vitro and in vivo. Further studies demonstrated that AGAP2-AS1 could function as a competing endogenous RNA (ceRNA) by sponging miR-16-5p in HCC cells. Functionally, gain- and loss-of-function studies showed that miR-16-5p promoted HCC progression and alteration of miR-16-5p abolished the promotive effects of AGAP2-AS1 on HCC cells. Moreover, ANXA11 was identified as direct downstream targets of miR-16-5p in HCC cells, and mediated the functional effects of miR-16-5p and AGAP2-AS1 in HCC, resulting in AKT signaling activation. Clinically, AGAP2-AS1 and miR-16-5p expression were markedly correlated with adverse clinical features and poor prognosis of HCC patients. We showed that hypoxia was responsible for the overexpression of AGAP2-AS1 in HCC. And the promoting effects of hypoxia on metastasis and EMT of HCC cells were reversed by AGAP2-AS1 knockdown. Conclusions Taken together, this research supports the first evidence that AGAP2-AS1 plays an oncogenic role in HCC via AGAP2-AS1/miR-16-5p/ANXA11/AKT axis pathway and represents a promising therapeutic strategy for HCC patients. |
| first_indexed | 2024-12-11T18:47:04Z |
| format | Article |
| id | doaj.art-bfe2e1c1025142589297938ecbc109e3 |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-12-11T18:47:04Z |
| publishDate | 2019-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-bfe2e1c1025142589297938ecbc109e32022-12-22T00:54:26ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662019-05-0138111510.1186/s13046-019-1188-xLong non-coding RNA AGAP2-AS1, functioning as a competitive endogenous RNA, upregulates ANXA11 expression by sponging miR-16-5p and promotes proliferation and metastasis in hepatocellular carcinomaZhikui Liu0Yufeng Wang1Liang Wang2Bowen Yao3Liankang Sun4Runkun Liu5Tianxiang Chen6Yongshen Niu7Kangsheng Tu8Qingguang Liu9Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong UniversityAbstract Background Accumulating evidence has highlighted the potential role of long non-coding RNAs (lncRNAs) in the biological behaviors of hepatocellular carcinoma (HCC). Here, we elucidated the function and possible molecular mechanisms of the effect of lncRNA-AGAP2-AS1 on the biological behaviors of HCC. Methods EdU, Transwell and flow cytometry were used to determine proliferation, migration, invasion and apoptosis of HCC cells in vitro. The subcutaneous tumor model and lung metastasis mouse model in nude mice was established to detect tumor growth and metastasis of HCC in vivo. The direct binding of miR-16-5p to 3’UTR of ANXA11 was confirmed by luciferase reporter assay. The expression of AGAP2-AS1 and miR-16-5p in HCC specimens and cell lines were detected by real-time PCR. The correlation among AGAP2-AS1 and miR-16-5p were disclosed by a dual-luciferase reporter assay, RIP assay and biotin pull-down assay. Results Here, we demonstrated that AGAP2-AS1 expression was up-regulated in HCC tissues and cell lines, especially in metastatic and recurrent cases. Gain- and loss-of-function experiments indicated that AGAP2-AS1 promoted cell proliferation, migration, invasion, EMT progression and inhibited apoptosis of HCC cells in vitro and in vivo. Further studies demonstrated that AGAP2-AS1 could function as a competing endogenous RNA (ceRNA) by sponging miR-16-5p in HCC cells. Functionally, gain- and loss-of-function studies showed that miR-16-5p promoted HCC progression and alteration of miR-16-5p abolished the promotive effects of AGAP2-AS1 on HCC cells. Moreover, ANXA11 was identified as direct downstream targets of miR-16-5p in HCC cells, and mediated the functional effects of miR-16-5p and AGAP2-AS1 in HCC, resulting in AKT signaling activation. Clinically, AGAP2-AS1 and miR-16-5p expression were markedly correlated with adverse clinical features and poor prognosis of HCC patients. We showed that hypoxia was responsible for the overexpression of AGAP2-AS1 in HCC. And the promoting effects of hypoxia on metastasis and EMT of HCC cells were reversed by AGAP2-AS1 knockdown. Conclusions Taken together, this research supports the first evidence that AGAP2-AS1 plays an oncogenic role in HCC via AGAP2-AS1/miR-16-5p/ANXA11/AKT axis pathway and represents a promising therapeutic strategy for HCC patients.http://link.springer.com/article/10.1186/s13046-019-1188-xAGAP2-AS1Hepatocellular carcinomamiR-16-5pANXA11Proliferation |
| spellingShingle | Zhikui Liu Yufeng Wang Liang Wang Bowen Yao Liankang Sun Runkun Liu Tianxiang Chen Yongshen Niu Kangsheng Tu Qingguang Liu Long non-coding RNA AGAP2-AS1, functioning as a competitive endogenous RNA, upregulates ANXA11 expression by sponging miR-16-5p and promotes proliferation and metastasis in hepatocellular carcinoma Journal of Experimental & Clinical Cancer Research AGAP2-AS1 Hepatocellular carcinoma miR-16-5p ANXA11 Proliferation |
| title | Long non-coding RNA AGAP2-AS1, functioning as a competitive endogenous RNA, upregulates ANXA11 expression by sponging miR-16-5p and promotes proliferation and metastasis in hepatocellular carcinoma |
| title_full | Long non-coding RNA AGAP2-AS1, functioning as a competitive endogenous RNA, upregulates ANXA11 expression by sponging miR-16-5p and promotes proliferation and metastasis in hepatocellular carcinoma |
| title_fullStr | Long non-coding RNA AGAP2-AS1, functioning as a competitive endogenous RNA, upregulates ANXA11 expression by sponging miR-16-5p and promotes proliferation and metastasis in hepatocellular carcinoma |
| title_full_unstemmed | Long non-coding RNA AGAP2-AS1, functioning as a competitive endogenous RNA, upregulates ANXA11 expression by sponging miR-16-5p and promotes proliferation and metastasis in hepatocellular carcinoma |
| title_short | Long non-coding RNA AGAP2-AS1, functioning as a competitive endogenous RNA, upregulates ANXA11 expression by sponging miR-16-5p and promotes proliferation and metastasis in hepatocellular carcinoma |
| title_sort | long non coding rna agap2 as1 functioning as a competitive endogenous rna upregulates anxa11 expression by sponging mir 16 5p and promotes proliferation and metastasis in hepatocellular carcinoma |
| topic | AGAP2-AS1 Hepatocellular carcinoma miR-16-5p ANXA11 Proliferation |
| url | http://link.springer.com/article/10.1186/s13046-019-1188-x |
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