Long Noncoding RNA OIP5-AS1 Promotes the Progression of Liver Hepatocellular Carcinoma via Regulating the hsa-miR-26a-3p/EPHA2 Axis

doi:10.1016/j.omtn.2020.05.032

. 2020 Sep 4:21:229-241.

doi: 10.1016/j.omtn.2020.05.032. Epub 2020 Jun 1.

Long Noncoding RNA OIP5-AS1 Promotes the Progression of Liver Hepatocellular Carcinoma via Regulating the hsa-miR-26a-3p/EPHA2 Axis

Yu-Shui Ma¹, Kai-Jian Chu², Chang-Chun Ling³, Ting-Miao Wu⁴, Xu-Chao Zhu⁵, Ji-Bin Liu⁶, Fei Yu⁵, Zhi-Zhen Li², Jing-Han Wang², Qing-Xiang Gao², Bin Yi², Hui-Min Wang⁵, Li-Peng Gu⁵, Liu Li⁵, Lin-Lin Tian⁵, Yi Shi⁵, Xiao-Qing Jiang², Da Fu⁷, Xiong-Wen Zhang⁸

Affiliations

¹ Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, College of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China; Central Laboratory for Medical Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
² Department of Biliary Tract Surgery I, Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, China.
³ Department of General Surgery, The Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China.
⁴ Department of Radiology, The Forth Affiliated Hospital of Anhui Medical University, Hefei 230012, China.
⁵ Central Laboratory for Medical Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
⁶ Cancer Institute, Nantong Tumor Hospital, Nantong 226631, China.
⁷ Central Laboratory for Medical Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China; Department of Radiology, The Forth Affiliated Hospital of Anhui Medical University, Hefei 230012, China. Electronic address: fu800da900@126.com.
⁸ Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, College of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China. Electronic address: xwzhang@sat.ecnu.edu.cn.

PMID: 32585630
PMCID: PMC7321793
DOI: 10.1016/j.omtn.2020.05.032

Long Noncoding RNA OIP5-AS1 Promotes the Progression of Liver Hepatocellular Carcinoma via Regulating the hsa-miR-26a-3p/EPHA2 Axis

Yu-Shui Ma et al. Mol Ther Nucleic Acids. 2020.

. 2020 Sep 4:21:229-241.

doi: 10.1016/j.omtn.2020.05.032. Epub 2020 Jun 1.

Authors

Affiliations

¹ Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, College of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China; Central Laboratory for Medical Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
² Department of Biliary Tract Surgery I, Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, China.
³ Department of General Surgery, The Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China.
⁴ Department of Radiology, The Forth Affiliated Hospital of Anhui Medical University, Hefei 230012, China.
⁵ Central Laboratory for Medical Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
⁶ Cancer Institute, Nantong Tumor Hospital, Nantong 226631, China.
⁷ Central Laboratory for Medical Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China; Department of Radiology, The Forth Affiliated Hospital of Anhui Medical University, Hefei 230012, China. Electronic address: fu800da900@126.com.
⁸ Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, College of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China. Electronic address: xwzhang@sat.ecnu.edu.cn.

PMID: 32585630
PMCID: PMC7321793
DOI: 10.1016/j.omtn.2020.05.032

Retraction in

Retraction Notice to: Long Noncoding RNA OIP5-AS1 Promotes the Progression of Liver Hepatocellular Carcinoma via Regulating the hsa-miR-26a-3p/EPHA2 Axis.
Ma YS, Chu KJ, Ling CC, Wu TM, Zhu XC, Liu JB, Yu F, Li ZZ, Wang JH, Gao QX, Yi B, Wang HM, Gu LP, Li L, Tian LL, Shi Y, Jiang XQ, Fu D, Zhang XW. Ma YS, et al. Mol Ther Nucleic Acids. 2022 Oct 26;30:324. doi: 10.1016/j.omtn.2022.10.007. eCollection 2022 Dec 13. Mol Ther Nucleic Acids. 2022. PMID: 36381584 Free PMC article.

Abstract

Numerous studies have suggested that dysregulated long noncoding RNAs (lncRNAs) contributed to the development and progression of many cancers. lncRNA OIP5 antisense RNA 1 (OIP5-AS1) has been reported to be increased in several cancers. However, the roles of OIP5-AS1 in liver hepatocellular carcinoma (LIHC) remain to be investigated. In this study, we demonstrated that OIP5-AS1 was upregulated in LIHC tissue specimens and its overexpression was associated with the poor survival of patients with LIHC. Furthermore, loss-of function experiments indicated that OIP5-AS1 promoted cell proliferation and inhibited cell apoptosis both in vitro and in vivo. Moreover, binding sites between OIP5-AS1 and hsa-miR-26a-3p as well as between hsa-miR-26a-3p and EPHA2 were confirmed by luciferase assays. Finally, a rescue assay was performed to prove the effect of the OIP5-AS1/hsa-miR-26a-3p/EPHA2 axis on LIHC cell biological behaviors. Based on all of the above findings, our results suggested that OIP5-AS1 promoted LIHC cell proliferation and invasion via regulating the hsa-miR-26a-3p/EPHA2 axis.

Keywords: EPHA2; LIHC; OIP5-AS1; hsa-miR-26a-3p; prognosis.

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Figures

**Figure 1**
The Expression of OIP5-AS1 Was High in LIHC Samples and Cell Lines (A and B) The expression level (A) and correlation (B) of OIP5-AS1 in 54 pairs of LIHC tissues and adjacent noncancerous tissues were identified using quantitative real-time PCR. (C) Relative levels of OIP5-AS1 in patients with metastasis or without metastasis. (D) Expression levels of OIP5-AS1 in different stages are shown. (E) OIP5-AS1 expression level was examined in LIHC cell lines and a normal live cell line. (F) The Kaplan-Meier method was used to evaluate the relationship between OIP5-AS1 expression and overall survival of LIHC patients.

**Figure 2**
Effects of OIP5-AS1 on LIHC Cell Proliferation and Apoptosis (A and B) Knockdown of OIP5-AS1 in SMMC-7721 (A) and MHCC97H (B) cells was confirmed by quantitative real-time PCR. (C and D) Viabilities of SMMC-7721 (C) and MHCC97H (D) cells were evaluated by a CCK-8 assay. (E) Cell apoptosis was assessed in SMMC-7721 and MHCC97H cells after OIP5-AS1 silencing by flow cytometry analysis. (F) Invasion of SMMC-7721 and MHCC97H cells was detected by a transwell invasion assay. ∗∗p < 0.01.

**Figure 3**
Interaction between OIP5-AS1 and hsa-miR-26a-3p in LIHC (A) Sequence of the hsa-miR-26a-3p-binding site within the OIP5-AS1 predicted with starBase 2.0. Mutation was generated on the OIP5-AS1 in the complementary site for the seed region of hsa-miR-26a-3p. (B) Luciferase reporter assay was performed to detect the interaction between OIP5-AS1 with hsa-miR-26a-3p in HEK293T cells. (C) Expression of hsa-miR-26a-3p upon OIP5-AS1 silencing in LIHC cells was detected by quantitative real-time PCR. (D) hsa-miR-26a-3p expression in 54 pairs of LIHC tissues and adjacent noncancerous tissues. (E) Pearson’s correlation curve showed the negative relationship between OIP5-AS1 and hsa-miR-26a-3p in LIHC tissues. ∗∗p < 0.01.

**Figure 4**
Knockdown of hsa-miR-26a-3p Partially Reversed the Tumor Suppressor Role of OIP5-AS1 Silencing in LIHC (A) The expression of hsa-miR-26a-3p was decreased in cells co-transfected with sh-OIP5-AS1 and anti-hsa-miR-26a-3p compared with those only transfected with sh-OIP5-AS1. (B–D) Cell proliferation (B), apoptosis (C), and invasion (D) were determined as indicated. ∗∗p < 0.01.

**Figure 5**
OIP5-AS1 Promotes EPHA2 Expression by Regulating hsa-miR-26a-3p (A) Schematic representation of the hsa-miR-26a-3p binding sites in EPHA2 and the site mutagenesis. (B) Luciferase activity in HEK293T cells co-transfected with hsa-miR-26a-3p mimics or hsa-miR-26a-3p inhibitors and luciferase reporter plasmids containing wild-type EPHA2 or mutant EPHA2. (C and D) EPHA2 mRNA (C) and protein (D) levels in SMMC-7721 and MHCC97H cells following has-miR-26a-3p overexpression. (E) Relative mRNA expression levels of EPHA2 in 54 pairs of LIHC tissues and adjacent noncancerous tissues. (F) Pearson’s correlation curve shows the negative relationship between OIP5-AS1 and hsa-miR-26a-3p in LIHC tissues. (G and H) EPHA2 mRNA (G) and protein (H) levels in SMMC-7721 and MHCC97H cells after OIP5-AS1 silencing. (I and J) The interaction of OIP5-AS1, miR-26a-3p, and EPHA2 mRNA was proved by RNA immunoprecipitation (RIP) assays in SMMC-7721 (I) and MHCC97H cells (J). (K) Protein expression of EPHA2 measured using western blot analysis as indicated. (L) Pearson’s correlation curve shows the positive relationship between OIP5-AS1 and EPHA2 in LIHC tissues. ∗∗p < 0.01.

**Figure 6**
Antitumor Effects of OIP5-AS1 Silencing on Tumor Xenograft Mice (A) Representative tumor xenograft after the tumors were harvested. (B–D) Growth curve (B, SMMC-7721 cells; C, MHCC97H cells) and tumor weight (D) were measured. (E and F) quantitative real-time PCR detection of the expression levels of hsa-miR-26a-3p (E) and EPHA2 (F) in tumor xenografts. (G) Western blot detection of the protein level of EPHA2 in tumor xenografts. (H) Representative images of immunohistochemical detection of the proliferation index Ki67 *in vivo*. ∗∗p < 0.01.

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References

1. Wu S.D., Ma Y.S., Fang Y., Liu L.L., Fu D., Shen X.Z. Role of the microenvironment in hepatocellular carcinoma development and progression. Cancer Treat. Rev. 2012;38:218–225. - PubMed
1. Liu L.L., Fu D., Ma Y., Shen X.Z. The power and the promise of liver cancer stem cell markers. Stem Cells Dev. 2011;20:2023–2030. - PubMed
1. Shao M., Yang Q., Zhu W., Jin H., Wang J., Song J., Kong Y., Lv X. lncHOXA10 drives liver TICs self-renewal and tumorigenesis via HOXA10 transcription activation. Mol. Cancer. 2018;17:173. - PMC - PubMed
1. Kim Y., Jo M., Schmidt J., Luo X., Prakash T.P., Zhou T., Klein S., Xiao X., Post N., Yin Z., MacLeod A.R. Enhanced potency of GalNAc-conjugated antisense oligonucleotides in hepatocellular cancer models. Mol. Ther. 2019;27:1547–1557. - PMC - PubMed
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[1] Wu S.D., Ma Y.S., Fang Y., Liu L.L., Fu D., Shen X.Z. Role of the microenvironment in hepatocellular carcinoma development and progression. Cancer Treat. Rev. 2012;38:218–225. - PubMed

[2] Wu S.D., Ma Y.S., Fang Y., Liu L.L., Fu D., Shen X.Z. Role of the microenvironment in hepatocellular carcinoma development and progression. Cancer Treat. Rev. 2012;38:218–225. - PubMed

[3] Liu L.L., Fu D., Ma Y., Shen X.Z. The power and the promise of liver cancer stem cell markers. Stem Cells Dev. 2011;20:2023–2030. - PubMed

[4] Liu L.L., Fu D., Ma Y., Shen X.Z. The power and the promise of liver cancer stem cell markers. Stem Cells Dev. 2011;20:2023–2030. - PubMed

[5] Shao M., Yang Q., Zhu W., Jin H., Wang J., Song J., Kong Y., Lv X. lncHOXA10 drives liver TICs self-renewal and tumorigenesis via HOXA10 transcription activation. Mol. Cancer. 2018;17:173. - PMC - PubMed

[6] Shao M., Yang Q., Zhu W., Jin H., Wang J., Song J., Kong Y., Lv X. lncHOXA10 drives liver TICs self-renewal and tumorigenesis via HOXA10 transcription activation. Mol. Cancer. 2018;17:173. - PMC - PubMed

[7] Kim Y., Jo M., Schmidt J., Luo X., Prakash T.P., Zhou T., Klein S., Xiao X., Post N., Yin Z., MacLeod A.R. Enhanced potency of GalNAc-conjugated antisense oligonucleotides in hepatocellular cancer models. Mol. Ther. 2019;27:1547–1557. - PMC - PubMed

[8] Kim Y., Jo M., Schmidt J., Luo X., Prakash T.P., Zhou T., Klein S., Xiao X., Post N., Yin Z., MacLeod A.R. Enhanced potency of GalNAc-conjugated antisense oligonucleotides in hepatocellular cancer models. Mol. Ther. 2019;27:1547–1557. - PMC - PubMed

[9] Suksanpaisan L., Xu R., Tesfay M.Z., Bomidi C., Hamm S., Vandergaast R., Jenks N., Steele M.B., Ota-Setlik A., Akhtar H. Preclinical development of oncolytic immunovirotherapy for treatment of HPVPOS cancers. Mol. Ther. Oncolytics. 2018;10:1–13. - PMC - PubMed

[10] Suksanpaisan L., Xu R., Tesfay M.Z., Bomidi C., Hamm S., Vandergaast R., Jenks N., Steele M.B., Ota-Setlik A., Akhtar H. Preclinical development of oncolytic immunovirotherapy for treatment of HPVPOS cancers. Mol. Ther. Oncolytics. 2018;10:1–13. - PMC - PubMed

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Retracted article

Long Noncoding RNA OIP5-AS1 Promotes the Progression of Liver Hepatocellular Carcinoma via Regulating the hsa-miR-26a-3p/EPHA2 Axis

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Long Noncoding RNA OIP5-AS1 Promotes the Progression of Liver Hepatocellular Carcinoma via Regulating the hsa-miR-26a-3p/EPHA2 Axis

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