MicroRNA‑936 inhibits the malignant phenotype of retinoblastoma by directly targeting HDAC9 and deactivating the PI3K/AKT pathway
Authors: Heng Li
Lishuai Xu
Qian Shi
Xiaoli Yang
Junjun Zhang
Weidong Li
Minfeng Wang
Journal: Oncology Reports (2020)
Discipline: CLINICAL MEDICINE
Keywords: retinoblastoma; microRNA-936; histone deacetylase 9; HDAC9; PI3K/AKT pathway.
Affiliations: Department of Ophthalmology and Optometry, North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China., Department of Cardiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637100, P.R. China., Department of Ophthalmology, Yixing Eye Hospital, Yixing, Jiangsu 214200, P.R. China., Department of Ophthalmology, Suining Central Hospital, Suining, Sichuan 637000, P.R. China., Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.

Abstract:  MicroRNA‑936 (miR‑936) has been reported to play important roles in the progression of non‑small cell lung cancer and glioma. However, the expression and functions of miR‑936 in retinoblastoma (RB) remain elusive and need to be further elucidated. Herein, the aims were to measure miR‑936 expression in RB, identify the functional importance of miR‑936 in the oncogenicity of RB, and investigate the underlying molecular mechanisms. Reverse‑transcription quantitative PCR was carried out to determine miR‑936 expression in RB tissues and cell lines. Cell proliferation, colony formation, apoptosis, migration, and invasion in vitro and tumor growth in vivo were examined respectively by Cell Counting Kit‑8, colony formation, flow cytometric, and Transwell migration and invasion assays and a subcutaneous heterotopic xenograft experiment. The potential target of miR‑936 was predicted by bioinformatic analysis and was subsequently validated by luciferase reporter assay, reverse‑transcription quantitative PCR, and western blotting. miR‑936 expression was weak in both RB tissues and cell lines and was correlated with differentiation, lymph node metastasis and TNM staging in RB. RB cell proliferation, colony formation, migration, and invasion in vitro and tumor growth in vivo were attenuated by exogenous miR‑936, whereas apoptosis was enhanced by miR‑936 overexpression. Further molecular investigation identified histone deacetylase 9 (HDAC9) as a direct target gene of miR‑936 in RB cells. HDAC9 depletion had effects similar to those of miR‑936 overexpression in RB cells. Recovery of HDAC9 expression counteracted the tumor‑suppressive action of miR‑936 on the oncogenicity of RB cells. Ectopic miR‑936 expression deactivated the PI3K/AKT pathway in RB cells in vitro and in vivo by decreasing HDAC9 expression. Downregulated miR‑936 is related to poor prognosis in RB, and its upregulation inhibits RB aggressiveness via direct targeting of HDAC9 mRNA and thereby inactivation of the PI3K/AKT pathway. 

Retracted: No

PubPeer comments:
 Fig 7A.  Representative images of subcutaneous xenografts derived from the agomir-936- or agomir-NC-transfected Y79 cells . ![file] These tumors elsewhere appeared as *[left]* Fig 7B from [Cheng et al (2020)] .  A representative image of the [Sw1990] tumors at the end of the experiment . ![file] , 
 Figs 2D, 4D, 5D. The low resolution of these flow-cytometry plots is regrettable. Perhaps the publisher has limited space for large files. ![file] Even so, I hope that readers can see the similarities to certain panels of Figs 2E, 4D, 6E, 7G from [Deng et al (2019)] . ![file] ![] , 
 Lots off unexpected similarities. Some of the matching plates have somehow acquired or lost a few cell colonies. - *[upper left]* Fig 6B from  The microRNA-130a-5p RUNX2 STK32A network modulates tumor invasive and metastatic potential in non-small cell lung cancer ([Ma et al 2020] ). - *[upper centre]* **Fig 2C**. - *[upper right]* Fig 1E from  LncRNA HOTTIP leads to osteoarthritis progression via regulating miR-663a Fyn-related kinase axis ([He et al 2021] ). - *[below]* Fig 3e from  LncRNA XIST upregulates TRIM25 via negatively regulating miR-192 in hepatitis B virus-related hepatocellular carcinoma ([Wang et al 2021] ). ![file] , 
 - *[left]* Fig 5G from  Bone marrow mesenchymal stem cells-derived exosomal microRNA-193a reduces cisplatin resistance of non-small cell lung cancer cells via targeting LRRC1 ([Wu et al 2020] ). - *[right]* **Fig 4C**. ![file] , 
 - *[left]* Fig 3C from  MicroRNA-423 Drug Resistance and Proliferation of Breast Cancer Cells by Targeting ZFP36 ([Xia et al 2020] ) **[retracted]**. - *[right]* **Fig 5C**. ![file] , 
 Retracted [18 August 2022] .  Following the publication of the above paper, it was drawn to the Editors attention by a concerned reader that certain of the flow cytometric data featured in Figs. 2D, 4D and 5D, the colony formation assay data shown in Figs. 2C, 4C and 5C, and the tumor images shown in Fig. 7A were strikingly similar to data appearing in different form in other articles by different authors. Owing to the fact that the contentious data in the above article were already under consideration for publication, or had already been published, prior to its submission to Oncology Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. ,