Long non-coding RNA MEG3 inhibits cell growth of gliomas by targeting miR-93 and inactivating PI3K/AKT pathway
Authors: Yuxiong Li
Xin Liang
Ling Zhang
Journal: Oncology Reports (2017)
Discipline: CLINICAL MEDICINE
Keywords: Gliomas; Long non-coding RNAs; MEG3; Tumorigenesis; Proliferation
Affiliations: Department of Neurosurgery, Yulin City Hospital of Traditional Chinese Medicine, Yulin, Shaanxi 719000, P.R. China.

Abstract:  Gliomas are the most common cancers in the brain, accompanied with high morbility, occurrence, disability and mortality. Long non-coding RNAs (lncRNAs) have been proposed as promoter or inhibitor in many cancer processes. Previous findings have indicated that lncRNA-maternally expressed gene 3 (MEG3) is involved in tumorigenesis of several cancers, including glioma. However, the underlying mechanism of MEG3 in glioma remains elusive. In our study, MEG3 was found downregulated in glioma tissues compared with normal brain tissues. Downregulated expression of MEG3 was also detected in two human glioma cell lines (U-251, M059J) compared with normal astrocyte cells. MEG3 was then overexpressed by ligating to a lentiviral vector. Overexpressed MEG3 inhibited the proliferation of U-251 cells, and restrained the expression of proliferation marker proteins Ki67 and proliferating cell nuclear antigen (PCNA). However, cell apoptosis rate of U-251 cells and the expression of apoptosis marker proteins (caspase-3 and caspase-9) were elevated by MEG3. Furthermore, miR-93 was predicted a direct target of lncRNA-MEG3 by bioinformatics analysis. Overexpressed MEG3 counteracted the role of miR-93 in facilitating proliferation and inhibiting apoptosis in U-251 cells. Moreover, MEG3 restained the activation of phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT) pathway by reducing cytomembrane translocation of AKT. Finally, the in vivo experiment revealed that MEG3 strongly reduced tumor growth, tumor volume and the expression of Ki67 and PCNA. lncRNA-MEG3 also inhibited the level of miR-93 and the expression of PI3K/AKT pathway related proteins in vivo. Taken together, our research indicated a MEG3-miR-93-PI3K-AKT pathway in regulating the growth of glioma, providing a promising therapy for glioma. 

Retracted: Yes

PubPeer comments:
 Fig 6A.  MEG3 inhibits tumor growth in vivo. Xenograft mouse model was created by subcutaneous injection of U-251 cells pretreated with or without lncRNA-MEG3 to SPF nude mice. (A) Representative tumors from two groups of mice are shown .  Curiously, two unrelated laboratories were photographing tumours with the same ruler and on the same paper fabric absorbent bench-cover, if the creases are any guide. At right, Fig 7A from [Zhang et al (2017)] . At left , 7A from [Li et al (2018)] .  Rearranged and rescaled:  The same creased bench-cover, though with a different ruler. Fig 4D of [Li et al (2018b)] .  , 
 Fig 6A again.  lncRNA-MEG3 rows appears to be the same as in FIg 8A of [Fan et al (2017)] . Different cell-lines specified as sources of the xenografts, and no authors in common.  , 
 Please be noted, the same or very similar crease of Surgical pad are showing on the following 11 chinese papers including this paper. Also, the samples on the pad are somehow shared in those papers. UCA1 Regulates the Growth and Metastasis of Pancreatic Cancer bySponging miR-135a. Oncology research (2017) . DOI: 10.3727 096504017x14888987683152.  H19 promotes the migration and invasion of colon cancer by spongingmiR-138 to upregulate the expression of HMGA1. INTERNATIONAL JOURNAL OF ONCOLOGY (2017). DOI: 10.3892 ijo.2017.3941.  Silencing of lncRNA CCDC26 Restrains the Growth and Migration of Glioma Cells In Vitroand In Vivo via Targeting miR-203. Oncology research (2018). DOI: 10.3727 096504017x14965095236521.  Long Noncoding RNA SChLAP1 Accelerates the Proliferation and Metastasis of Prostate Cancervia Targeting miR-198 and Promoting the MAPK1 Pathway. Oncology research (2018) . DOI: 10.3727 096504017x14944585873631.  HOTAIR contributes to cell proliferation and metastasis of cervical cancer via targetting MAPK1 axis. Bioscience reports (2018). DOI: 10.1042 bsr20171563.  Long non-coding RNA MEG3 inhibits cell growth of gliomas by targeting miR-93 andinactivating PI3K AKT pathway. Oncology reports (2017). DOI: 10.3892 or.2017.5871.  The inhibitory effect of MEG3 miR-214 AIFM2 axis on the growth of T-cell lymphoblastic lymphoma. INTERNATIONAL JOURNAL OF ONCOLOGY. DOI: 10.3892 ijo.2017.4006.  Inhibition of BAMBI reduces the viability and motility of colon cancervia activating TGFu2011u03b2 Smad pathway in vitro and in vivo. ONCOLOGY LETTERS. 10.3892 ol.2017.6811.  HNF1Au2011AS1 promotes growth and metastasis of esophageal squamous cellcarcinoma by sponging miRu2011214 to upregulate the expression of SOX-4. INTERNATIONAL JOURNAL OF ONCOLOGY. DOI: 10.3892 ijo.2017.4034.  Astragaloside IV inhibits progression of glioma via blocking MAPK ERKsignaling pathway. Biochemical and Biophysical Research Communications (2017). DOI: 10.1016 j.bbrc.2017.07.052.  Epigenetic silence of HOTAIR contributes to the metastasis of pancreaticcancer via targeting miR-138. Oncology Research (2017). DOI: 10.3727 096504017X15138544374391.  Possibly the following one: Long Noncoding RNA MEG3 Inhibits Cell Proliferation and Metastasis in Chronic Myeloid Leukemia via Targeting miR-184. Oncology research (2018) . DOI: 10.3727 096504017x14980882803151  , 
 Below: Fig 4C.  miR-93 is involved in the growth of glioma. U-251 cells were pretreated with lncRNA-MEG3 and or miR-93 mimics or mimic control alone. ... (C) Flow cytometry was performed to determine the percentages of apoptosis in U-251 cells . Above: Fig 2E from [Wang et al (2018)] .  The inhibition of CCDC26 suppresses cell viability in gliomas. U-251 and M059J cell lines were transfected with the CCDC26-siRNA or siRNA scramble, respectively. ... (E) Cell apoptosis in U-251 and M059J cells was examined through flow cytometry .  How to explain the similarities? , 
 Retracted [27 October 2020] ----------------------------------------------- Following the publication of this paper, it was drawn to the authors attention by an interested reader that certain of the tumours featured in Fig. 6A of the above paper were strikingly similar to those featured in Fig. 8A of an article appearing in International Journal of Oncology (Fan F-Y, Deng R, Yi H, Sun H-P, Zeng Y, He G-C and Su Y: The inhibitory effect of MEG3 miR-214 AIFM2 axis on the growth of T-cell lymphoblastic lymphoma. Int J Oncol 51: 316u2013326, 2017). The Editor asked the authors for an explanation to account for the appearance of strikingly similar data in their paper independently, and they responded to request that the paper be retracted from Oncology Reports. All the authors agreed that the article should be retracted. The Editor apologizes to the readership for any inconvenience caused. , 
 In the interests of dead-horse flogging, here I compare - *[left]* Fig 5E. - *[right]* Fig 4C from  Salvianolic acid B inhibits inflammatory response and cell apoptosis via the PI3K Akt signaling pathway in IL-1u03b2-induced osteoarthritis chondrocytes ([Zhu et al 2018] ).  ,