MicroRNA-338-5p plays a tumor suppressor role in glioma through inhibition of the MAPK-signaling pathway by binding to FOXD1
Authors: Bin Luo
Yu-Qi Zhang
Wei Ni
Xin-Long Ma
Jin Zhu
Feng Shang
Journal: Journal of Cancer Research and Clinical Oncology (2018)
Discipline: CLINICAL MEDICINE
Keywords: FOXD1; Glioma cells; Invasion; MAPK-signaling pathway; MicroRNA-338-5p
Affiliations: Department of Neurosurgery, Yuquan Hospital, Tsinghua University, No. 5 Shijingshan Road, Shijingshan District, Beijing, 100040, People's Republic of China., Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, 100053, People's Republic of China., Department of Ophthalmology, Peking University Third Hospital, Beijing, 100191, People's Republic of China., Department of Neurosurgery, Yuquan Hospital, Tsinghua University, No. 5 Shijingshan Road, Shijingshan District, Beijing, 100040, People's Republic of China. .

Abstract:  Purpose: MicroRNAs (miRs) play an important role in many cancers and can affect cancer cell behavior, including glioma. This study aims at investigating the effects of miR-338-5p on the senescence, migration, invasion, and apoptosis of glioma cells via MAPK-signaling pathway by binding to FOXD1. Methods: Gene expression microarray analysis was performed to screen differentially expressed miRNAs associated with glioma. Glioma tissues and adjacent tissues were collected. siRNA, mimic, and inhibitor were introduced for investigating the tumor suppressor role of miR-338-5p in glioma. Proliferation, migration, invasion, senescence, cell-cycle distribution, and apoptosis after transfection were detected by MTT assay, scratch test, Transwell assay, Œ≤-galactosidase staining, and flow cytometry, respectively. Results: FOXD1 was identified as the up-regulated gene in glioma based on microarray data of GSE65626. FOXD1 was the target gene of miR-338-5p. Glioma tissues had increased expression of FOXD1, MEK-2, ERK-1, DAF, PCNA, and Bcl-2, and decreased expression of miR-338-5p and Bax. In cell experiments, after transfected with overexpressed miR-338-5p, higher expression of miR-338-5p, Bax, CD133, ZEB1, SOX2, SNAI1, and MMP2, but lower expression of FOXD1, MEK-2, ERK-1, Bcl-2, DAF, and PCNA were found accompanied with weaker proliferation, migration and invasion as well as stemness abilities but stronger senescence and higher apoptosis rate. Conclusion: We found that overexpression of miR-338-5p suppresses glioma cell proliferation, migration, and invasion and accelerates its senescence and apoptosis by decreasing FOXD1 expression via inhibition of activation of MAPK-signaling pathway. 

Retracted: No

PubPeer comments:
  Fig. 8 Overexpressed miR-338-5p or siRNA-FOXD1 inhibits cell invasion detected by Transwell assay. a Invasion ability detected by Transwell assay . Examples of NC and miR-338-5p inhibitor + siRNA-FOXD1 conditions are details of a single larger image.  , 
  ... hsa-miR-338-5p, with its downregulated expression in glioma and inhibitory function on glioma progression, is only reported by a very few studies (Besse et al. 2016; **Lei et al. 2017**; Liu et al. 2017), and its specific mechanism in glioma still remains unclear.  As previously reported, miR-338-5p is capable of suppressing proliferation, migration, invasion, and promoting apoptosis of glioblastoma cells by targeting EFEMP1 in a direct manner **(Lei et al. 2017)**, which can support our finding. *Lei D, Zhang F, Yao D, Xiong N, Jiang X, Zhao H (2017) MiR-338-5p suppresses proliferation, migration, invasion, and promote apoptosis of glioblastoma cells by directly targeting EFEMP1. Biomed Pharmacother (Biomedecine pharmacotherapie) 89:957u2013965* --------------------------------------------------------------------------------- The dependence on Lei et al (2017) is unfortunate, given [the number of data-integrity concerns] with that paper. , 
 Figs 3B, and 5B  protein expression of FOXD1, MEK-2, EPK-1, PCNA, DAF, Bax and Bcl-2 in glioma and adjacent tissues ;  protein expression of Bax, FOXD1, MEK-2, ERK-1, Bcl-2, DAF, and PCNA in cells . Is it usual for the bands in Western Blots to retain their linearity and shape so rigidly as the proteins advance along the gel?  ,