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• Research Paper Volume 14, Issue 8 pp 3540-3553

  MicroRNA-181a-5p prevents the progression of esophageal squamous cell carcinoma in vivo and in vitro via the MEK1-mediated ERK-MMP signaling pathway

  Relevance score: 8.524992

  Mingbo Wang, Chao Huang, Wenda Gao, Yonggang Zhu, Fan Zhang, Zhenhua Li, Ziqiang Tian

  Keywords: ESCC, miR-181a-5p, MEK1

  Published in Aging on April 25, 2022

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  MicroRNAs (miRNAs) have been revealed to play a crucial role in oncogenesis of esophageal squamous cell carcinoma (ESCC). However, the biological role of miR-181a-5p in ESCC is currently less explored. The current study was designed to assess whether miR-181a-5p affects ESCC progression and further investigate relevant underlying mechanisms. Based on the data of GSE161533, GSE17351, GSE75241 and GSE67269 downloaded from GEO database, MAP2K1 (MEK1) was revealed to be one overlapping gene of the top 300 DGEs. Additionally, using the predicting software, miR-181a-5p was projected as the presumed target miRNA. Immunohistochemical staining and RT-qPCR research revealed that miR-181a-5p expression was decreased in human tumor tissues relative to surrounding peri-cancerous tissues. In an in vivo experiment, miR-181a-5p mimics could inhibit tumor growth and metastasis of ESCC. Gene expression profiles in combination with gene ontology (GO) and KEGG pathway analysis revealed that MAP2K1 (MEK1) gene and ERK-MMP pathway were implicated in ESCC progression. MiR-181a-5p mimics inhibited the activity of p-ERK1/2, MMP2 and MMP9 in vivo, as shown by Western blotting and immunohistochemistry labeling. There were no variations in the expression of p-P38 and p-JNK proteins. Additionally, miR-181a-5p mimics lowered p-ERK1/2, MMP2 and MMP9 levels in ECA109 cells, which were restored by MEK1-OE lentivirus. MEK1-OE Lentivirus significantly reversed the function induced by miR-181a-5p mimics in ECA109 cells. Moreover, further investigation indicated that the capability of migration, invasion and proliferation was repressed by miR-181a-5p mimics in ECA109 cells. In short, repressed ERK-MMP pathway mediated by miR-181a-5p can inhibit cell migration, invasion and proliferation by targeting MAP2K1 (MEK1) in ESCC.

• Research Paper Volume 14, Issue 4 pp 1865-1878

  miR-223-3p inhibits the progression of atherosclerosis via down-regulating the activation of MEK1/ERK1/2 in macrophages

  Relevance score: 5.662054

  Daofeng You, Qiuge Qiao, Katsushige Ono, Mei Wei, Wenyun Tan, Cuihua Wang, Yangong Liu, Gang Liu, Mingqi Zheng

  Keywords: atherosclerosis, MEK1/ERK1/2 signaling pathway, inflammatory response, macrophages, miR-223-3p

  Published in Aging on February 24, 2022

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  Background: microRNAs (miRNAs) have drawn more attention to the progression of atherosclerosis (AS), due to their noticeable inflammation function in cardiovascular disease. Macrophages play a crucial role in disrupting atherosclerotic plaque, thereby we explored the involvement of miR-223-3p in the inflammatory response in macrophages.

  Methods: RT-qPCR was used to analyze the miR-223-3p levels in carotid arteries and serum of AS patients. ROC curve was used to assess the diagnostic value of miR-223-3p. Movat staining was applied to evaluate the morphological differences. FISH was used to identify the expression of miR-223-3p in macrophages of atherosclerotic lesions. Bioinformatic analysis was performed. Double-immunofluorescence and western blot were performed to assess the inflammatory cytokine secretion and p-ERK1/2. C16-PAF was injected into the culture medium of the miR-223-3p mimic/NC-transfected macrophages with ox-LDL.

  Results: MiR-223-3p was up-regulated in AS patients and was associated with a higher overall survival rate. MiR-223-3p was co-localized with CD68+ macrophages in vulnerable atherosclerotic lesions. MiR-223-3p mimics decreased atherosclerotic lesions, macrophages numbers whereas increased SMCs numbers in the lesions. The TNF-a immune-positive areas were reduced by miR-223-3p mimics. MAP2K1 was negatively associated with miR-223-3p. MiR-223-3p mimics reduced the inflammation and the MEK1/ERK1/2 signaling pathway in vivo and in vitro. C16-PAF reversed the effects of miR-223-3p mimics on inflammation and ERK1/2 signaling pathway.

  Conclusions: MiR-223-3p negatively regulates inflammatory responses by the MEK1/ERK1/2 signaling pathway. Our study provides new insight into how miR-223-3p protects against atherosclerosis, representing a broader therapeutic prospect for treating atherosclerosis by miR-223-3p.

• Research Paper Volume 12, Issue 14 pp 14885-14896

  Circular RNA DHX33 promotes malignant behavior in ccRCC by targeting miR-489-3p/MEK1 axis

  Relevance score: 6.156128

  Jie Wang, Jian-Qiu Zhang, Xiao-Lei Zhao, Jing-Yu Lu, Ze-Ming Weng, Zhen-Min Ding, Feng-Qiang Yang

  Keywords: clear cell renal cell carcinoma, circDHX33, miR-489-3p, MEK1

  Published in Aging on July 27, 2020

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  Mounting evidence indicates that circular RNAs modulate the initiation of clear cell renal cell carcinoma (ccRCC). However, their specific roles in the malignancy of ccRCC is understudied. Here, we present a novel circular RNA, circDHX33, that is up-regulated in ccRCC cell lines and tissues. Upregulated circDHX33 in ccRCC patients significantly correlates with advanced TNM stage and metastasis. Suppressing circDHX33 expression inhibits the proliferation and invasion of cultured cells, and suppresses tumor growth in vivo. Mechanistically, we show that circDHX33 promotes ccRCC progression by sponging miR-489-3p and modulating MEK1 expression. In conclusion, our findings suggest that circDHX33 plays a role in promoting ccRCC via the miR-489-3p/MEK1 axis and may serve as a novel therapeutic target for the treatment of ccRCC patients

  

  Screening of ccRCC-related circRNAs in GSE137836 dataset. (A, B) Hierarchical clustering analysis and volcano plots of significantly differentially expressed circRNAs in ccRCC tissues from the GSE137836 dataset. (C) GO enrichment analysis for dysregulated circRNAs gene symbols. (D) 5 upregulated circRNAs in 8 paired ccRCC tissues was determined by using RT-qPCR. *p<0.05, **p<0.01.

  
  
  

  

  circDHX33 was highly expressed in ccRCC. (A) Schematic diagram of circDHX33. (B) Random hexamer or oligo (dT)18 primers were used in the reverse transcription experiments. (C) The relative RNA levels were determined by qRT-PCR. (D) The expression of circDHX33 in 47 paired ccRCC tissues was detected by qRT-PCR. (E, F) High circDHX33 expression was linked to advanced TNM stage and metastasis in ccRCC patients. *p<0.05, **p<0.01.

  
  
  

  

  circDHX33 promoted the proliferation and invasion in ccRCC cells. (A) The expression of circDHX33 in RCC cell lines. (B) The efficiency of circDHX33 knockdown in 786O and A498 cells. (C–F) Cell viabilities were assessed by CCK-8 and colony formation and tests. (G, H) Cell invasion was assess using Transwell assay. *p<0.05, **p<0.01.

  
  
  

  

  circDHX33 targeted miR-489-3p as a miRNA sponge. (A) circDHX33 distribution was explored by subcellular fractionation assay. (B, C) Target miRNAs of circDHX33 was predicted by miRanda and RNAhybrid. (D, E) The relative levels of miRNA candidates in 786O and A498 cells lysates were detected by pull-down assay. (F) MiR-489-3p had the complementary sites with the circDHX33. (G) MiR-489-3p mimics reduced the luciferase activity of the circDHX33-WT group. (H) The correlation between circDHX33 and miR-489-3p was confirmed by RIP assay. *p<0.05, **p<0.01.

  
  
  

  

  circDHX33/miR-489-3p axis in ccRCC. (A, B) The level of miR-489-3p in ccRCC tissues and cell lines was estimated with RT-qPCR. (C, D) Low miR-489-3p levels correlated with poor overall survival rate in patients. (E) circDHX33 expression was negatively correlated with miR-489-3p expression in ccRCC tissues. (F) circDHX33 negatively regulated expression of miR-489-3p in 786O and A498 cells. (G, H) miR-489-3p suppression abolished the effects of circDHX33 inhibition on 786O cells proliferation and invasion abilities. *p<0.05, **p<0.01.

  
  
  

  

  MEK1 served as the target of miR-489-3p. (A, B) MEK1 was a potential putative target gene of miR-489-3p. (C) MEK1 expression was significantly upregulated in KIRC tissues. (D, E) MEK1 expression in ccRCC tissues was determined by RT-qPCR and IHC. (F, G) High MEK1 expression was significantly associated with poor prognosis in patients. (H, I) MiR-489-3p mimics reduced MEK1 expression in 786O and A498 cells. (J) MiR-489-3p mimics reduced luciferase activity of the MEK1-Wt group. (K) miR-489-3p expression was negatively correlated with MEK1 expression in ccRCC tissues. KIRC: Kidney renal clear cell carcinoma. *p<0.05, **p<0.01.

  
  
  

  

  circDHX33/miR-489-3p/MEK1 axis in ccRCC. (A) MiR-489-3p suppression in 786O and A498 cells abolished the effects of circDHX33 inhibition on MEK1 expression. (B) circDHX33 expression was positively correlated with MEK1 expression in ccRCC tissues. (C, D) MEK1 overexpression abolished the effects of circDHX33 inhibition on 786O cells proliferation and invasion abilities. *p<0.05, **p<0.01.

  
  
  

  

  circDHX33 promoted tumor growth in vivo. (A–C) circDHX33 knockdown reduced tumor growth in vivo. (D) circDHX33 knockdown reduced Ki67 expression in mice tissues. (E) circDHX33 knockdown reduced MEK1 levels and increased miR-489-3p levels in mice tissues. *p<0.05, **p<0.01.