miR-375 is involved in Hippo pathway by targeting YAP1/TEAD4-CTGF axis in gastric carcinogenesis

Autor: Alfred S. L. Cheng, Joanna H.M. Tong, Feng Wu, Jun Yu, Jinglin Zhang, Yuhang Zhou, Yi Pan, Yujuan Dong, Chi Chun Wong, Jesse Chung Sean Pang, Ka Fai To, Anthony W.H. Chan, Raymond W.M. Lung, Wei Kang, Shiyan Wang, Tingting Huang, Bin Zhang, Wing Po Chak, Weiqin Yang, Alvin Ho-Kwan Cheung
Jazyk: angličtina
Rok vydání: 2018
Předmět:
0301 basic medicine
Cancer Research
Carcinogenesis
Muscle Proteins
medicine.disease_cause
0302 clinical medicine
RNA
Small Interfering

YAP1
Regulation of gene expression
Gene knockdown
Mice
Inbred BALB C

integumentary system
lcsh:Cytology
TEA Domain Transcription Factors
DNA-Binding Proteins
Gene Expression Regulation
Neoplastic

030220 oncology & carcinogenesis
Gene Knockdown Techniques
Signal Transduction
Immunology
Down-Regulation
Mice
Nude

Biology
Protein Serine-Threonine Kinases
Models
Biological

Article
03 medical and health sciences
Cellular and Molecular Neuroscience
Stomach Neoplasms
Cell Line
Tumor

microRNA
medicine
Animals
Humans
Hippo Signaling Pathway
lcsh:QH573-671
Adaptor Proteins
Signal Transducing

Hippo signaling pathway
Base Sequence
Connective Tissue Growth Factor
YAP-Signaling Proteins
Cell Biology
Phosphoproteins
CTGF
MicroRNAs
030104 developmental biology
Cancer research
Ectopic expression
Transcription Factors
Zdroj: Cell Death & Disease
Cell Death and Disease, Vol 9, Iss 2, Pp 1-16 (2018)
ISSN: 2041-4889
Popis: miR-375 is a tumor-suppressive microRNA (miRNA) in gastric cancer (GC). However, its molecular mechanism remains unclear. The aim of this study is to comprehensively investigate how miR-375 is involved in Hippo pathway by targeting multiple oncogenes. miR-375 expression in gastric cancer cell lines and primary GC was investigated by qRT-PCR. The regulation of YAP1, TEAD4, and CTGF expression by miR-375 was evaluated by qRT-PCR, western blot, and luciferase reporter assays, respectively. The functional roles of the related genes were examined by siRNA-mediated knockdown or ectopic expression assays. The clinical significance and expression correlation analysis of miR-375, YAP1, and CTGF were performed in primary GCs. TCGA cohort was also used to analyze the expression correlation of YAP1, TEAD4, CTGF, and miR-375 in primary GCs. miR-375 was down-regulated in GC due to promoter methylation and histone deacetylation. miR-375 downregulation was associated with unfavorable outcome and lymph node metastasis. Ectopic expression of miR-375 inhibited tumor growth in vitro and in vivo. Three components of Hippo pathway, YAP1, TEAD4 and CTGF, were revealed to be direct targets of miR-375. The expression of three genes showed a negative correlation with miR-375 expression and YAP1 re-expression partly abolished the tumor-suppressive effect of miR-375. Furthermore, CTGF was confirmed to be the key downstream of Hippo-YAP1 cascade and its knockdown phenocopied siYAP1 or miR-375 overexpression. YAP1 nuclear accumulation was positively correlated with CTGF cytoplasmic expression in primary GC tissues. Verteporfin exerted an anti-oncogenic effect in GC cell lines by quenching CTGF expression through YAP1 degradation. In short, miR-375 was involved in the Hippo pathway by targeting YAP1-TEAD4-CTGF axis and enriched our knowledge on the miRNA dysregulation in gastric tumorigenesis.
Databáze: OpenAIRE