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Gene Regulation and Targeted Therapy in Gastric Cancer Peritoneal Metastasis: Radiological Findings from Dual Energy CT and PET/CT
Published on: January 22, 2018
MicroRNA-7 as a potential therapeutic target for aberrant NF-κB-driven distant metastasis of gastric cancer
Tingbo Ye1, Meihua Yang2, Daochao Huang1
1Chongqing key Laboratory of Child Infection and Immunity, Chongqing key Laboratory of Pediatric, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology cooperation base of Child development and Critical disorders, Children's Hospital of Chongqing Medical University, No.136 Zhongshan Erd Road, Yuzhong District, Chongqing, 400014, China.
Background:
Dysregulated miR-7 and aberrant NF-κB activation were reported in various human cancers. However, the expression profile, clinical relevance and dysregulated mechanism of miR-7 and NF-κB RelA/p65 in human gastric cancers (GC) metastasis remain largely unknown. This study is to investigate the expression profile, clinical relevance and dysregulated mechanism of miR-7 and NF-κB RelA/p65 in GC and to explore the potential therapeutic effect of miR-7 to GC distant metastasis.
Methods:
TCGA STAD and NCBI GEO database were used to investigate the expression profile of miR-7 and NF-κB RelA/p65 and clinical relevance. Lentivirus-mediated gene delivery was applied to explore the therapeutic effect of miR-7 in GC. Real-time PCR, FACS, IHC, IF, reporter gene assay, IP, pre-miRNA-7 processing and binding assays were performed.
Results:
Low miR-7 correlated with high RelA/p65 in GC with a clinical relevance that low miR-7 and high RelA/p65 as prognostic indicators of poor survival outcome of GC patients. Moreover, an impaired pre-miR-7 processing caused by dysregulated Dicer1 expression is associated with downregulated miR-7 in GC cells. Functionally, delivery of miR-7 displays therapeutic effects to GC lung and liver metastasis by alleviating hemangiogenesis, lymphangiogenesis as well as inflammation cells infiltration. Mechanistically, miR-7 suppresses NF-κB transcriptional activity and its downstream metastasis-related molecules Vimentin, ICAM-1, VCAM-1, MMP-2, MMP-9 and VEGF by reducing p65 and p-p65-ser536 expression. Pharmacologic prevention of NF-κB activator LPS obviously restored miR-7-suppressed NF-κB transcriptional activation and significantly reverted miR-7-inhibited cell migration and invasion.
Conclusions:
Our data suggest loss of miR-7 in GC promotes p65-mediated aberrant NF-κB activation, facilitating GC metastasis and ultimately resulting in the worse clinical outcome. Thus, miR-7 may act as novel prognostic biomarker and potential therapeutic target for aberrant NF-κB-driven GC distant metastasis.
Insights
Loss of miR-7 in gastric cancer (GC) promotes NF-κB activation, driving metastasis and poor outcomes. Restoring miR-7 shows therapeutic potential for treating GC distant metastasis.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metastasis Research
Background:
- Dysregulated miR-7 and NF-κB (Nuclear Factor kappa-light-chain-enhancer of activated B cells) signaling are implicated in human cancers.
- The specific roles of miR-7 and NF-κB RelA/p65 in gastric cancer (GC) metastasis and their underlying mechanisms remain largely unexplored.
Purpose of the Study:
- To investigate the expression profile and clinical significance of miR-7 and NF-κB RelA/p65 in GC.
- To elucidate the mechanism by which miR-7 and NF-κB RelA/p65 influence GC metastasis.
- To evaluate the therapeutic potential of miR-7 in combating GC distant metastasis.
Main Methods:
- Analysis of The Cancer Genome Atlas (TCGA) STAD and NCBI GEO databases for expression profiling and clinical relevance.
- Lentivirus-mediated gene delivery to assess miR-7's therapeutic effects in GC models.
- Utilized techniques including real-time PCR, FACS, IHC, IF, reporter gene assays, and IP for mechanistic investigations.
Main Results:
- Low miR-7 expression correlated with high RelA/p65 levels in GC, serving as poor prognostic indicators.
- Impaired pre-miR-7 processing due to dysregulated Dicer1 contributed to reduced miR-7 levels in GC cells.
- miR-7 delivery demonstrated therapeutic effects against lung and liver metastasis by reducing angiogenesis and inflammation, and suppressed NF-κB activity and metastasis-related genes.
Conclusions:
- Loss of miR-7 in GC promotes p65-mediated NF-κB activation, driving metastasis and adverse clinical outcomes.
- miR-7 presents potential as a novel prognostic biomarker for GC.
- miR-7 emerges as a promising therapeutic target for NF-κB-driven GC distant metastasis.
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