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Published on: March 30, 2019
MicroRNA-302s Might Regulate ARL4C-Mediated Gastric Cancer Progression via p53 Signaling: Bioinformatics Analysis and
Ning Xie1,2, Yifei Pan3, Jian Wu4
1Department of Gastroenterology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China.
Background:
Our previous studies demonstrate that ARL4C is the most critical clinical biomarker for gastric cancer (GC) patients among ARL family members (ARLs) and functions as an oncogene in GC. However, its underlying mechanisms in GC need to be further illustrated. In this study, we aim to explore the upstream and downstream molecular mechanisms of ARL4C in GC cells.
Methods:
The genetic alteration of ARL4C in GC is analyzed by cBioPortal database. Potential ARL4C-targeted microRNAs (miRs) are predicted by three databases. The high-throughput RNA sequencing is performed to explore the underlying mechanisms of ARL4C in GC cells. The effects of predicted microRNAs on ARL4C, the RNA-sequencing results validation and the biological functions of ARL4C in GC cells are illustrated by in vitro experiments.
Results:
Genetic analyses indicate that ARL4C is significantly upregulated in GC, which is not caused by gene amplification. MicroRNAs prediction shows the high relevance between ARL4C and miR-302 members. Moreover, miR-302c or miR-302d transfection reduces ARL4C protein expression in GC cells. Based on the high-throughput RNA sequencing of ARL4C-knockdown cells, enrichment analyses demonstrate that ARL4C is closely related to cell growth and involved in p53 signaling. Moreover, there are strong gene-gene interactions between ARL4C and genes in p53 signaling, and ARL4C downregulation could inhibit the protein expression of MDM2, a critical gene in p53 pathway. Further functional experiments demonstrate that ARL4C silencing leads to cell cycle arrest and increased cell apoptosis in AGS and MKN45 cells.
Conclusion:
Our data suggest that miR-302c and miR-302d may function as the upstream regulators of ARL4C. And, ARL4C might promote GC cell cycle progression via regulating p53 signaling. Our findings provide novel insights into the key role of ARL4C and the underlying mechanisms in GC progression, thus facilitating the development of ARL4C-targeted therapy.
Insights
ARL4C is an oncogene in gastric cancer (GC). MiR-302c and miR-302d regulate ARL4C, which promotes GC cell cycle progression through the p53 signaling pathway.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genomics
Background:
- ARF4C is a critical clinical biomarker and oncogene in gastric cancer (GC).
- The precise molecular mechanisms of ARL4C in GC require further elucidation.
- This study investigates the upstream and downstream molecular pathways of ARL4C in GC cells.
Purpose of the Study:
- To explore the upstream regulatory mechanisms of ARL4C in GC.
- To elucidate the downstream molecular targets and functions of ARL4C in GC.
- To identify potential therapeutic targets for GC based on ARL4C pathways.
Main Methods:
- Genetic alterations of ARL4C were analyzed using the cBioPortal database.
- Potential microRNA (miR) regulators of ARL4C were predicted via bioinformatics.
- High-throughput RNA sequencing was employed to identify ARL4C-associated molecular mechanisms.
- In vitro experiments validated miR effects and ARL4C functions in GC cells.
Main Results:
- ARL4C is significantly upregulated in GC, independent of gene amplification.
- miR-302c and miR-302d were identified as potential upstream regulators, reducing ARL4C expression.
- ARL4C knockdown revealed its association with cell growth and the p53 signaling pathway.
- ARL4C silencing induced cell cycle arrest and apoptosis, partly via MDM2 regulation.
Conclusions:
- miR-302c and miR-302d act as upstream regulators of ARL4C in GC.
- ARL4C promotes GC cell cycle progression by modulating the p53 signaling pathway.
- These findings offer insights into ARL4C's role in GC and suggest ARL4C-targeted therapies.
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