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Published on: May 21, 2019
MicroRNA-217 modulates pancreatic cancer progression via targeting ATAD2
Madhuri Dutta1, Biswajit Das2, Debasish Mohapatra2
1Biochemistry and Cell Biology Laboratory, School of Basic Sciences, Indian Institute of Technology Bhubaneswar, Odisha 752050, India.
Aims:
Pancreatic cancer is a fatal disease across the world with 5 years survival rate less than 10%. ATAD2, a valid cancer drug-target, is overexpressed in pancreatic malignancy with high oncogenic potential. However, the mechanism of the upregulated expression of ATAD2 in pancreatic cancer is unknown. Since microRNAs (miRNAs) could potentially control target mRNA expressions, and are involved in cancer as tumor-suppressors, oncomiR or both, we examine the possibility of miRNA-mediated regulation of ATAD2 in pancreatic cancer cells (PCCs).
Main Methods:
Our in-silico approach first identifies hsa-miR-217 as a candidate regulator for ATAD2 expression. For further validation, luciferase reporter assay is performed. We overexpress hsa-miRNA-217 and assess cellular viability, migration, apoptosis and cell cycle progression in three different PCCs (BxPC3, PANC1, and MiaPaCa2).
Key Findings:
We find hsa-miRNA-217 has potential binding site at the 3'UTR of ATAD2. Luciferase assay confirms that ATAD2 is a direct target of hsa-miR-217. Overexpression of hsa-miR-217 drastically downregulates ATAD2 expression in PCCs, thus, corroborating binding studies. The elevated expression of hsa-miRNA-217 diminishes cell proliferation and migration as well as induces apoptosis and cell cycle arrest in PCCs. Finally, siRNA mediated ATAD2 knockdown or overexpression of hsa-miRNA-217 in PCCs showed inactivation of the AKT signaling pathway. Therefore, hsa-miR-217 abrogates pancreatic cancer progression through inactivation of the AKT signaling pathway and this might be partly due to miR-217 mediated suppression of ATAD2 expression.
Significance:
The application of hsa-miR-217 mimic could be a promising therapeutic strategy for the treatment of pancreatic cancer patients in near future.
Insights
MicroRNA-217 (miR-217) targets ATAD2, a gene overexpressed in pancreatic cancer. Inhibiting ATAD2 with miR-217 may offer a new therapeutic strategy for pancreatic cancer.
Area of Science:
- Molecular oncology
- Gene regulation
- Cancer therapeutics
Background:
- Pancreatic cancer has a poor prognosis with a 5-year survival rate below 10%.
- ATAD2 is a validated drug target overexpressed in pancreatic cancer, contributing to its oncogenic potential.
- The precise mechanisms driving ATAD2 upregulation in pancreatic cancer remain unclear.
Purpose of the Study:
- To investigate the potential role of microRNAs (miRNAs) in regulating ATAD2 expression in pancreatic cancer cells (PCCs).
- To identify specific miRNAs that target and downregulate ATAD2 in the context of pancreatic malignancy.
Main Methods:
- In-silico analysis to identify candidate miRNA regulators of ATAD2.
- Luciferase reporter assays to validate direct targeting of ATAD2 by hsa-miR-217.
- Experimental manipulation of hsa-miR-217 levels in PCCs (BxPC3, PANC1, MiaPaCa2) to assess effects on cell viability, migration, apoptosis, and cell cycle.
Main Results:
- hsa-miR-217 was identified as a direct regulator of ATAD2, binding to its 3'UTR.
- Overexpression of hsa-miR-217 led to significant downregulation of ATAD2 in PCCs.
- Elevated hsa-miR-217 expression suppressed cell proliferation and migration, induced apoptosis, and caused cell cycle arrest.
- Both ATAD2 knockdown and hsa-miR-217 overexpression inactivated the AKT signaling pathway, suggesting its role in pancreatic cancer progression.
Conclusions:
- hsa-miR-217 suppresses pancreatic cancer progression, partly through the downregulation of ATAD2 and subsequent inactivation of the AKT pathway.
- Therapeutic strategies utilizing hsa-miR-217 mimics show promise for future pancreatic cancer treatment.
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