MicroRNA181c inhibits prostate cancer cell growth and invasion by targeting multiple ERK signaling pathway components
Zhengzheng Su1, Mengni Zhang1, Miao Xu1
1Department of Pathology and State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
Background:
The ERK signaling pathway is frequently deregulated in tumorigenesis, mostly by classical mechanisms such as gene mutation of its components (eg, RAS and RAF). However, whether and how multiple key components of ERK pathway are regulated by microRNAs are not clear.
Methods:
We firstly predicted post-transcriptional regulation of multiple key components of the ERK signaling pathway by miR181c through bioinformatics analysis, and then confirmed the post-transcriptional regulation by dual luciferase reporter gene assays and Western blot analysis. The biological effects of miR181c on prostate cancer cell proliferation, apoptosis, migration, and invasion were measured by CCK-8 assay, flow cytometry, wound scratch assay, transwell cell migration, and invasion assays.
Results:
miR181c post-transcriptionally regulated multiple key members of the ERK signaling pathway, including extracellular signal-regulated kinase 2 (ERK2), ribosomal S6 kinase 2 (RSK2), serum response factor (SRF), and FBJ murine osteosarcoma viral oncogene homolog (c-Fos). Ectopic expression of miR181c mimics effectively suppressed prostate cancer cell proliferation, migration, and invasion, but promoted cell apoptosis. Furthermore, miR181c treatment combined with the multi-kinase inhibitor sorafenib significantly enhanced these anti-tumor effects.
Conclusions:
Downregulation of miR181c results in deregulated ERK signaling and promotes prostate cancer cell growth and metastasis.
Insights
MicroRNA 181c (miR181c) regulates the ERK signaling pathway, suppressing prostate cancer cell growth and metastasis. Downregulation of miR181c promotes tumor progression, highlighting its therapeutic potential.
Area of Science:
- Molecular Biology
- Cancer Research
- Signaling Pathways
Background:
- The Extracellular signal-Regulated Kinase (ERK) signaling pathway is crucial in tumorigenesis, often dysregulated by gene mutations.
- The role of microRNAs (miRNAs) in regulating multiple ERK pathway components remains unclear.
Purpose of the Study:
- To investigate the post-transcriptional regulation of key ERK pathway components by miR181c.
- To evaluate the impact of miR181c on prostate cancer progression and its potential as a therapeutic target.
Main Methods:
- Bioinformatic analysis to predict miR181c targets within the ERK pathway.
- Dual luciferase reporter gene assays and Western blot to confirm post-transcriptional regulation.
- In vitro assays (CCK-8, flow cytometry, wound scratch, Transwell) to assess miR181c's effects on prostate cancer cells.
Main Results:
- miR181c was confirmed to post-transcriptionally regulate ERK2, RSK2, SRF, and c-Fos.
- Overexpression of miR181c inhibited prostate cancer cell proliferation, migration, and invasion, while promoting apoptosis.
- Combination therapy with miR181c mimics and sorafenib enhanced anti-tumor effects.
Conclusions:
- Downregulation of miR181c contributes to ERK pathway dysregulation, promoting prostate cancer growth and metastasis.
- miR181c acts as a tumor suppressor in prostate cancer, with potential therapeutic applications, especially when combined with kinase inhibitors.
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