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Development of microRNA-145 for therapeutic application in breast cancer
Seok-Jun Kim1, Ji-Sun Oh, Ji-Young Shin
1Gastric Cancer Branch, Division of Translational & Clinical Research I, National Cancer Center Research Institute and Hospital, Ilsandong-gu, Goyang-si, Gyeonggi-do, Republic of Korea.
Abstract:
MicroRNAs, small non-coding RNAs, are key regulators of tumorigenesis and cancer metastasis through inhibition of gene expression. Therefore, there is increasing interest in developing anti-cancer therapies using microRNAs. In this study, we determined the therapeutic potency of microRNA-145(miR-145) against breast cancer. We found a reverse-correlation between the expression of miR-145 and its target genes, such as fascin-1, c-myc, SMAD2/3 and IGF-1R in breast cancer cell lines and breast cancer patient tissues. Transfected miR-145 mimicking double-stranded oligonucleotides was directly reduced cell proliferation and motility via interaction with 3'UTR of target gene and also indirectly regulates Wnt signaling. An inhibitor of miR-145 nullified this decreasing effect of miR-145 on cell proliferation and motility. We prepared an adenoviral constructed miR-145(Ad-miR-145) and subjected it to breast cancer cells in vitro and orthotopic breast cancer mice in vivo. Ad-miR-145 suppressed cell growth and motility in both the in vitro and in vivo systems. Furthermore, a treatment combining Ad-miR-145 with 5-FU significantly showed anti-tumor effects, compared to treating alone. In conclusion, this study demonstrated that miR-145 suppresses tumor growth by inhibition of multiple tumor survival effectors, and more we suppose that miR-145 is potentially useful in the therapy of breast cancers.
Insights
MicroRNA-145 (miR-145) effectively suppresses breast cancer growth and metastasis by inhibiting key target genes. This study highlights miR-145
Area of Science:
- Molecular Biology
- Oncology
- Gene Regulation
Background:
- MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression and are implicated in cancer development.
- Dysregulation of miRNA expression is common in various cancers, including breast cancer, affecting tumorigenesis and metastasis.
- MicroRNA-145 (miR-145) has emerged as a potential tumor suppressor, but its therapeutic efficacy in breast cancer requires further investigation.
Purpose of the Study:
- To evaluate the therapeutic potential of microRNA-145 (miR-145) as an anti-cancer agent against breast cancer.
- To investigate the molecular mechanisms underlying miR-145's action in breast cancer cells and tissues.
Main Methods:
- Analysis of the inverse correlation between miR-145 expression and its target genes (e.g., fascin-1, c-myc, SMAD2/3, IGF-1R) in breast cancer cell lines and patient tissues.
- Transfection of miR-145 mimics and inhibitors to assess effects on cell proliferation and motility.
- In vitro and in vivo studies using an adenoviral vector carrying miR-145 (Ad-miR-145) in breast cancer cells and orthotopic mouse models.
- Evaluation of combination therapy with Ad-miR-145 and 5-fluorouracil (5-FU).
Main Results:
- A reverse correlation was observed between miR-145 expression and its target genes in breast cancer.
- miR-145 mimics reduced breast cancer cell proliferation and motility by targeting specific genes and regulating Wnt signaling.
- An miR-145 inhibitor reversed these suppressive effects.
- Ad-miR-145 demonstrated significant suppression of tumor growth and motility in vitro and in vivo.
- Combination therapy of Ad-miR-145 and 5-FU exhibited enhanced anti-tumor effects.
Conclusions:
- MicroRNA-145 (miR-145) acts as a tumor suppressor in breast cancer by inhibiting multiple survival pathways.
- miR-145 demonstrates significant therapeutic potential for breast cancer treatment, both alone and in combination therapy.
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