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The NRG3/ERBB4 signaling cascade as a novel therapeutic target for canine glioma
Shunsuke Noguchi1, Marina Inoue1, Tomotsugu Ichikawa2
1Laboratory of Veterinary Radiology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-58 Rinku Ourai Kita, Izumisano-shi, Osaka, 598-8531, Japan.
Abstract:
Canine glioma is a common brain tumor with poor prognosis despite surgery and/or radiation therapy. Therefore, newer and more effective treatment modalities are needed. Neuregulin 3 (NRG3) has known to be a ligand of ERBB4. This study aimed to investigate the usefulness of the NRG3/ERBB4 signaling cascade as a novel therapeutic target in canine glioma. We found out that microRNA (miR)-190a was downregulated in canine brain tumor tissues, including glioma and meningioma. miR-190a directly targeted NRG3 and inhibited the growth of canine glioma cells. The level of p-Akt, which is a downstream target of ERBB4 signaling, was decreased by transfection with miR-190a. NRG3 silencing also suppressed cell growth and decreased the levels of p-Akt and p-ERK1/2, and NRG3 overexpression exhibited opposed effects in canine glioma J3T-1 cells. The mRNA level of erbb4 was significantly upregulated in glioma tissues compared with that in normal brain tissues and meningioma tissues. Furthermore, compared with gefitinib and lapatinib, afatinib exerted a greater inhibitory effect on the growth of canine glioma cells. In conclusion, NRG3/ERBB4 signaling is negatively regulated by miR-190a and contributes to the growth of canine glioma cells, indicating that it may be a promising therapeutic target in canine glioma.
Insights
MicroRNA-190a targets Neuregulin 3 (NRG3) to inhibit canine glioma growth. Targeting the NRG3/ERBB4 pathway with drugs like afatinib shows promise for treating canine brain tumors.
Area of Science:
- Veterinary Oncology
- Molecular Biology
- Cancer Signaling Pathways
Background:
- Canine glioma presents a poor prognosis, necessitating novel therapeutic strategies.
- The Neuregulin 3 (NRG3)/ERBB4 signaling pathway is implicated in various cancers.
- Identifying new molecular targets is crucial for improving canine glioma treatment outcomes.
Purpose of the Study:
- To investigate the role of the NRG3/ERBB4 signaling cascade as a potential therapeutic target in canine glioma.
- To determine the regulatory relationship between microRNA-190a (miR-190a) and NRG3 in canine glioma cells.
Main Methods:
- Analysis of miR-190a and NRG3 expression in canine brain tumor tissues.
- In vitro experiments involving miR-190a transfection and NRG3 silencing/overexpression in canine glioma cells.
- Assessment of downstream signaling molecules, including p-Akt and p-ERK1/2.
- Evaluation of the efficacy of ERBB4 inhibitors (gefitinib, lapatinib, afatinib) on canine glioma cell growth.
Main Results:
- miR-190a was found to be downregulated in canine glioma and meningioma tissues.
- miR-190a directly targets NRG3, inhibiting canine glioma cell proliferation.
- NRG3 silencing suppressed cell growth and reduced p-Akt and p-ERK1/2 levels, while NRG3 overexpression had opposite effects.
- ERBB4 mRNA levels were significantly upregulated in glioma tissues.
- Afatinib demonstrated a greater inhibitory effect on canine glioma cell growth compared to gefitinib and lapatinib.
Conclusions:
- The NRG3/ERBB4 signaling pathway is negatively regulated by miR-190a and promotes canine glioma cell growth.
- This pathway represents a promising therapeutic target for canine glioma.
- Targeting NRG3/ERBB4 signaling, potentially with afatinib, could offer a new treatment modality for canine brain tumors.
