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From miRNA sponges to mTOR blockades: mapping the multidimensional landscape of ameloblastoma pathogenesis and
Jingsong Mao1, Qingxuan Gai1, Xinling Bao1
1Department of Oral Histopathology, School and Hospital of Stomatology, China Medical University, Shenyang, China.
Background:
Ameloblastoma is a benign but locally aggressive odontogenic tumor with frequent recurrence after conservative surgery. Evidence accumulated since 2010 implicates dysregulated non-coding RNAs (ncRNAs)-notably microRNAs (miRNAs) and circular RNAs (circRNAs)-as higher-order regulators of oncogenic signaling.
Objective:
This study aimed to synthesize peer-reviewed mechanistic and translational evidence on ncRNA networks in ameloblastoma, with explicit grading by evidence tier and emphasis on druggable nodes.
Methods:
We conducted a structured narrative search of PubMed, Scopus, and Web of Science (January 2010-May 31, 2025) using controlled terms for "ameloblastoma," "microRNA," "circRNA," and key pathways (MAPK, PI3K-Akt-mTOR, Wnt/β-catenin, IL-33/STAT3; Hippo/YAP-TAZ considered contextually). Peer-reviewed studies with experimental validation in ameloblastoma were prioritized, while purely computational predictions and unrelated tumor entities were excluded.
Results:
Across patient tissues, cell models, and limited in vivo studies, recurrent miRNA changes-i.e., loss of miR-524-5p, miR-141-3p, and miR-1-3p and gain of miR-29a-3p-converge on MAPK/ERK and PI3K-Akt-mTOR signaling. Loss of miR-524-5p derepresses IL-33/ST2, amplifying NF-κB/STAT3 and PI3K signaling (preclinical). miR-29a-3p targets CTNNBIP1 to reinforce Wnt/β-catenin (preclinical). miR-141-3p is anti-migratory and has been reported to upregulate NCAM1 in ameloblastoma models (preclinical). miR-1-3p restrains LAMP2-mediated autophagy (preclinical). Overexpressed circRNAs (e.g., circ-MAP3K7 and circ-HIPK3) can titrate tumor-suppressive miRNAs and sustain pathway activity (preclinical). No randomized clinical trials in ameloblastoma exist to date.
Conclusions:
A coherent ncRNA network appears to maintain druggable signaling convergence in ameloblastoma. Translation will require multicenter validation of the ncRNA biomarkers, early-phase trials testing rational MAPK-mTOR combinations with ncRNA modulation, and jaw-targeted delivery approaches. Claims herein are limited to peer-reviewed, ameloblastoma-relevant evidence.
Insights
Dysregulated non-coding RNAs (ncRNAs) drive ameloblastoma, a locally aggressive tumor. Targeting ncRNA networks offers potential therapeutic strategies by modulating key signaling pathways like MAPK and PI3K-Akt-mTOR.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Ameloblastoma is a benign, locally aggressive odontogenic tumor known for frequent recurrence post-surgery.
- Dysregulated non-coding RNAs (ncRNAs), including microRNAs (miRNAs) and circular RNAs (circRNAs), are increasingly implicated in ameloblastoma's oncogenic signaling pathways.
- Understanding these ncRNA networks is crucial for developing effective therapeutic strategies.
Purpose of the Study:
- To synthesize mechanistic and translational evidence on ncRNA networks in ameloblastoma.
- To grade the evidence supporting these networks by tier.
- To identify druggable nodes within these ncRNA networks for potential therapeutic targeting.
Main Methods:
- Conducted a structured narrative search of PubMed, Scopus, and Web of Science from January 2010 to May 2025.
- Utilized controlled terms for "ameloblastoma," "microRNA," "circRNA," and key signaling pathways (MAPK, PI3K-Akt-mTOR, Wnt/β-catenin, IL-33/STAT3).
- Prioritized peer-reviewed studies with experimental validation in ameloblastoma, excluding purely computational predictions.
Main Results:
- Recurrent miRNA alterations (loss of miR-524-5p, miR-141-3p, miR-1-3p; gain of miR-29a-3p) converge on MAPK/ERK and PI3K-Akt-mTOR signaling.
- Specific miRNAs modulate key pathways: miR-524-5p affects IL-33/ST2/NF-κB/STAT3/PI3K; miR-29a-3p impacts Wnt/β-catenin; miR-141-3p influences migration and NCAM1 expression; miR-1-3p regulates autophagy.
- Overexpressed circRNAs (e.g., circ-MAP3K7, circ-HIPK3) can sequester tumor-suppressive miRNAs, sustaining pathway activity.
Conclusions:
- A coherent ncRNA network appears to maintain druggable signaling convergence in ameloblastoma.
- Multicenter validation of ncRNA biomarkers is necessary for clinical translation.
- Future research should focus on early-phase trials testing MAPK-mTOR inhibitors combined with ncRNA modulation and explore targeted delivery approaches for jaw lesions.
