From miRNA sponges to mTOR blockades: mapping the multidimensional landscape of ameloblastoma pathogenesis and precision targeting.

Abstract

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.