Research Article Potential Biomarkers and Signaling Pathways Associated with the Pathogenesis of Primary Ameloblastoma: A Systems Biology Approach Zeynab Bayat , 1 Azin Mirzaeian , 1 and Amir Taherkhani 2 1 Department of Oral and Maxillofacial Medicine, Faculty of Dentistry, Hamadan University of Medical Sciences, Hamadan, Iran 2 Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran Correspondence should be addressed to Amir Taherkhani; amir.007.taherkhani@gmail.com Received 12 April 2022; Accepted 7 September 2022; Published 16 September 2022 Academic Editor: Amol Gadbail Copyright © 2022 Zeynab Bayat et al. is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Objective. Ameloblastoma is a benign odontogenic tumor that may lead to ameloblastic carcinoma. is study aimed to determine potential signaling pathways and biological processes, critical genes and their regulating transcription factors (TFs), and miRNAs, as well as protein kinases involved in the etiology of primary ameloblastoma. Methods. e dataset GSE132472 was obtained from the GEO database, and multivariate statistical analyses were applied to identify differentially expressed genes (DEGs) in primary ameloblastoma tissues compared to the corresponding normal gingiva samples. A protein-protein interaction (PPI) map was built using the STRING database. e Cytoscape software identified significant modules and the hub genes within the PPI network. Gene Ontology annotation and signaling pathway analyses were executed by employing the DAVID and Reactome databases, respectively. Significant TFs and miRNAs acting on the hub genes were identified using the iRegulon plugin and MiRWalk 2.0 database, respectively. A protein kinase enrichment analysis was conducted using the online Kinase Enrichment Analysis 2 (KEA2) web server. e approved drugs acting on the hub genes were also found. Results. A total of 1,629 genes were differentially expressed in primary ameloblastoma (P value <0.01 and |Log2FC| > 1). HRAS, CDK1, MAPK3, ERBB2, COL1A1, CYCS, and BRCA1 demonstrated high degree and betweenness centralities in the PPI network. E2F4 was the most significant TF acting on the hub genes. BTK was the protein kinase significantly enriched by the TFs. Cholesterol biosynthesis was considerably involved in primary ameloblastoma. Conclusions. is study provides an intuition into the potential mechanisms involved in the etiology of ameloblastoma. 1. Introduction Odontogenic tumors are a class of heterogeneous lesions arising from the tooth-forming tissue, including ectome- senchyme and epithelium remnants associated with the teeth’ formation [1, 2]. ese tumors could affect individuals of different ages, with peripheral or central tumor locations in the maxillary or mandibular region, leading to facial swelling [3, 4]. Ameloblastoma is an odontogenic tumor originating from the cells close to the tooth-root derived from the ectoderm germ layer. Although ameloblastoma is the pathology in 1% of all tumors in the jaw region, they are known as the second commonest odontogenic tumor. ey occur equally in men and women with ages ranging from 30 to 50, with approximately 80% of the cases in the mandible. ey are principally benign tumors; however, they show aggressive behavior and could lead to ameloblastic carci- noma (also known as malignant ameloblastoma). e re- currence rate of ameloblastoma is high if the lesions are not cut off perfectly during surgery [5]. Although several types of research have been executed to elucidate molecular changes in odontogenic tumors such as ameloblastoma, their exact underlying mechanisms, including cellular differentiation and tumorigenesis, are unclear and need more studies in this field [6]. Inside human cells, thousands of genes, transcriptomes, and proteins function in various complicated biological networks, including protein-protein interaction (PPI), gene Hindawi International Journal of Dentistry Volume 2022, Article ID 3316313, 14 pages https://doi.org/10.1155/2022/3316313