The clinical significance and correlative signaling pathways of paired box gene 9 in development and carcinogenesis

Abstract

Paired box 9 (PAX9) gene belongs to the PAX family, which encodes a family of metazoan transcription factors documented by a conserved DNA binding paired domain 128-amino-acids, critically essential for physiology and development. It is primarily expressed in embryonic tissues, such as the pharyngeal pouch endoderm, somites, neural crest-derived mesenchyme, and distal limb buds. PAX9 plays a vital role in craniofacial development by maintaining the odontogenic potential, mutations, and polymorphisms associated with the risk of tooth agenesis, hypodontia, and crown size in dentition. The loss-of-function of PAX9 in the murine model resulted in a short life span due to the arrest of cleft palate formation and skeletal abnormalities. According to recent studies, the PAX9 gene has a significant role in maintaining squamous cell differentiation, odontoblast differentiation of pluripotent stem cells, deregulation of which is associated with tumor initiation, and malignant transformation. Moreover, PAX9 contributes to promoter hypermethylation and alcohol- induced oro-esophageal squamous cell carcinoma mediated by downregulation of differentiation and apoptosis. Likewise, PAX9 activation is also reported to be associated with drug sensitivity. In summary, this current review aims to understand PAX9 function in the regulation of development, differentiation, and carcinogenesis, along with the underlying signaling pathways for possible cancer therapeutics.

Keywords: Apoptosis; Carcinogenesis; Differentiation; Gene therapy; PAX9; Promoter hypermethylation; Transcription factor.