Table 3.

Summary describing the role of FOXI3 in development and its hypothesized role in cancer progression.

Processes	Role of FOXI3 in embryogenesis	Hypothesized role of FOXI3 in cancer
Epithelial mesenchymal transition (EMT)	Early cartilage differentiation including development of epibranchial placodes, inner ear, and pharyngeal arch derivatives (Jussila et al., 2015)	May promote EMT, inducing metastasis
Bone development	1. Promotes murine craniofacial development (Jussila et al., 2015) 2. Induces early bone and cartilage formation, i.e., pharyngeal and otic placode development in mice and chickens (Coffer and Burgering, 2004; Voulgari and Pintzas, 2009) 3. Regulates ectodermal development in Chinese crested dogs and Mexican and Peruvian hairless dogs (Tuteja and Kaestner, 2007b; Shirokova et al., 2016).	Regulates bone matrix proteins, promoting osteomimicry of cancer cells, promoting bone metastasis
Bone microenvironment	Fibroblast growth factor 1. Regulates FGF in vertebrate bone development (Khatri and Groves, 2013) 2. Osteoclast/blast differentiation (Khatri and Groves, 2013) Bone morphogenetic protein Distal limb morphogenesis, mesoderm formation, and cell differentiation (Wiener et al., 2013; Tassano et al., 2015)	FGFs, SPOCK1, Dlx, RUNX2, MAF, PthrP, HAS2, SVEP1, TGFβ3, and other factors in bone matrix may modulate FOXI3 expression, promoting solid tumor bone metastasis
Ionocyte and ion channels	1. Regulates ionocyte differentiation in zebrafish embryos (Gao et al., 2013; Chen et al., 2016) 2. Functions as a molecular switch converting cells to ionocytes (Chen et al., 2016)	Mutation of sub-cellular FOXI3A/B interferes with ion channel function, disrupting cell homeostasis and promoting tumor metastasis
Notch signaling	Jagged-2 Regulates skin ionocyte formation and differentiation in zebrafish embryos by regulating Jagged-2 in the Notch Signaling Pathway (Gao et al., 2013; Chen et al., 2016)	FOXI3 overexpression may modulate Jagged-2, dysregulating the Notch pathway, promoting cancer invasion