**4. Conclusion**

*Gene Expression and Control*

brane protein called Smoothened (SMO).

to abnormal cellular proliferation and differentiation, which is strongly associated with the development of certain tumors [66, 67]. This section will describe genes that are involved in pathogenesis of odontogenic keratocysts through Sonic hedgehog pathway (Shh). The members of this pathway include secreted SHH ligand, which binds to its receptor *PTCH*, a 12-pass transmembrane protein, as described previously (**Figure 7**). In the absence of SHH ligand, PTCH inhibits a transmem-

In odontogenic keratocysts, *PTCH* mutations include LOH, deletions, point mutations, and others. The consequence of *PTCH* mutations are the constitutive activation of Shh pathway. When *PTCH* is mutated and inactivated, it is expected that SMO would be disinhibited and thus activated. This is exactly what is found in odontogenic keratocysts, where Smo overexpression has been shown by transcriptional and immunohistochemical studies [67–69]. Besides overexpression of SMO and PTCH, other downstream genes such as *GLI1*, *CCND1*, and *BCL-2* have been shown to be overexpressed in odontogenic keratocysts, indicating that these SHH

Another downstream target of Shh signaling is a transcription factor SOX-2 [70] that is expressed in progenitor cells in epithelial tissues. SOX-2 expression is associated with elements of tooth development, especially in the region of the third molars in the lower jaw, which is the place where OKCs are usually located [71, 72]. Besides studies on Shh pathway, a list of genes that are upregulated in odontogenic keratocysts is shown in **Table 2**. Bioinformatic analysis has shown that other genes, such as *TP53* and *PCNA*, appear as the leaders and initiators of gene expression that is important for the development of odontogenic keratocysts [61, 73, 74]. Their analysis has shown that genes related to cell cycle and apoptosis are often dysregulated in these cysts, implying the recurrence of these cysts. Studies have shown that *TP53*, *PCNA*, p63, and Ki-67 expression is higher in keratocysts than in other types of odontogenic cysts. *TP53* is a tumor suppressor gene with several different functions in the cell including apoptosis, cell cycle arrest, and DNA repair. The second gene that is found to be associated with odontogenic keratocysts is proliferating cell nuclear antigen (*PCNA*), which encodes a protein located in the nucleus and associated with DNA polymerase delta. It acts as a homotrimer and is

**Gene name Method of detection References** PCNA IHC [74] CCND1 IHC and real-time PCR [67] IL-6 IHC [75] VEGFA IHC [76] BCL2 IHC, real-time PCR, Western blot [77] FHIT IHC [25] GLI1 IHC [78] TP63 IHC [76] KRT6B IHC [79] TP53 Bioinformatic analysis [73] SMO IHC and transcriptional analysis [67–69]

*Genes that show high expression in odontogenic keratocysts, detected either at the RNA or protein level* 

pathway genes contribute to the development of these lesions.

**70**

**Table 2.**

*(modified from [63]).*

*IHC, immunohistochemistry; PCR, polymerase chain reaction.*

This chapter summarizes gene expression profiles of radicular cysts as the most common member of odontogenic cysts and keratocysts, a specific entity of epithelial developmental cysts, in order to uncover possible mechanism of pathogenesis that would help in the timely diagnosis and discovery of novel therapeutic options for these two types of jaw cysts. Pathogenesis of radicular cysts is associated with differential expression of genes involved in bone metabolism (RANK-RANKL-OPG pathway) and inflammation (chemokines and their receptors). However, the most extensively studied genes in the pathogenesis of radicular cysts belong to the family of matrix metalloproteinases (MMPs), which show increased expression.

Specific entities of odontogenic cysts are odontogenic keratocysts, which are prone to recidive. This trait of keratocysts to recur makes them similar to tumors, which can be also seen in their gene expression profiles. The hallmark of odontogenic keratocysts is mutation in *PTCH* gene, which is a receptor in Sonic hedgehog signaling (Shh) pathway. Mutations in PTCH gene lead to the constitutive activation of this pathway. Besides overexpression of PTCH, other downstream genes such as *SMO*, *GLI1*, *CCND1*, and *BCL-2* have been shown to be overexpressed in odontogenic keratocysts, indicating that these SHH pathway genes contribute to the development of these lesions.
