Roles of WNT5A in Modulating Enamel Epithelium Tumorigenic Behavior Public Deposited

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  • June 7, 2019
  • Sukarawan, Waleerat
    • Affiliation: School of Dentistry, Oral and Craniofacial Biomedicine PhD Program
  • Odontogenic tumors originate from the remains of migrating enamel epithelium after the completion of normal tooth genesis. These enamel epithelium remnants exhibit the ability to recapitulate the events that occur during tooth formation. Several lines of evidence suggest that aberrance in the signaling pathways similar to the ones that are used during tooth development might be the cause of odontogenic tumorigenesis and maintenance. In this study we demonstrated that WNT5A (wingless-type MMTV integration site family, member 5A) expression was intense in both the epithelial component of ameloblastomas, the most common epithelial odontogenic tumor, and in the cervical loop area during normal human tooth formation. In addition, we discovered that enamel epithelium (LS-8) cell-derived clones expressing high (S) levels of WNT5A exhibited characteristics of tumorigenic cells, including growth factor independence, loss of anchorage dependence, loss of contact inhibition, tumor formation in vivo and increased cell migration when compared to controls (LS-8, EV). In order to elucidate the signaling pathways underlying these findings, pharmacological inhibitors specific for different downstream effectors in the known WNT5A signaling cascade were used in the in vitro cell growth transformation assay. We determined that specific JNK (c-Jun N-terminal kinase) (SP600125) and ROCK (Rho-associated, coiled-coil containing protein kinase) (Y27632) inhibitors suppressed the tumorigenic growth properties of enamel epithelium overexpressing WNT5A. Furthermore, strong phosphorylated JNK expression was detected in ameloblastomas in a similar pattern to WNT5A expression. Finally, increased levels of phosphorylated JNK expression was observed in enamel epithelium clones that overexpressed WNT5A as well as cells treated with recombinant WNT5A. Our data indicate that the Rho/JNK pathway could be the downstream signal of WNT5A in modulating tumorigenic behaviors of enamel epithelium.
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  • ... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the curriculum of School of Dentistry (Oral Biology)
  • Wright, J. Timothy
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  • University of North Carolina at Chapel Hill

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