Expression and Regulation of the ΔN and TAp63 Isoforms in Salivary Gland Tumorigenesis

Abstract

The TP63 gene, a TP53 homologue, encodes for two main isoforms by different promoters: one retains (TA) and the other lacks (⌬N) the transactivation domain. p63 plays a critical role in the maintenance of basal and myoepithelial cells in ectodermally derived tissues and is implicated in tumorigenesis of several neoplastic entities. However, the biological and regulatory roles of these isoforms in salivary gland tumorigenesis remain unknown. Our results show a reciprocal expression between TA and ⌬N isoforms in both benign and malignant salivary tumors. The most dominantly expressed were the ⌬N isoforms, whereas the TA isoforms showed generally low levels of expression, except in a few tumors. High ⌬Np63 expression characterized tumors with aggressive behavior, whereas tumors with high TAp63 expression were significantly smaller and less aggressive. In salivary gland cells, high expression of ⌬Np63 led to enhanced cell migration and invasion and suppression of cell senescence independent of TAp63 and/or TP53 gene status. We conclude the following: i) overexpression of ⌬Np63 contributes to salivary tumorigenesis, ii) ⌬Np63 plays a dominant negative effect on the TA isoform in the modulation of cell migration and invasion, and iii) the ⌬N isoform plays an oncogenic role and may represent an attractive target for therapeutic intervention in patients with salivary carcinomas.

DOG1, alpha-amylase and p63 expression in acinic cell carcinoma of salivary gland; immunohistochemical, clinical and radiological study

“…In the presenting study, we found 13 out of 14 ACC cases negative for p63 antibody this coincides with studies done by Weiler et al, [28], Sams and Gnep [29] and Mitani et al [30]. Weiler et al, [28] reported that all cases of ACC subjected to his study showed 100% p63 negativity.…”

“…Mitani et al, [30] studied the reciprocal p63 TA and ΔN isoform expression in certain benign and malignant salivary gland tumors, of these ACC and found that salivary duct and ACC, tumors that lack myoepithelial and/or basal cells, were deficient for both isoforms and hence, all cases of ACC were negative for p63 immunostaining in contrast to tumors with myoepithelial and/or basal cell participation.…”

15-Hydroxyprostaglandin Dehydrogenase-derived 15-Keto-prostaglandin E2 Inhibits Cholangiocarcinoma Cell Growth through Interaction with Peroxisome Proliferator-activated Receptor-γ, SMAD2/3, and TAP63 Proteins

“…2) TAP63 overexpression prevented 15-PGDH depletion-mediated increase of cell proliferation, colony formation, and migration. These findings are noteworthy, given that TAP63 is a member of the p53 family and functions as a key tumor suppressor distinct from p53 to mediate various biological processes, including cell proliferation, differentiation, and apoptosis (35,38,(42)(43)(44)(45)(46)(47)(48)(49)(50).…”

Quantitative single cell analysis of cell population dynamics during submandibular salivary gland development and differentiation

“…These cells can be generally classified as secretory acinar cells that produce the saliva, ductal cells that both modify and transport the saliva, or myoepithelial cells that are thought to both provide the contractile force to induce saliva secretion out of the acini and to maintain tissue architecture (Ogawa, 2003; Mitani et al, 2011), similar to the role of myoepithelial cells in the mammary gland (Hu et al, 2008; Moumen et al, 2011). Two progenitor cell markers have been identified in the mouse SMG that are expressed by cells that can give rise to all of the epithelial lineages of the gland in certain contexts.…”