Targeted Expression of GLI1 in the Salivary Glands Results in an Altered Differentiation Program and Hyperplasia

Abstract

Hedgehog (Hh) signaling is a regulator of salivary gland morphogenesis, but its role in postnatal glands has only recently begun to be addressed. To examine the effects of deregulated Hh signaling in the salivary gland, we expressed the Hh effector protein GLI1, in salivary epithelial cells using both cytokeratin 5 and mouse mammary tumor virus (MMTV) transgenic systems. Ectopic pathway activation resulted in restrained acinar differentiation, formation of cystic lesions, and prominent appearance of ductal structures. Moreover, induced expression of GLI1 aids the formation of hyperplastic lesions, which closely resemble GLI1-induced changes in murine skin and mammary glands, suggesting that GLI1 targets cells with similar characteristics in different tissues. Furthermore, GLI1-expressing salivary epithelial cells are actively dividing, and GLI1-induced lesions are proliferative, an incident accompanied by enhanced expression of the Hh target genes, cyclin D1, and Snail. GLI1-induced salivary lesions regress after transgene withdrawal and become histologically normalized. Taken together, our data reveal the ability of GLI1 to modulate salivary acinar differentiation and to promote proliferation of ductal epithelial cells.

Neurotrophic factor GDNF promotes survival of salivary stem cells

“…These include the WNT and NOTCH signaling pathways for SC self renewal and lineage determination (53)(54)(55)(56), ASCL3 for proliferation (57), and GSK3β for cell differentiation (58). In addition, the SC niche clearly plays an important role in the fate of SCs (59).…”

Rescue Effects and Underlying Mechanisms of IntraglandShhGene Delivery on Irradiation-Induced Hyposalivation

“…32,33 However, transient Hh activation in salivary glands, such as overexpression of Gli1 transgene for 15 weeks and overexpression of Shh transgene for 1 week, did not result in any detectable tumor in mice. 15,34 Gene therapy for salivary gland hypofunction has several unique advantages, including easy access to most parenchymal cells via duct cannulation, the capacity to produce high amounts of protein, and tight encapsulation that minimizes concern about transgene spread. 35 We reported earlier that in wild-type mice with subcutaneous head and neck squamous cell carcinoma, the delivery of Ad-Shh to SMGs by retrograde ductal instillation efficiently activated the Hh/Gli pathway in SMGs, but did not activate the Hh/Gli pathway in tumors and did not affect the growth and response to radiotherapy of tumors, 15 indicating that local Hh activation in salivary glands will not promote the growth and radioresistance of preexisting tumors outside salivary glands.…”

The Transcription Factor GLI1 Interacts with SMAD Proteins to Modulate Transforming Growth Factor β-Induced Gene Expression in a p300/CREB-binding Protein-associated Factor (PCAF)-dependent Manner

“…In addition to gliomas, GLI1 is highly expressed in multiple neoplasms such as small cell lung, pancreatic, stomach, and prostate cancer where its expression is in general associated with unfavorable overall patient survival (4 -8). Numerous reports have demonstrated that the sole overexpression of GLI1 is sufficient to induce transformation in vitro and in vivo (9,10). For instance, transgenic overexpression of GLI1 in epithelial cells generates hyperplastic lesions and tumor development (9,10).…”

“…Numerous reports have demonstrated that the sole overexpression of GLI1 is sufficient to induce transformation in vitro and in vivo (9,10). For instance, transgenic overexpression of GLI1 in epithelial cells generates hyperplastic lesions and tumor development (9,10). These findings support the notion that increased expression of GLI1 is sufficient for the development of a subset of tumors.…”