Salivary leptin induces increased expression of growth factors in oral keratinocytes

Abstract

We investigated the influence of salivary leptin, purified by affinity chromatography, on the proliferation of human oral keratinocytes. Furthermore we determined the time-and dose-dependency of the incubation with salivary leptin on the production of epidermal growth factor (EGF) and keratinocyte growth factor (KGF), which are growth factors relevant to keratinocyte proliferation. The analysis was performed both intra-and extracellularly. The relationship between the three cytokines in cell proliferation was studied by successive blocking with specific antibodies. The incubation of oral keratinocytes with recombinant and native leptin led to a significantly increased, dose-dependent cell proliferation (P,0·001). A further significant increase in proliferation was observed after incubating the cells with sterile filtered saliva (P,0·001). The increase in proliferation could not be observed by simultaneous incubation with salivary leptin and specific antibodies against either leptin or KGF (P,0·001). We found a significant dose-dependency between leptin incubation and production of KGF and EGF at the RNA and protein level. Both cytokines were expressed intracellularly and released into the culture medium, where they could be quantified by ELISA. Furthermore, there was a dose-and time-dependent increase in the phosphorylation of STAT-1 and STAT-3, indicating that Ob-R b (the long form of the leptin receptor) expressed by the keratinocytes is functional. It is conceivable that the leptin-induced proliferation in keratinocytes is mediated by this signalling pathway. This is the first study to show a physiological role of salivary leptin as a growth factor for keratinocyte proliferation in the oral cavity. We could demonstrate its influence on the production of other growth factors essential for this proliferative effect. Based on the findings of our study we assume an important role for salivary leptin in wound healing within the vulnerable oral cavity.

Leptin receptor expression and Gln223Arg polymorphism as prognostic markers in oral and oropharyngeal cancer

“…According to our results, low LEPR expression increased the risk of lymph node metastasis by 4-fold when compared with that seen for tumors exhibiting strong expression. Weak LEPR expression had a similar effect as the Gln223Arg polymorphism, weak leptin-LEPR interaction, and increased circulating leptin (Kurahara et al, 1999;Gröschl et al, 2005); these effects have been previously suggested as facilitators of tumor invasion and metastasis (Hohberger et al, 2008;Liu et al, 2013).…”

Association of leptin −2548G/A and leptin receptor Q223R polymorphisms with increased risk for oral cancer

“…Leptin receptors are situated on the cell surface of target tissues, including keratinocytes of the oral region (Gröschl et al 2005). Two common functional DNA polymorphisms in the genes of leptin and its receptor (LEP and LEPR) aVect plasma levels of leptin.…”

“…The eVects of leptin are mediated through the binding and activation of its receptor (LEPR), which is almost ubiquitously distributed indicating that leptin probably plays an important role in a quite diverse range of physiologic functions both in the hypothalamus and the periphery (Fietta 2005). In the oral region particularly, locally produced (by salivary glands) and circulating leptin seems to induce both wound healing by promoting keratinocyte proliferation, as well as taste sensitivity by taste bud cells (Shigemura et al 2003;Gröschl et al 2005).…”

Salivary Leptin as a Candidate Diagnostic Marker in Salivary Gland Tumors

“…One demonstrated effect of salivary leptin is the enhancement of proliferation of oral mucosal cells (20 ). However, a potential impact of salivary leptin on tumorigenesis has not yet been investigated.…”