Ghrelin promotes oral tumor cell proliferation by modifying GLUT1 expression

Abstract

In our study, ghrelin was investigated with respect to its capacity on proliferative effects and molecular correlations on oral tumor cells. The presence of all molecular components of the ghrelin system, i.e., ghrelin and its receptors, was analyzed and could be detected using real-time PCR and immunohistochemistry. To examine cellular effects caused by ghrelin and to clarify downstream-regulatory mechanisms, two different oral tumor cell lines (BHY and HN) were used in cell culture experiments. Stimulation of either cell line with ghrelin led to a significantly increased proliferation. Signal transduction occurred through phosphorylation of GSK-3β and nuclear translocation of β-catenin. This effect could be inhibited by blocking protein kinase A. Glucose transporter1 (GLUT1), as an important factor for delivering sufficient amounts of glucose to tumor cells having high requirements for this carbohydrate (Warburg effect) was up-regulated by exogenous and endogenous ghrelin. Silencing intracellular ghrelin concentrations using siRNA led to a significant decreased expression of GLUT1 and proliferation. In conclusion, our study describes the role for the appetite-stimulating peptide hormone ghrelin in oral cancer proliferation under the particular aspect of glucose uptake: (1) tumor cells are a source of ghrelin. (2) Ghrelin affects tumor cell proliferation through autocrine and/or paracrine activity. (3) Ghrelin modulates GLUT1 expression and thus indirectly enhances tumor cell proliferation. These findings are of major relevance, because glucose uptake is assumed to be a promising target for cancer treatment.

Response of MG63 osteoblasts on bacterial challenge is dependent on the state of differentiation

“…Cells (800 000/dish) were stimulated with A. actinomycetemcomitans and P. gingivalis for 30 or 120 minutes. Western blot and analysis were performed as described previously . The following primary antibodies were used: rabbit IgG anti‐p38 (dilution 1:1000) and rabbit IgG anti‐phospho‐p38 (dilution 1:1000), rabbit IgG anti‐ERK1/2 (dilution 1:1000), and rabbit IgG anti‐phospho‐ERK1/2 (dilution 1:1000).…”

The Evaluation of Ghrelin Expression In Oral Leukoplakia And Oral Squamous Cell Carcinoma: An Immunohistochemical Study

“…We found that the ghrelin expression level in OSCC was lower than those in oral epithelial tissue and leukoplakia; moreover, the ghrelin expression in OSCC was found especially in keratin pearls. In the second study, Kraus et al 15 found increased expression of ghrelin and its receptors in OSCC compared with healthy gingiva and benign tissue. The studies evaluating OSCC ghrelin levels yielded conflicting results.…”

“…In our samples, all the oral leukoplakia showed hyperkeratosis without dysplasia. The histologic diagnosis of oral leukoplakia was not mentioned in Kraus et al 15 It is possible that the ghrelin level begins to change with dysplastic changes in oral leukoplakia. Recently, it is stated inflammatory conditions of oral mucosa is one of the biggest challenges to distunguish bening lesions from potentially malignant lesions, and dysplastic/malignant ones from inflammatory conditions.…”

“…Only one study has compared the ghrelin level of leukoplakia with those of healthy tissue and OSCC. Kraus et al 15 found 10-fold elevated ghrelin mRNA and ghrelin levels in leukoplakia compared with healthy gingiva, whereas the ghrelin levels of oral leukoplakia and OSCC were similar. This contrasts with our finding that the oral leukoplakia ghrelin level was similar to that of normal oral mucosa and eight-fold more than that in OSCC.…”

“…Although much information has been obtained, the role of ghrelin in carcinogenesis and cancer is not fully understood. 14,15,16 To clarify this issue, several studies have compared ghrelin expression in malignant and normal or benign tissues and showed that ghrelin expression may be up-or down-regulated in cancer. It is thought that this difference might constitute a diagnostic tool to differentiate carcinoma from normal tissue.…”