leptin and Mouth-Neoplasms

Leptin, an important hormone controlling energy homeostasis, has been linked to the pathogenesis of oral squamous cell carcinoma (OSCC). Evidence indicates that head and neck cancer patients undergoing radiotherapy show decreased leptin levels after radiotherapy treatment. Thus, we investigated, through phenotypic and molecular analyses, whether leptin can compromise the therapeutic effect of ionizing radiation and neoplastic behavior of OSCC cells.. The human OSCC-derived cell lines SCC9 and SCC4 were treated with human recombinant leptin and exposed to 6 Gy of irradiation. We performed the in vitro assays of cell migration, death, proliferation, and colony-forming ability. The reactive oxygen species (ROS) levels and proteome analysis by mass spectrometry were also conducted.. Leptin was able to increase cell proliferation, migration, and colony-forming ability, despite the suppressive effect induced by irradiation. Furthermore, the leptin promoted a significant reduction of ROS intracellular accumulation, and increased expression of the cancer-related proteins, as ACTC1, KRT6A, and EEF2 in irradiated OSCC cells.. Our findings suggest that leptin impairs responsivity of OSCC cells to the ionizing radiation, reducing the suppressive effects of irradiation on the neoplastic phenotype, and increasing protein expression critical to carcinogenesis.

Topics: Actins; Carcinoma, Squamous Cell; Cell Movement; Cell Proliferation; Gene Expression; Humans; Keratin-6; Leptin; Mouth Neoplasms; Radiation, Ionizing; Reactive Oxygen Species; Tumor Cells, Cultured

Oral cancer is causally associated with environmental carcinogens, and the susceptibility to carcinogen-mediated tumorigenesis is proposed to be genotype-dependent. Leptin (LEP) and leptin receptor (LEPR) both play a crucial role in the mediation of physiological reactions and carcinogenesis and may serve as a candidate biomarker of oral cancer. The current case-control study aimed to examine the effects of LEP -2548 G/A (rs7799039), LEPR K109R (rs1137100), and LEPR Q223R (rs1137101) single-nucleotide polymorphisms (SNPs) with or without interacting to environmental carcinogens on the risk for oral squamous cell carcinoma. The SNPs of three genetic allele, from 567 patients with oral cancer and 560 healthy controls in Taiwan were analyzed. The results shown that the patients with polymorphic allele of LEP -2548 have a significant low risk for the development of clinical stage (A/G: adjusted odds ratio [AOR] = 0.670, 95% confidence interval [CI] = 0.454-0.988, P < 0.05; A/G + G/G: AOR = 0.676, 95% CI = 0.467-0.978, P < 0.05) compared to patients with ancestral homozygous A/A genotype. In addition, an interesting result was found that the impact of LEP -2548 G/A SNP on oral carcinogenesis in subjects without tobacco consumption is higher than subjects with tobacco consumption. These results suggest that the genetic polymorphism of LEP -2548 G/A (rs7799039), LEPR K109R (rs1137100), and LEPR Q223R (rs1137101) were not associated to the susceptibility of oral cancer; SNP in LEP -2548 G/A showed a poor clinicopathological development of oral cancer; population without tobacco consumption and with polymorphic LEP -2548 G/A gene may significantly increase the risk to have oral cancer.

Topics: Carcinogenesis; Case-Control Studies; Confidence Intervals; Disease Progression; Female; Gene Frequency; Genetic Predisposition to Disease; Humans; Leptin; Male; Middle Aged; Mouth Neoplasms; Odds Ratio; Polymorphism, Single Nucleotide; Receptors, Leptin; Smoking

Leptin, one of the main hormones controlling energy homeostasis, has been associated with different cancer types. In oral cancer, its effect is not well understood. We investigated, through in vitro and in vivo assays, whether leptin can affect the neoplastic behavior of oral squamous cell carcinoma. Expression of genes possibly linked to the leptin pathway was assessed in leptin-treated oral squamous cell carcinoma cells and also in tissue samples of oral squamous cell carcinoma and oral mucosa, including leptin, leptin receptor, hypoxia-inducible factor 1-alpha, E-cadherin, matrix metalloproteinase-2, matrix metalloproteinase-9, Col1A1, Ki67, and mir-210. Leptin treatment favored higher rates of cell proliferation and migration, and reduced apoptosis. Accordingly, leptin-treated oral squamous cell carcinoma cells show decreased messenger RNA caspase-3 expression, and increased levels of E-cadherin, Col1A1, matrix metalloproteinase-2, matrix metalloproteinase-9, and mir-210. In tissue samples, hypoxia-inducible factor 1-alpha messenger RNA and protein expression of leptin and leptin receptor were high in oral squamous cell carcinoma cases. Serum leptin levels were increased in first clinical stages of the disease. In animal model, oral squamous cell carcinoma-induced mice show higher leptin receptor expression, and serum leptin level was increased in dysplasia group. Our findings suggest that leptin seems to exert an effect on oral squamous cell carcinoma cells behavior and also on molecular markers related to cell proliferation, migration, and tumor angiogenesis.

Topics: Adult; Animals; Apoptosis; Carcinoma, Squamous Cell; Cell Hypoxia; Cell Line, Tumor; Cell Movement; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Leptin; Male; Mice; Middle Aged; Mouth Neoplasms; Neoplasm Invasiveness; Neoplasm Staging; Neovascularization, Pathologic; Receptors, Leptin; Xenograft Model Antitumor Assays

Leptin levels are associated with appetite and energy expenditure in healthy individuals. The present study aims to evaluate serum and salivary leptin concentrations in patients with squamous cell carcinoma of the buccal mucosa.. Enrolled participants in this study included 41 patients with squamous cell carcinoma of the buccal mucosa and 40 healthy control patients. Serum leptin levels were measured via enzyme-linked immunosorbent assay (ELISA) method in all subjects and reported in units of nanograms per millilitre. Salivary leptin levels were measured by a highly sensitive and specific non-equilibrium version of a dedicated custom radioimmunoassay.. A significant reduction in salivary and serum leptin levels in patients with squamous cell carcinoma of the buccal mucosa was observed in comparison to control subjects. In addition, a significant correlation was shown between serum and salivary leptin levels on one hand and body mass index, with various histopathological and TNM (tumour nodes metastasis) staging variants of squamous cell carcinoma of the buccal mucosa on another. A highly significant correlation was shown between salivary and serum leptin levels in both groups.. The results of this study demonstrate a possible mechanism of salivary and serum leptin levels in squamous cell carcinoma of the buccal mucosa.. Salivary leptin might play a role in squamous cell carcinoma of the buccal mucosa.

Topics: Body Mass Index; Carcinoma, Squamous Cell; Case-Control Studies; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Female; Humans; Leptin; Male; Middle Aged; Mouth Mucosa; Mouth Neoplasms; Radioimmunoassay; Saliva

Leptin been mainly produced by adipose tissue and cancer cells is the most studied adipokine, amongst the several cytokines. Leptin is an antiapoptotic molecule and inducer of cancer stem cells as well as activates cell proliferation. Its oncogenic, mitogenic, proinflammatory and proangiogenic actions lead to its vital roles in tumourigenesis. Two common functional DNA polymorphisms in the genes of leptin G2548A (LEP) and leptin receptor A668G (LEPR) affect the amount of circulating cytokine-type hormone leptin with risk for development of oral squamous cell carcinoma (OSCC). The present study investigated whether these LEP and LEPR gene polymorphisms are affecting risk for OSCC by comparing the genotypes of patients with controls. A total of 306 OSCC and 228 controls participated in this study. We have determined the frequency of LEP (G2548A) and LEPR (A668G) gene polymorphisms in OSCC cases and controls by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). The incidence of leptin gene G2548A homozygous mutant AA polymorphism was significantly increased in the OSCC patients (p = 0.002, odds ratio (OR) = 2.4, 95 % confidence interval (CI) = 1.37-4.22) when compared with controls, and leptin receptor A668G homozygous mutant GG polymorphism was significantly high in the OSCC patients as compared to controls (p = 0.000, OR = 3.8, 95 % CI = 1.98-7.62). The polymorphism of homozygous mutant allele A of leptin gene and G allele of leptin receptor may be associated with increased risk for OSCC. The observations showed regular increase of supporting role of leptin in OSCC. The present study showed an association of AA genotype and A allele of LEP G2548A as well as GG genotype and G allele of LEPR A668G polymorphisms with increased risk for OSCC in north Indian patients. Moreover, the combination of both the polymorphisms may be involved in susceptibility and progression of OSCC.

Topics: Adult; Carcinoma, Squamous Cell; Female; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Humans; India; Leptin; Male; Mouth Neoplasms; Polymorphism, Single Nucleotide; Receptors, Leptin; Risk Factors

The leptin gene product is released into the blood stream, passes through the blood-brain barrier, and finds the leptin receptor (LEPR) in the central nervous system. This hormone regulates food intake, hematopoiesis, inflammation, immunity, differentiation, and cell proliferation. The LEPR Gln223Arg polymorphism has been reported to alter receptor function and expression, both of which have been related with prognostics in several tumor types. Furthermore, several studies have shown a relationship between the Gln223Arg polymorphism and tumor development, and its role in oral and oropharyngeal squamous cell carcinoma is now well understood. In this study, 315 DNA samples were used for LEPR Gln223Arg genotyping and 87 primary oral and oropharyngeal squamous cell carcinomas were used for immunohistochemical expression analysis, such that a relationship between these and tumor development and prognosis could be established. Homozygous LEPR Arg223 was found to be associated with a 2-fold reduction in oral and oropharyngeal cancer risk. In contrast, the presence of the Arg223 allele in tumors was associated with worse disease-free and disease-specific survival. Low LEPR expression was found to be an independent risk factor, increasing the risk for lymph node metastasis 4-fold. In conclusion, the Gln223Arg polymorphism and LEPR expression might be valuable markers for oral and oropharyngeal cancer, suggesting that LEPR might serve as a potential target for future therapies.

Topics: Adult; Aged; Alleles; Amino Acid Substitution; Biomarkers, Tumor; Blood-Brain Barrier; Body Mass Index; Female; Genotype; Humans; Leptin; Male; Middle Aged; Mouth Neoplasms; Oropharyngeal Neoplasms; Polymorphism, Genetic; Prognosis; Receptors, Leptin; Risk Factors

Cachexia contributes significantly to mortality in cancer patients; role of cytokines in inducing cachexia is an emerging view. Leptin, a homologous protein of cytokine family, is found to be decreased in serum with cachexia. The purpose of this study was to compare serum leptin levels of oral squamous cell carcinoma patients with that of control group and correlate it with body mass index.. Serum samples of 31 oral squamous cell carcinoma patients and that of 28 healthy individuals were subjected to evaluation of serum leptin levels (ng/ml) using enzyme-linked immunosorbent assay.. A significant reduction in leptin level of oral squamous cell carcinoma patients was observed. Definite correlation between body mass index and serum leptin and also between serum leptin levels of various histopathological variants of oral squamous cell carcinoma was observed.. The results of this study suggest that evaluation of serum leptin level can provide status of cachexia in oral squamous cell carcinoma patients.

Topics: Adult; Age Factors; Aged; Area Under Curve; Biomarkers; Body Mass Index; Cachexia; Carcinoma, Squamous Cell; Female; Humans; Leptin; Male; Middle Aged; Mouth Neoplasms; Neoplasm Staging; ROC Curve; Sensitivity and Specificity; Sex Factors; Young Adult

We investigated the possible association of DNA polymorphisms -2548G/A and Q223R in the leptin (LEP) and leptin receptor (LEPR) genes, respectively, which both affect the amount of circulating cytokine-type hormone leptin, with risk for development of oral cancer.. Polymerase chain reaction-based restriction analysis was performed in DNA samples of 150 patients with oral squamous cell carcinoma (OSCC) and 152 healthy control subjects of equivalent gender, age, and ethnicity (Greeks and Germans).. Compared to controls, the homozygous high gene expression genotype A/A of the LEP -2548G/A polymorphism was significantly increased in the subgroups of patients with advanced cancer stages (P = 0.0001; OR 9.0, 95% CI 2.62-30.89), with a positive family history of cancer (P = 0.0346; OR 3.55, 95% CI 1.15-11.01), without tobacco abuse (P = 0.0051; OR 9.69, 95% CI 1.03-91.24), and without alcohol abuse (P = 0.0472; OR 2.16, 95% CI 0.87-5.37). The homozygous low-leptin-binding genotype G/G of the LEPR Q223R polymorphism was strongly associated with an increased risk for OSCC for all patients (P = 0.0028; OR 4.11, 95% CI 1.30-12.97) as well for most of the patient subgroups.. The above findings are consistent with the growth-promoting role of leptin in cancer and its induction effect on angiogenesis and metastasis. This is the first study indicating the association of these LEP and LEPR gene polymorphisms with increased risk for OSCC.

Topics: Amino Acid Substitution; Carcinoma, Squamous Cell; DNA Primers; Gene Frequency; Genotype; Germany; Greece; Homozygote; Humans; Leptin; Medical History Taking; Middle Aged; Mouth Neoplasms; Neoplasm Staging; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Receptors, Leptin; Reference Values; Risk Factors

This study was conducted to determine if an oral squamous cell carcinoma alters mRNA expression of serotonin transporter (5-HTT) in the central nervous system. KB cell line derived from a human oral squamous cell carcinoma was inoculated into nude mice, and mRNA expression level of 5-HTT in the dorsal raphe nucleus (DRN) was examined by in situ hybridization when the tumor mass reached to -10% of total body weight. Plasma leptin levels were determined by radioimmunoassay method using a commercial kit. 5-HTT mRNA level was significantly decreased in the DRN of tumor bearing mice, compared to the age-matching non-tumor control. Plasma leptin level decreased concomitantly in tumor bearing mice. These results suggest that oral carcinoma may suppress 5-HTT gene expression in the central nervous system, perhaps in relation with decreased plasma leptin level.

Topics: Animals; Body Weight; Carcinoma, Squamous Cell; DNA, Complementary; Gene Expression Regulation, Neoplastic; Humans; Leptin; Male; Membrane Glycoproteins; Membrane Transport Proteins; Mice; Mice, Inbred BALB C; Mice, Nude; Mouth Neoplasms; Nerve Tissue Proteins; Radioimmunoassay; Raphe Nuclei; RNA, Messenger; Serotonin; Serotonin Plasma Membrane Transport Proteins

Recent evidence has shown that circulating levels of insulin-like growth factor-I (IGF-I) and leptin are regulated by nutrition support. Our objective was to investigate the reliability of IGF-I and leptin in monitoring the efficacy of nutrition support and nutrition status in oral tumor patients.. Fifty-one male patients scheduled to receive resection operation for oral tumor were recruited. Fasted blood samples were collected before surgery (d0), on the first postoperative day before feeding (d1), and on the seventh postoperative day (d7) with nasogastric tube feeding (35 kcal x kg(-1) x d(-1)). Fifty male healthy volunteers were recruited as controls.. After adjustment for age, patients had significantly greater serum concentrations of transferrin and significantly lower serum concentrations of prealbumin and tumor-necrosis factor-alpha than did healthy volunteers on d0. In oral tumor patients, resection with prolonged fasting significantly increased levels of growth hormone and interleukin-6 and significantly decreased levels prealbumin, retinol-binding protein, IGF-I, and leptin, and these alterations were reversed by nutrition support for 6 d in oral tumor patients. Serum IGF-I was further increased on d7 compared with d0. In addition, leptin was the only nutrition-related serum protein showing significantly positive correlation with body mass index in healthy volunteers and patients.. Our results suggested that simultaneous measurements of serum IGF-I and leptin may provide information with regard to the efficacy of nutrition support and nutrition status in oral tumor patients undergoing surgery.

Topics: Adult; Aged; Enteral Nutrition; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Interleukin-6; Leptin; Male; Middle Aged; Mouth Neoplasms; Nutritional Status; Prealbumin; Predictive Value of Tests; Retinol-Binding Proteins; Treatment Outcome; Tumor Necrosis Factor-alpha