Diabetes enhances cell proliferation but not Bax/Bcl-2-mediated apoptosis during oral oncogenesis

Vairaktaris, Eleftherios; Kalokerinos, G.; Goutzanis, Lampros; Yapijakis, Christos; Derka, Spyridoula; Vassiliou, Stavros; Spyridonidou, Sofia; Vylliotis, Antonis; Nkenke, Emeka; Lazaris, Andreas C.; Patsouris, Efstratios

doi:10.1016/j.ijom.2007.06.012

Cited by 8 publications

(10 citation statements)

References 23 publications

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“…The expression of cell proliferation marker Ki-67 is higher in almost all stages of oral oncogenesis compared to normal ones [17]. In contrast, Ki67 expression in our study was low in the DM and normal group.…”

Section: Discussioncontrasting

confidence: 62%

The Impact of Type II Diabetes on Tongue Dysplasia and p16-Related Aging Process: An Experimental Study

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Yazıcı

Arslan

et al. 2019

Analytical Cellular Pathology

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Objective To evaluate the effect of streptozotocin-induced experimental diabetes mellitus on p16, p53, Ki67, and Bcl2 expressions and histopathological changes in the tongue of the rats. Material and Methods Twenty-two adult female Sprague-Dawley rats were used. The rats were randomly divided into 2 groups (n = 14) as control (C) (n = 8) and diabetic (DM) (n = 6). The rats in the DM group were given streptozotocin as a single intraperitoneal dose for induction of diabetes. Histopathological and immunohistochemical evaluations of formalin-fixed and paraffin-embedded tissue sections of the tongue were used. Results Significant differences were observed between the DM group and the control group in terms of epithelial thickness, length of filiform papillae, and width of filiform papillae (p = 0.005, p = 0.001, and p = 0.006, respectively). There was no significant difference between the groups in terms of mononuclear inflammatory cell infiltration, capillary proliferation, and dysplasia (p = 0.204, p = 0.244, and p = 0.204, respectively). As a result of immunohistochemical studies, no significant difference was found between the groups in terms of p53, Ki67, and Bcl-2 expressions (p = 0.588, p = 0.662, and p = 0.686, respectively). A significant difference was found between the groups when p16 expression was evaluated (p = 0.006). Conclusions In our study, streptozotocin-induced experimental diabetes mellitus induced p16 expression but did not show any difference in p53, Bcl-2, and Ki67 levels. It should be considered in the studies that the pathological changes at the early stages of the relationship between DM and oral cancer may be related to p16 expression; however, it may also be linked with p16-related aging process.

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Section: Discussioncontrasting

confidence: 62%

The Impact of Type II Diabetes on Tongue Dysplasia and p16-Related Aging Process: An Experimental Study

Altun

Yazıcı

Arslan

et al. 2019

Analytical Cellular Pathology

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“…The chemically induced oral oncogenesis process in diabetic rats was considered to promote the activation of the Ras ⁄ Raf ⁄ MAPK signal transduction pathway by induction of receptors erbB2 and erbB3, mainly leading to increased cell proliferation. (16) Additionally, the expression of the proliferation marker Ki-67 was significantly higher in diabetic rats both in previous chemically induced oral oncogenesis (28) and the present study. Judging from the common findings in previous and present studies, it is also evident that diabetic conditions result in increased cell proliferation during tumorigenesis by enhanced proliferative activity of squamous epithelium.…”

Section: Discussionsupporting

confidence: 76%

Enhanced tumorigenesis of forestomach tumors induced by N‐Methyl‐N′‐nitro‐N‐nitrosoguanidine in rats with hypoinsulinemic diabetes

et al. 2010

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Hyperinsulinemia and hyperglycemia in prediabetic and diabetic patients are thought to increase the risk of developing neoplasms because insulin is a growth factor with pre-eminent metabolic but also mitogenic effects. To determine the effect of hypoinsulinemic diabetic conditions on carcinogenesis, we examined N-Methyl-N¢-nitro-N-nitrosoguanidine (MNNG)-induced forestomach carcinogenesis in hypoinsulinemic diabetic WBN ⁄ Kob rats aged about 45 weeks (DM) compared with non-diabetic younger WBN ⁄ Kob rats (C1), non-diabetic Wistar rats age-matched to DM (C2), and non-diabetic Wistar rats age-matched to C1 (C3). All rats were treated with MNNG by gavage and were killed at 40 weeks after dosing. Various-sized tumors were disseminated throughout the forestomach of all rats, and the ratio of the area of tumors to the whole forestomach area was 23.3% in the DM group and was higher than in the C1-3 (4.2-14.3%) groups. The incidence of carcinoma was much higher in the DM group (36.8%) than in the C1-3 (7.1-16.7%) groups, and the incidence of papilloma was also significantly higher in the DM group (84.2%) than in the C1-3 (28.5-50.0%) groups. The average thickness of the squamous epithelium in the non-neoplastic mucosa was significantly greater in the DM group (50.8 lm) than in the C1-3 (29.6-37.9 lm) groups. Immunohistochemically, the Ki-67-positive index in the non-tumorous mucosa of the DM group (42.0%) was significantly higher than that of the C1-3 groups (18.8-33.3%). These results suggest that prolonged hyperglycemic conditions without hyperinsulinemia enhance tumorigenesis of MNNG-induced tumors by enhanced proliferative activity of the squamous epithelium in the rat forestomach. (Cancer Sci 2010; 101: 1604-1609 C urrent epidemiologic studies have reported that diabetes mellitus may be one of the risk factors for carcinogenesis.(1-4) Although the underlying carcinogenic mechanism in patients with diabetes mellitus remains unclear, concomitant hyperinsulinemia,hyperglycemia, (6)(7)(8)(9)(10) and obesity (11,12) have been postulated as the factors causing the increased risk for tumor development from some experimental and epidemiologic studies. Hyperinsulinemia most likely favors cancer in diabetic patients, as insulin is not only a growth factor with pre-eminent metabolic effects but is also mitogenic to many kinds of cells. However, the clinical relevance of the cancer-promoting effect of insulin in diabetic patients is still unclear. (13) Hypoinsulinemic hyperglycemic conditions had been reported to increase the risk for cancer in streptozotocin-induced diabetic animals.(14-16) However, streptozotocin is also a mutagen, (17) so it remains unclear if the hyperglycemia-enhanced carcinogenesis is exclusive in this model. Insulin-independent promotion of chemically-induced liver tumor has been recently reported in hypoinsulinemic diabetic Akita mice, (18) and it is suggested that hyperinsulinemia has no relevance to tumorigenesis promotion. However, there are as yet few reports about hypoinsulinemic diabetic conditio...

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“…A relationship between oral cancer and DM has been demonstrated by previous researchers [30] – [32] . Patients suffering from oral cancer in conjunction with DM are face with highly invasive cancer cells, and low survival rates [26] .…”

Section: Discussionmentioning

confidence: 64%

Cell Migration Is Regulated by AGE-RAGE Interaction in Human Oral Cancer Cells In Vitro

Shieh

et al. 2014

PLoS ONE

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Advanced glycation end products (AGEs) are produced in an irreversible non-enzymatic reaction of carbohydrates and proteins. Patients with diabetes mellitus (DM) are known to have elevated AGE levels, which is viewed as a risk factor of diabetes-related complications. In a clinical setting, it has been shown that patients with oral cancer in conjunction with DM have a higher likelihood of cancer metastasis and lower cancer survival rates. AGE-RAGE (a receptor of AGEs) is also correlated with metastasis and angiogenesis. Recent studies have suggested that the malignancy of cancer may be enhanced by glyceraldehyde-derived AGEs; however, the underlying mechanism remains unclear. This study examined the apparently close correlation between AGE-RAGE and the malignancy of SAS oral cancer cell line. In this study, AGEs increased ERK phosphorylation, enhanced cell migration, and promoted the expression of RAGE, MMP2, and MMP9. Using PD98059, RAGE antibody, and RAGE RNAi to block RAGE pathway resulted in the inhibition of ERK phosphorylation. Cell migration, MMP2 and MMP9 expression were also reduced by this treatment. Our findings demonstrate the importance of AGE-RAGE with regard to the malignancy of oral cancer, and help to explain the poor prognosis of DM subjects with oral cancer.

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Diabetes enhances cell proliferation but not Bax/Bcl-2-mediated apoptosis during oral oncogenesis

Cited by 8 publications

References 23 publications

The Impact of Type II Diabetes on Tongue Dysplasia and p16-Related Aging Process: An Experimental Study

The Impact of Type II Diabetes on Tongue Dysplasia and p16-Related Aging Process: An Experimental Study

Enhanced tumorigenesis of forestomach tumors induced by N‐Methyl‐N′‐nitro‐N‐nitrosoguanidine in rats with hypoinsulinemic diabetes

Cell Migration Is Regulated by AGE-RAGE Interaction in Human Oral Cancer Cells In Vitro

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