High Glucose Induced Upregulation of Cyclin a Associating with a Short Survival of Patients with Cholangiocarcinoma: A Potential Target for Treatment of Patients with Diabetes Mellitus

Saengboonmee, Charupong; Detarya, Marutpong; Sangkhamanon, Sakkarn; Sawanyawisuth, Kanlayanee; Seubwai, Wunchana; Wongkham, Sopit

doi:10.1080/01635581.2021.1961830

Cited by 3 publications

(2 citation statements)

References 54 publications

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“…As high glucose levels promote cancer cell growth in vitro and in vivo 16,38 , the administration of liraglutide might control plasma glucose levels in the treated mice within relatively lower ranges than the control and then slow the tumor growth. In agreement with reports showing that insulin levels and GLP-1R agonists were not associated with increased risk of intrahepatic and perihilar CCA [21][22][23]31 , our previous study showed insulin did not enhance CCA cell proliferation in vitro 39 and suggests that using GLP-1R agonists in iCCA patients with DM might be safe. This study also demonstrated for the first time that liraglutide suppressed GLP-1R expression in iCCA cells, both in vitro and vivo and incorporated with suppression of iCCA cell migration and reduction of tumor growth in iCCA xenografts.…”

Section: Discussionsupporting

confidence: 92%

Liraglutide exhibits potential anti-tumor effects on the progression of intrahepatic cholangiocarcinoma, in vitro and in vivo

Trakoonsenathong,

Kunprom,

Aphivatanasiri

et al. 2024

Sci Rep

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Glucagon-like peptide 1 receptor (GLP-1R) agonist is an emerging anti-diabetic medication whose effects on the risk and progression of cholangiocarcinoma (CCA) are controversial. This study aimed to elucidate the roles of GLP-1R and its agonists on intrahepatic CCA (iCCA) progression. Expressions of GLP-1R in iCCA tissues investigated by immunohistochemistry showed that GLP-1R expressions were significantly associated with poor histological grading (P = 0.027). iCCA cell lines, KKU-055 and KKU-213A, were treated with exendin-4 and liraglutide, GLP-1R agonists, and their effects on proliferation and migration were assessed. Exendin-4 and liraglutide did not affect CCA cell proliferation in vitro, but liraglutide significantly suppressed the migration of CCA cells, partly by inhibiting epithelial-mesenchymal transition. In contrast, liraglutide significantly reduced CCA tumor volumes and weights in xenografted mice (P = 0.046). GLP-1R appeared downregulated when CCA cells were treated with liraglutide in vitro and in vivo. In addition, liraglutide treatment significantly suppressed Akt and STAT3 signaling in CCA cells, by reducing their phosphorylation levels. These results suggested that liraglutide potentially slows down CCA progression, and further clinical investigation would benefit the treatment of CCA with diabetes mellitus.

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Section: Discussionsupporting

confidence: 92%

Liraglutide exhibits potential anti-tumor effects on the progression of intrahepatic cholangiocarcinoma, in vitro and in vivo

Trakoonsenathong,

Kunprom,

Aphivatanasiri

et al. 2024

Sci Rep

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“…Our studies showed that high glucose stimulates inflammatory pathways in CCA cells, namely STAT3 and NF-κB ( 20 , 24 ). Furthermore, high glucose can promote CCA progression via the activation of glycogen synthase kinase-3β (GSK3β)/β-catenin pathways ( 18 ), epidermal growth factor receptors ( 29 ), increased expression of cell cycle machinery ( 30 ), and increased reactive oxygen species ( 31 ).…”

Section: Discussionmentioning

confidence: 99%

Involvement of interleukin-1β in high glucose-activated proliferation of cholangiocarcinoma

Khawkhiaw,

Chomphoo,

Kunprom

et al. 2024

Transl Gastroenterol Hepatol

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Background Diabetes mellitus (DM) is associated with the increased risk of development and the advancement of cholangiocarcinoma (CCA). High glucose levels were previously shown for upregulating interleukin-1β (IL-1β) in CCA cells with unclear functions. The present study, thus, aimed to investigate molecular mechanisms linking DM to CCA progression, with IL-1β hypothesized as a communicating cytokine. Methods CCA cells were cultured in media with normal (5.6 mM) or high (25 mM) glucose, resembling euglycemia and hyperglycemia, respectively. Expressions of IL-1β and IL-1 receptor (IL-1R) in CCA tissues from patients with and without DM were examined using immunohistochemistry. Functional analyses of IL-1β were performed using siRNA and recombinant human IL-1R antagonist (rhIL-1RA), in which Western blots investigated the knockdown efficacy. BALB/c Rag-2 -/- Jak3 -/- (BRJ) mice were implanted with CCA xenografts to investigate hyperglycemia’s effects on CCA growth and the anti-tumor effects of IL-1RA. Results CCA tumors from patients with hyperglycemia showed significantly higher IL-1β expression than those from non-DM patients, while IL-1β was positively correlated with fasting blood glucose (FBG) levels. CCA cells cultured in high glucose showed increased IL-1β expression, resulting in increased proliferation rates. Suppressing IL-1β signaling by si-IL-1β or rhIL-1RA significantly reduced CCA cell proliferation in vitro . Anakinra, a synthetic IL-1RA, also exerted significant anti-tumor effects in vivo and significantly reversed the effects of hyperglycemia-induced growth in CCA xenografts. Conclusions IL-1β plays a crucial role in CCA progression in a high-glucose environment. Targeting IL-1β might, then, help improve therapeutic outcomes of CCA in patients with DM and hyperglycemia.

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γ-aminobutyric acid B2 receptor: A potential therapeutic target for cholangiocarcinoma in patients with diabetes mellitus

Saengboonmee¹,

Sorin²,

Sangkhamanon³

et al. 2023

World J Gastroenterol

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The human intestine is a natural environment ecosystem of a complex of diversified and dynamic microorganisms, determined through a process of competition and natural selection during life. Those intestinal microorganisms called microbiota and are involved in a variety of mechanisms of the organism, they interact with the host and therefore are in contact with the organs of the various systems. However, they play a crucial role in maintaining host homeostasis, also influencing its behaviour. Thus, microorganisms perform a series of biological functions important for human well-being. The host provides the microorganisms with the environment and nutrients, simultaneously drawing many benefits such as their contribution to metabolic, trophic, immunological, and other functions. For these reasons it has been reported that its quantitative and qualitative composition can play a protective or harmful role on the host health. Therefore, a dysbiosis can lead to an association of unfavourable factors which lead to a dysregulation of the physiological processes of homeostasis. Thus, it has previously noted that the gut microbiota can participate in the pathogenesis of autoimmune diseases, chronic intestinal inflammation, diabetes mellitus, obesity and atherosclerosis, psychic disorders (e.g., neurological diseases, autism, etc. ) colorectal cancer, and more.

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High Glucose Induced Upregulation of Cyclin a Associating with a Short Survival of Patients with Cholangiocarcinoma: A Potential Target for Treatment of Patients with Diabetes Mellitus

Cited by 3 publications

References 54 publications

Liraglutide exhibits potential anti-tumor effects on the progression of intrahepatic cholangiocarcinoma, in vitro and in vivo

Liraglutide exhibits potential anti-tumor effects on the progression of intrahepatic cholangiocarcinoma, in vitro and in vivo

Involvement of interleukin-1β in high glucose-activated proliferation of cholangiocarcinoma

γ-aminobutyric acid B2 receptor: A potential therapeutic target for cholangiocarcinoma in patients with diabetes mellitus

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