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

Abstract

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.

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

“…The underlying mechanisms are known to involve the effects of hyperglycemia and probably the effects of hormonal disturbances 16 , 17 , 30 , 31 . Our previous reports demonstrated that high glucose level is a promoting factor for CCA via the activating effects on multiple signaling pathways 16 – 18 . However, where the effects of exogenous insulin on CCA development and progression remain controversial 31 , some anti-diabetic medications, e.g., metformin, show potential effects on the reduction of risk of CCA development and tumor aggressiveness 32 , 33 .…”

“…Diabetic hyperglycemia can induce growth and metastatic activities of CCA cells in vitro via multiple pathways, i.e., signal transducer and activator of transcription 3 (STAT3) 16 , nuclear factor-kappa B (NF-κB) 17 , and glycogen synthase kinase 3/β-catenin pathways 18 . In addition, metformin, the first-line therapy for DM type 2, exerts anti-proliferative and anti-metastatic activities against CCA cells by targeting STAT3 and NF-κB 19 and enhancing chemotherapeutic sensitivity of CCA to cisplatin, the standard chemotherapy 20 .…”

GABBR2 as a Downstream Effector of the Androgen Receptor Induces Cisplatin Resistance in Bladder Cancer

“…By contrast, little is known about the role of GABBR2 in neoplastic conditions. Limited and somehow conflicting data have demonstrated that GABA B receptor agonists either promote (e.g., breast [ 34 ], kidney [ 35 ], and prostate [ 36 ] cancers) or inhibit (e.g., lung cancer [ 37 ], cholangiocarcinoma [ 38 , 39 ]) the cell growth of nonurothelial malignancies. Particularly, in the prostate cancer study [ 36 ], an AR-negative cell line was tested, although the role of AR signaling in its progression and treatment has been extremely well established.…”

“…Nonetheless, the elevated expression of GABBR2 has been reported in several types of neoplasm such as thyroid adenoma and carcinoma [ 47 ] and non-small cell lung cancer [ 37 ]. In cholangiocarcinoma specimens, high GABBR2 expression was strongly associated with more aggressive nonpapillary histology yet small tumor size [ 39 ]. By analyzing a public database (i.e., The Cancer Genome Atlas (TCGA)), GABBR2 overexpression was linked to lower T and N staging categories and better prognosis in patients with breast cancer [ 48 ].…”

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

“…Other medications that increase insulin secretion or its bioavailability, e.g., sulfonylurea and insulin analogs, neither show the effects on CCA development and progression ( 17 ). On the other hand, hyperglycemia and other medications are suggested for their involvement in CCA progression or recession ( 18 , 19 ). Later studies are, therefore, mainly focused on the impacts of high glucose levels and anti-diabetic medications on the modifications of risk and progression of CCA.…”