cholecalciferol and Cholangiocarcinoma

The transcriptional coactivator with PDZ binding motif (TAZ) is reported as one of the nuclear effectors of Hippo-related pathways. TAZ is found overexpressed in many primary tumors and could regulate many biological processes. However, little is known about the role of TAZ in Intrahepatic Cholangiocarcinoma (ICC). In this study, we found that TAZ is expressed more in ICC tissues than in peritumoral tissue, and a robust expression of TAZ is correlated with a lower overall survival rate of ICC patients after hepatectomy. TAZ knockdown results in an increase in cell apoptosis, a promotion of cell-cycle arrest and a decrease in tumor size and weight in vivo through an increased expression of p53. Vitamin D3 can also inhibit cell proliferation by promoting p53 expression in ICC cells. A reduction in TAZ can also enhance the sensitivity of tumor cells to vitamin D by regulating the p53/CYP24A1 pathway. In conclusion, TAZ is associated with the proliferation and drug-resistance of ICC cells, and could be a novel therapeutic target for the treatment of ICC.

Topics: Animals; Antineoplastic Agents; Apoptosis; Bile Duct Neoplasms; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cholangiocarcinoma; Cholecalciferol; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Hepatectomy; Humans; Intracellular Signaling Peptides and Proteins; Kaplan-Meier Estimate; Male; Mice, Mutant Strains; Middle Aged; RNA Interference; Signal Transduction; Time Factors; Trans-Activators; Transcription Factors; Transcriptional Coactivator with PDZ-Binding Motif Proteins; Transfection; Tumor Burden; Tumor Suppressor Protein p53; Vitamin D3 24-Hydroxylase; Xenograft Model Antitumor Assays

Cholangiocarcinoma is a deadly biliary tumour with limited treatment strategies. Vitamin (1,25(OH)2D) has anti-proliferative effects on several cancers. Vitamin D3 is synthesized by the enzyme, CYP27B1, and signals via the nuclear vitamin D3 receptor. The enzyme, CYP24A1, degrades vitamin D3.. (i) Measure the expression of CYP27B1, CYP24A1, and vitamin D3 receptor in human nonmalignant and cholangiocarcinoma lines and biopsy control or tumour samples; and (ii) evaluate the effects of vitamin D3 on vitamin D3 synthesis and cholangiocarcinoma growth.. In vitro studies were performed in malignant and nonmalignant cholangiocytes. Vitamin D3 receptor, CYP24 and CYP27 expression was measured in cell lines and biopsy samples. Cell lines were stimulated with vehicle or vitamin D3 from 30min to 48h. Cell viability was assessed by MTS assays and BrdU incorporation. Vitamin D3 receptor, CYP24A1 and CYP27B1 expression was measured in cholangiocarcinoma cells stimulated with vehicle or vitamin D3.. In cholangiocarcinoma lines and biopsy samples, vitamin D3 receptor and CYP24A1 expression increased compared to controls, whereas CYP27B1 expression was decreased or unchanged. Vitamin D3 induced nuclear translocation of vitamin D3 receptor in cholangiocarcinoma and decreased cholangiocarcinoma growth.. Treatment with vitamin D3 decreased CYP24A1, whereas CYP27B1 expression increased. Modulation of vitamin D3 synthesis may be important in the management of cholangiocarcinoma.

Topics: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Cell Line, Tumor; Cell Proliferation; Cholangiocarcinoma; Cholecalciferol; Humans; Protein Transport; Receptors, Calcitriol; RNA, Messenger; Steroid Hydroxylases; Vitamin D3 24-Hydroxylase; Vitamins

Sixty-three male 5-week-old Syrian hamsters received the carcinogen N-nitrosobis(2-oxopropyl)amine (BOP) s.c. in 5 weekly injections (the first, 70 mg/kg body, and the remaining, 20mg/kg each). The hamsters that received BOP were given intragastric administration of 0.2 ml of medium chain triglyceride (MCT) with or without 0.04 μg of 1α-hydroxyvitamin D3 [1α(OH)D3] through a feeding tube for 12 weeks. Thus, 3 groups were assigned:Group 1;BOP alone (n＝20), Group 2;BOP＋MCT (n＝18) and Group 3;BOP＋1α(OH)D3 (n＝25). The mean body weight of Group 3 was lower than those of Groups 1 and 2 at the end of the experiment (p＜0.001,Tukey-Kramer HSD test). At the end of week 12, all surviving hamsters were put to sleep. The incidences of liver tumors were 80%, 72% and 32% in Groups 1, 2 and 3, respectively. The incidence of tumors in Group 3 was significantly lower than in Group 1 and Group 2 (p＜0.05, χ2-test). All tumors were cholangiocarcinoma. These results indicated that BOP-induced cholangiocarcinogenesis was suppressed by the supplemental administration of 1α(OH)D3.

Topics: Animals; Antineoplastic Agents; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Carcinogens; Cholangiocarcinoma; Cholecalciferol; Cricetinae; Male; Mesocricetus; Nitrosamines

Topics: Adenocarcinoma; Calcium; Cholangiocarcinoma; Cholecalciferol; Common Bile Duct Neoplasms; Humans; Pancreatic Neoplasms; Pancreaticoduodenectomy; Pilot Projects; Prospective Studies; Safety