癌症研究
丙谷胺
下调和上调
肝损伤
癌变
祖细胞
干细胞
纤维化
基因剔除小鼠
刺猬
医学
生物
内科学
内分泌学
胆囊收缩素
受体
胆囊收缩素受体
癌症
细胞生物学
信号转导
基因
生物化学
作者
Martha D. Gay,Jack C. Drda,Wenqiang Chen,Yong Huang,Amal A. Yassin,Tetyana Duka,Hong-Bin Fang,Narayan Shivapurkar,Jill P. Smith
出处
期刊:American Journal of Physiology-gastrointestinal and Liver Physiology
[American Physiological Society]
日期:2024-01-22
标识
DOI:10.1152/ajpgi.00208.2023
摘要
Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer-related deaths worldwide. Chronic inflammation and fibrosis are the greatest risk factors for the development of HCC. Although the cell of origin for HCC is uncertain, many theories believe this cancer may arise from liver progenitor cells or stem cells. Here, we describe the activation of hepatic stem cells that over-express the cholecystokinin-B receptor (CCK-BR) after liver injury with either a DDC diet (0.1% 3, 5-diethoxy-carbonyl 1,4-dihydrocollidine) or a NASH-inducing CDE diet (choline deficient ethionine) in murine models. Pharmacologic blockade of the CCK-BR with a receptor antagonist proglumide or knockout of the CCK-BR in genetically engineered mice during the injury diet reduces the expression of hepatic stem cells and prevents the formation of 3-dimensional tumorspheres in culture. RNA sequencing of livers from DDC-fed mice treated with proglumide or DDC-fed CCK-BR knockout mice showed downregulation of differentially expressed genes involved in cell proliferation and oncogenesis and upregulation of tumor suppressor genes compared to controls. Inhibition of the CCK-BR decreases hepatic transaminases, fibrosis, cytokine expression, and alters the hepatic immune cell signature rendering the liver microenvironment less oncogenic. Furthermore, proglumide hastened recovery after liver injury by reversing fibrosis and improving markers of synthetic function. Proglumide is an older drug that is orally bioavailable and being repurposed for liver conditions. These findings support a promising therapeutic intervention applicable to patients to prevent the development of HCC and decrease hepatic fibrosis.
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