This investigation demonstrates the role of the gastrointestinal peptide cholecystokinin (CCK) in hepatocellular carcinoma (HCC) and how CCK-BR blockade reverses the premalignant state of the hepatic extracellular matrix hence, rendering it less susceptible to the development of HCC. Thereby, CCK-BR blockade is a novel approach for the prevention/treatment of HCC. Hepatocellular carcinoma (HCC) is the fastest growing cancer worldwide in part due to the obesity epidemic and fatty liver disease, particularly nonalcoholic steatohepatitis (NASH). Chronic inflammation with the release of cytokines and chemokines with activation of hepatic stellate cells results in changes of the liver extracellular matrix (ECM) that predisposes to the development of HCC. Blood levels of the gastrointestinal peptide cholecystokinin (CCK) are increased in humans and mice consuming a high-fat diet. We found that the CCK-B receptor (CCK-BR) expression increased in the livers of mice with NASH. Treatment of mice with a CCK-BR antagonist, proglumide, prevented NASH, lowered hepatic inflammatory cytokines and chemokines, reduced oxidative stress, decreased F4/80+ hepatic macrophages, and prevented HCC. CCK-AR and CCK-BR expression was increased in both murine and human HCC cell lines compared with that of normal liver, and CCK stimulated the growth of wild-type and CCK-A receptor knockout HCC cells in vitro, but not CCK-BR knockout cells suggesting that the CCK-BR mediates proliferation. Proglumide therapy significantly reduced growth by 70% and 73% in mice bearing Dt81Hepa1–6 or in RIL-75 HCC tumors, respectively. IHC of a human liver tissue array with a selective CCK-BR antibody revealed staining of human HCC and no staining in normal liver. Prevention Relevance: This investigation demonstrates the role of the gastrointestinal peptide cholecystokinin (CCK) in hepatocellular carcinoma (HCC) and how CCK-BR blockade reverses the premalignant state of the hepatic extracellular matrix hence, rendering it less susceptible to the development of HCC. Thereby, CCK-BR blockade is a novel approach for the prevention/treatment of HCC.

中文翻译：

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靶向胆囊收缩素受体：治疗和预防肝细胞癌的新方法

这项研究证明了胃肠肽缩胆囊素 (CCK) 在肝细胞癌 (HCC) 中的作用，以及 CCK-BR 阻断如何逆转肝细胞外基质的癌前状态，从而使其不易发生 HCC。因此，CCK-BR 阻断是一种预防/治疗 HCC 的新方法。肝细胞癌 (HCC) 是全球增长最快的癌症，部分原因是肥胖流行和脂肪肝疾病，特别是非酒精性脂肪性肝炎 (NASH)。伴随肝星状细胞活化释放细胞因子和趋化因子的慢性炎症导致肝细胞外基质 (ECM) 的变化，从而易患 HCC。摄入高脂肪饮食的人类和小鼠的胃肠道肽缩胆囊素 (CCK) 的血液水平升高。我们发现 NASH 小鼠肝脏中的 CCK-B 受体 (CCK-BR) 表达增加。用 CCK-BR 拮抗剂丙谷胺治疗小鼠可预防 NASH，降低肝脏炎症细胞因子和趋化因子，减少氧化应激，减少 F4/80+ 肝巨噬细胞，并预防 HCC。与正常肝脏相比，小鼠和人 HCC 细胞系中 CCK-AR 和 CCK-BR 的表达均增加，CCK 在体外刺激野生型和 CCK-A 受体敲除 HCC 细胞的生长，但不刺激 CCK-BR敲除细胞表明 CCK-BR 介导增殖。在携带 Dt81Hepa1-6 的小鼠或 RIL-75 HCC 肿瘤中，丙谷胺治疗分别显着降低了 70% 和 73% 的生长。具有选择性 CCK-BR 抗体的人肝组织阵列的 IHC 显示人 HCC 染色，而在正常肝脏中没有染色。预防相关性：这项研究证明了胃肠肽缩胆囊素 (CCK) 在肝细胞癌 (HCC) 中的作用，以及 CCK-BR 阻断如何逆转肝细胞外基质的癌前状态，从而使其不易发生 HCC。因此，CCK-BR 阻断是一种预防/治疗 HCC 的新方法。这项研究证明了胃肠肽缩胆囊素 (CCK) 在肝细胞癌 (HCC) 中的作用，以及 CCK-BR 阻断如何逆转肝细胞外基质的癌前状态，从而使其不易发生 HCC。因此，CCK-BR 阻断是一种预防/治疗 HCC 的新方法。这项研究证明了胃肠肽缩胆囊素 (CCK) 在肝细胞癌 (HCC) 中的作用，以及 CCK-BR 阻断如何逆转肝细胞外基质的癌前状态，从而使其不易发生 HCC。因此，CCK-BR 阻断是一种预防/治疗 HCC 的新方法。