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涉及 CDK1 的细胞周期蛋白依赖性激酶途径是胆管癌的潜在治疗靶点。

The cyclin‑dependent kinase pathway involving CDK1 is a potential therapeutic target for cholangiocarcinoma.

机构信息

Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa 920‑8640, Japan.

出版信息

Oncol Rep. 2020 Jan;43(1):306-317. doi: 10.3892/or.2019.7405. Epub 2019 Nov 8.

Abstract

Cholangiocarcinoma is an aggressive malignancy with high mortality, and effective therapeutic agents for this cancer are limited. Cyclin‑dependent kinase (CDK) pathways are therapeutic targets for various types of cancers; however, their involvement in cholangiocarcinoma remains unclear. The present study examined the biological significance of CDK pathways in cholangiocarcinoma. An immunohistochemical analysis of cholangiocarcinoma tissue sections revealed the upregulated expression of phosphorylated cyclin‑dependent kinase 1 (p‑CDK1), p‑CDK2, cyclin B1, and cyclin E1 in carcinoma cells. The nuclear expression of p‑CDK1 and cyclin B1 was positively correlated with the presence of lymph node metastasis and the clinical stage, and p‑CDK1 expression was also associated with poor patient survival. The treatment of human cholangiocarcinoma cell lines (CCKS‑1, TFK‑1 and HUCCT‑1) with the multi‑CDK inhibitor roscovitine decreased p‑CDK1 expression, inhibited cell proliferation, arrested the cell cycle at the G1 or G2/M phase, and significantly inhibited carcinoma cell invasion. In vivo studies using a murine xenograft model revealed that an intraperitoneal injection of roscovitine significantly inhibited cholangiocarcinoma cell growth. Roscovitine induced apoptosis in cholangiocarcinoma cells in vitro and in vivo. These results demonstrated the potential of the CDK pathway involving CDK1 as a therapeutic target for cholangiocarcinoma. Furthermore, the immunohistochemical expression of p‑CDK1 may be a useful prognostic marker of cholangiocarcinoma.

摘要

胆管癌是一种具有高死亡率的侵袭性恶性肿瘤,针对这种癌症的有效治疗药物有限。细胞周期蛋白依赖性激酶(CDK)途径是各种类型癌症的治疗靶点;然而,其在胆管癌中的作用尚不清楚。本研究探讨了 CDK 途径在胆管癌中的生物学意义。免疫组织化学分析胆管癌组织切片显示,磷酸化 CDK1(p-CDK1)、p-CDK2、细胞周期蛋白 B1 和细胞周期蛋白 E1 在癌细胞中表达上调。p-CDK1 和细胞周期蛋白 B1 的核表达与淋巴结转移和临床分期的存在呈正相关,p-CDK1 表达也与患者生存不良有关。用多 CDK 抑制剂罗洛司汀处理人胆管癌细胞系(CCKS-1、TFK-1 和 HUCCT-1)可降低 p-CDK1 表达,抑制细胞增殖,使细胞周期在 G1 或 G2/M 期停滞,并显著抑制癌细胞侵袭。在使用小鼠异种移植模型的体内研究中,腹腔内注射罗洛司汀可显著抑制胆管癌细胞生长。罗洛司汀在体外和体内诱导胆管癌细胞凋亡。这些结果表明 CDK 途径涉及 CDK1 作为胆管癌的治疗靶点具有潜力。此外,p-CDK1 的免疫组织化学表达可能是胆管癌的一个有用的预后标志物。

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