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靶向细胞周期蛋白依赖性激酶 7 抑制肝内胆管癌的肿瘤进展。

Therapeutic Targeting of CDK7 Suppresses Tumor Progression in Intrahepatic Cholangiocarcinoma.

机构信息

Department of Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China.

Department of Pediatric Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China.

出版信息

Int J Biol Sci. 2020 Feb 10;16(7):1207-1217. doi: 10.7150/ijbs.39779. eCollection 2020.

DOI:10.7150/ijbs.39779
PMID:32174795
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7053328/
Abstract

Intrahepatic cholangiocarcinoma (ICC) is a lethal malignancy with high mortality and lack of effective therapeutic targets. Here, we found that expression of cyclin-dependent kinase 7 (CDK7) was significantly associated with higher tumor grade and worse prognosis in 96 ICC specimens. Depletion of CDK7 significantly inhibited cell growth, induced a G2/M cell cycle arrest, and reduced the migratory and invasive potential in ICC cells. Subsequent experiments demonstrated that ICC cells were highly sensitive to the CDK7 inhibitor THZ1. A low concentration of THZ1 markedly inhibited cell growth, cell cycle, migration, and invasion in ICC cell lines. RNA-sequencing (RNA-seq) analysis revealed that THZ1 treatment decreased the levels of massive oncogene transcripts, particularly those associated with cell cycle and cell migration. Quantitative reverse transcriptase PCR (qRT-PCR) analysis confirmed that transcription of oncogenes involved in cell cycle regulation (, , and ) and the c-Met pathway (, and ) was selectively repressed by THZ1. In addition, THZ1 exhibited significant anti-tumor activity in a patient-derived xenograft (PDX) model of ICC, without causing detectable side effects.

摘要

肝内胆管癌（ICC）是一种致命的恶性肿瘤，死亡率高，缺乏有效的治疗靶点。在这里，我们发现，在 96 例 ICC 标本中，细胞周期蛋白依赖性激酶 7（CDK7）的表达与较高的肿瘤分级和较差的预后显著相关。CDK7 的耗竭显著抑制了 ICC 细胞的生长，诱导了 G2/M 细胞周期阻滞，并降低了其迁移和侵袭能力。随后的实验表明，ICC 细胞对 CDK7 抑制剂 THZ1 高度敏感。低浓度的 THZ1 可显著抑制 ICC 细胞系的细胞生长、细胞周期、迁移和侵袭。RNA 测序（RNA-seq）分析显示，THZ1 处理降低了大量癌基因转录本的水平，特别是那些与细胞周期和细胞迁移相关的转录本。实时定量逆转录聚合酶链反应（qRT-PCR）分析证实，THZ1 选择性地抑制了细胞周期调控（、和）和 c-Met 通路（、和）相关癌基因的转录。此外，THZ1 在 ICC 的患者来源异种移植（PDX）模型中表现出显著的抗肿瘤活性，而没有引起可检测的副作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/86f8/7053328/89f70013e975/ijbsv16p1207g007.jpg
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