Br J Cancer:抑制CBX4可有效抑制肝癌细胞索拉非尼耐药性的产生

2021-01-25 xiaozeng MedSci原创

肝细胞癌(HCC)作为全球第三大癌症相关死亡主要原因(占所有癌症相关死亡的8.2%),其发病率逐年上升且具有较高的死亡率。

肝细胞癌(HCC)作为全球第三大癌症相关死亡主要原因(占所有癌症相关死亡的8.2%),其发病率逐年上升且具有较高的死亡率。由于HCC的早期诊断困难,且较高的复发率,术后转移以及化疗耐药性等因素也使得患者的生存率较低。

口服多激酶抑制剂索拉非尼(Sorafenib)被认为是目前晚期肝癌患者的一线全身治疗选择。尽管该疗法的患者平均总生存期(OS)显著提高,但较高的耐药率却大大的限制了索拉非尼疗法的获益。既往研究显示,肿瘤干细胞(CSC)的富集可能在最初治疗后的数年提高患者对索拉非尼的耐药性。


然而,目前尚不清楚CSC是如何影响索拉非尼在肝癌中的作用,相关分子机制、CSC对肝癌耐药性的调节作用也有待阐明。因此,探索靶向耐药性的发展和演变对于提高肝癌化疗疗效非常重要。

索拉非尼耐药性诱导癌症干细胞特性的产生

CBX4(染色体盒同源物4)位于染色体17q25.3上,其编码的CBX4蛋白是PcG蛋白家族成员之一。PcG蛋白是一种转录阻遏因子,主要参与调节发育、衰老、干细胞特性和癌症的发生发展。既往研究显示,过高的CBX4表达水平对应着较差的肝癌患者的OS期,说明CBX4是肝癌的一个独立预后因素,种种证据显示,CBX4可能在维持肝癌CSC过程中发挥着至关重要的作用。


该研究旨在探究抑制CBX4调节癌症干细胞(CSCs)的潜在作用,并评估其对晚期肝癌(HCC)中索拉非尼耐药性的贡献。

miR424-CBX4影响索拉非尼耐药性移植瘤模型中的肿瘤生长

研究人员采用HCC细胞系以及索拉非尼耐药性的移植瘤小鼠模型来分析miR424对CSC特性的影响。通过RT-PCR和二代测序分别对HCC癌症患者和索拉非尼耐药(SR)细胞系中分析RNA表达情况,以验证相关网络中的关键microRNA和靶标。


研究人员发现,SR细胞系的microRNA和mRNA谱分析显示miR424及其直接靶标CBX4与干细胞特性、较差的存活率以及临床特征显著相关。功能实验显示,miR424能够抑制CBX4和CBX4诱导的YAP1蛋白的核转运,但与蛋白的产生无关。当采用CA3和UNC3866调节YAP1和CBX4的表达时,细胞的致瘤性和干性受到极大的抑制,说明这些化合物对SR HCC细胞具有强大的抗肿瘤作用。

相关调控通路示意图

总而言之,该研究结果显示,阻断CBX4的表达对于抑制晚期肝癌索拉非尼耐药性的产生至关重要。


原始出处:

Zhao, W., Ma, B., Tian, Z. et al. Inhibiting CBX4 efficiently protects hepatocellular carcinoma cells against sorafenib resistance. Br J Cancer (21 January 2021).

 

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    2021-01-27 yxch36
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    2021-01-26 留走人康

    肝癌,接下来就要细分了,对于体质好的病人,能否将PD-1类+抗血管新生+放疗等相结合,甚至有必要用TACE进行减负

    0

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