2022-06-07 文献阅读

（一）ARID1A prevents squamous cell carcinoma initiation and chemoresistance by antagonizing pRb/E2F1/c-Myc-mediated cancer stemness

主要结论：

（1）Mechanistic studies revealed that ARID1A blocked the interaction between cyclin-dependent kinases (CDKs) and retinoblastoma protein (Rb), reducing the phosphorylation of Rb. Dephosphorylated Rb suppressed E2F1 activity and then suppressed cancer stemness by inactivating c-Myc.
（2） ARID1A depletion significantly increased the chemoresistance of SCC and that a CDK inhibitor exhibited a favorable effect on rescuing the chemoresistance caused by ARID1A loss.
![NMX_JPD)0]XX]IHG{VBZY4J.png](https://upload-images.jianshu.io/upload_images/20924877-c231911ed361b705.png?imageMogr2/auto-orient/strip%7CimageView2/2/w/1240)

主要逻辑：

ARID1A基因在肿瘤中失活突变很多，作者想研究它在鳞状细胞癌中的作用。先在基因敲除小鼠模型中发现失活突变，肿瘤易发生，这个模型算是一个亮点；然后在细胞系中敲掉基因，发现促进干性，促进生长；然后细胞RNAseq测序，发现敲除的细胞中，MYC相关通路最大，点QP也验证ARID1A的低表达，会导致MYC的转录本和蛋白上升；既然ARID1A可以影响MYC转录本，是不是与调控MYC表达的转录因子相关，然后就在上调通路中也有E2F，它是一个转录因子，发现E2F与MYC的启动子区域存在结合；后续发现ARID1A影响p-Rb，E2F，证明三者有互作，就做通了一个轴；后面就还涉及到上调通路中有EMT，EMT与化疗耐药相关，所以可能是ARID1A化疗耐药的原因之一，用CDKi可以克服，而CDKi主要也是可以靶向p-Rb,影响MYC表达。

个人收获点：

1. the expression of stemness markers such as ABCG2, Nanog, and Sox2 and decreased the expression of differentiation markers such as Keratin 4 and Keratin 13.
   2.To further validate the role of ARID1A in the tumorigenic potential of SCC cells, a limiting dilution analysis was performed using KYSE410 cells expressing control or ARID1A shRNAs. 这里为了研究基因的致瘤能力，亦可反映肿瘤干性，作者用不同浓度的细胞数进行皮下成瘤，比较成瘤时间和大小。
   ![FY`MTL@[JWIDZ5}HWTKXH6.png
   3.EMT:the expression of the mesenchymal markers CDH2, ZEB1, and ZEB2 .
   EMT has been recognized as a contributor to chemoresistance in recent years [37];
   4.we predicted the sequence logo of E2F1 using the JASPAR database [32] (Fig. 5a), and further analysis showed that E2F1 could bind to several sequences in the c-Myc promoter region (2 kb upstream of the transcriptional start site) (Fig. 5b).
   ![AIS89ZAOPC]L691%V2YQ3Y.png

Loss of ARID1A Promotes Hepatocellular Carcinoma Progression via Up-regulation of MYC Transcription

diethylnitrosamine (DEN)：可以诱导肝癌

MYC can be regulated by ARID1A and this contributes to the regulation of cell proliferation.