Bromodomain and Extraterminal (BET) protein inhibition suppresses tumor progression and inhibits HGF-MET signaling through targeting cancer-associated fibroblasts in colorectal cancer.,Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

当前位置： X-MOL 学术 › BBA Mol. Basis Dis. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Bromodomain and Extraterminal (BET) protein inhibition suppresses tumor progression and inhibits HGF-MET signaling through targeting cancer-associated fibroblasts in colorectal cancer.
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease ( IF 6.2 ) Pub Date : 2020-08-12 , DOI: 10.1016/j.bbadis.2020.165923
Dongpeng Wen ₁ , Yuhan Wang ₂ , Zhehui Zhu ₂ , Zhenyu Huang ₂ , Long Cui ₂ , Tingyu Wu ₂ , Chen-Ying Liu ₂

Affiliation

Objective

Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality. The bromodomain and extra-terminal domain (BET) inhibitors suppresses the gene expressions of various oncogenes and shows a good efficacy in the preclinical CRC models. We investigate the mechanism of action of BET inhibitors in CRC.

Methods

The effect of BET inhibitor (JQ1) on the HGF-MET signaling was assessed by qPCR, western blot and immunohistochemical staining in CRC and cancer-associated fibroblasts (CAFs). The effect of JQ1 on the CAFs was investigated using the primary CAFs derived from CRC tissues and induced-CAFs derived from isolating foreskin fibroblasts. The effect of JQ1 on the gene expression profile of CAFs was explored by RNA-sequence, qPCR and bioinformatic analysis.

Results

JQ1 decreased the mRNA and protein levels of MET in CRC cells and downregulated the mRNA and protein levels of HGF in both CRC cells and CAFs. JQ1 attenuated the pro-migratory activity of CAFs through downregulation of HGF expression in CAFs. Meanwhile, JQ1 also reduced the ability of contracting collagen gels, decreased the cell proliferation, induced G1 arrest and repressed the pro-inflammatory gene expressions in CAFs. MYC expression was suppressed by JQ1 in CAFs. Knockdown of MYC induced G1 arrest in CAFs.

Conclusion

Our results demonstrate the inhibitory effect of BET inhibition on the HGF-MET signaling and the pro-tumor activity of CAFs, revealing a new mechanism by which BET inhibition suppresses CRC progression.

中文翻译：

Bromodomain和Extraterminal（BET）蛋白抑制作用通过靶向结直肠癌中与癌症相关的成纤维细胞来抑制肿瘤进展并抑制HGF-MET信号传导。

目的

大肠癌（CRC）是与癌症相关的死亡率的主要原因之一。溴结构域和末端外结构域（BET）抑制剂可抑制各种癌基因的基因表达，并在临床前CRC模型中显示出良好的疗效。我们研究了BET抑制剂在CRC中的作用机理。

方法

通过qPCR，蛋白质印迹和CRC和癌症相关成纤维细胞（CAFs）的免疫组织化学染色评估了BET抑制剂（JQ1）对HGF-MET信号的影响。使用源自CRC组织的初级CAF和源自分离包皮成纤维细胞的诱导CAF，研究了JQ1对CAF的影响。通过RNA序列，qPCR和生物信息学分析探索了JQ1对CAFs基因表达谱的影响。

结果

JQ1降低了CRC细胞中MET的mRNA和蛋白水平，并下调了CRC细胞和CAF中HGF的mRNA和蛋白水平。JQ1通过下调CAF中HGF的表达来减弱CAF的促迁移活性。同时，JQ1还降低了胶原蛋白凝胶的收缩能力，降低了细胞增殖，诱导了G1阻滞并抑制了CAFs中促炎基因的表达。在CAF中，JQ1抑制了MYC表达。降低MYC诱导CAF中G1的逮捕。