于君团队:角鲨烯环氧化酶或可作为大肠癌的治疗靶点
创作:十年雪落 审核:Lexi 03月07日
  • 结直肠癌患者的SQLE mRNA和蛋白质表达上调,SQLE高表达可预测较差的总生存率;
  • SQLE通过诱导细胞周期进程并抑制细胞凋亡,以促进结直肠癌细胞增殖;
  • 结直肠癌小鼠中,结肠特异性SQLE过表达促进肿瘤发生;
  • SQLE过表达导致肠道菌群失调,富集致病菌,增加次级胆汁酸,损伤肠道屏障功能;
  • 将SQLE转基因小鼠的粪菌移植给无菌小鼠,可损伤肠道屏障并促进结肠细胞增殖;
  • SQLE抑制剂特比萘芬与奥沙利铂和5-氟尿嘧啶协同抑制结直肠癌生长。
主编推荐语
Lexi
脂质代谢异常是结直肠癌的一个标志。角鲨烯环氧化酶(SQLE)是胆固醇生物合成的限速酶,在结直肠癌中被上调。香港中文大学的于君团队在Gut上发表的一项最新研究结果发现,SQLE可通过诱导细胞周期进程及抑制细胞凋亡,并导致肠道菌群失调,以促进肠道屏障功能受损及结直肠癌细胞增殖,从而加速小鼠结直肠癌的发生发展。在结直肠癌患者中,SQLE的表达上调,并与较差的预后相关。靶向抑制SQLE可与奥沙利铂和5-氟尿嘧啶协同作用,以抑制小鼠结直肠癌的生长。
关键字
延伸阅读本研究的原文信息和链接出处,以及相关解读和评论文章。欢迎读者朋友们推荐!
图片
Gut [IF:31.793]

Squalene epoxidase drives cancer cell proliferation and promotes gut dysbiosis to accelerate colorectal carcinogenesis

角鲨烯环氧化酶驱动癌细胞增殖并促进肠道菌群失调以加速结直肠癌发生

10.1136/gutjnl-2021-325851

03-01, Article

Abstract & Authors:展开

Abstract:收起
Objective Aberrant lipid metabolism is a hallmark of colorectal cancer (CRC). Squalene epoxidase (SQLE), a rate-limiting enzyme in cholesterol biosynthesis, is upregulated in CRC. Here, we aim to determine oncogenic function of SQLE and its interplay with gut microbiota in promoting colorectal tumourigenesis. Design Paired adjacent normal tissues and CRC from two cohorts were analysed (n=202). Colon-specific Sqle transgenic (Sqle tg) mice were generated by crossing Rosa26-lsl-Sqle mice to Cdx2-Cre mice. Stools were collected for metagenomic and metabolomic analyses. Results SQLE messenger RNA and protein expression was upregulated in CRC (p<0.01) and predict poor survival of patients with CRC. SQLE promoted CRC cell proliferation by inducing cell cycle progression and suppressing apoptosis. In azoxymethane-induced CRC model, Sqle tg mice showed increased tumourigenesis compared with wild-type mice (p<0.01). Integrative metagenomic and metabolomic analyses unveiled gut dysbiosis in Sqle tg mice with enriched pathogenic bacteria, which was correlated to increased secondary bile acids. Consistent with detrimental effect of secondary bile acids, gut barrier function was impaired in Sqle tg mice, with reduced tight junction proteins Jam-c and occludin. Transplantation of Sqle tg mice stool to germ-free mice impaired gut barrier function and stimulated cell proliferation compared with control mice stool. Finally, we demonstrated that terbinafine, a SQLE inhibitor, could be repurposed for CRC by synergising with oxaliplatin and 5-fluorouracil to inhibit CRC growth. Conclusion This study demonstrates that SQLE mediates oncogenesis via cell intrinsic effects and modulation of gut microbiota-metabolite axis. SQLE represents a therapeutic target and prognostic marker in CRC.

First Authors:
Chuangen Li,Yong Wang

Correspondence Authors:
Jun Yu

All Authors:
Chuangen Li,Yong Wang,Dabin Liu,Chi Chun Wong,Olabisi Oluwabukola Coker,Xiang Zhang,Changan Liu,Yunfei Zhou,Yali Liu,Wei Kang,Ka Fai To,Joseph JY Sung,Jun Yu

评论