Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China.
Department of Laboratory Animal Science, College of Basic Medical Sciences, Army Medical University, Chongqing, China.
Gut. 2022 Nov;71(11):2253-2265. doi: 10.1136/gutjnl-2021-325851. Epub 2022 Mar 1.
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.
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.
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.
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.
异常的脂质代谢是结直肠癌（CRC）的一个标志。角鲨烯环氧化酶（SQLE）是胆固醇生物合成中的限速酶，在 CRC 中上调。在这里，我们旨在确定 SQLE 的致癌功能及其与肠道微生物群相互作用在促进结直肠肿瘤发生中的作用。
分析了两个队列的配对相邻正常组织和 CRC（n=202）。通过将 Rosa26-lsl-Sqle 小鼠与 Cdx2-Cre 小鼠杂交，生成了结肠特异性 Sqle 转基因（Sqle tg）小鼠。收集粪便进行宏基因组和代谢组学分析。
SQLE 信使 RNA 和蛋白表达在 CRC 中上调（p<0.01），并预测 CRC 患者的生存不良。SQLE 通过诱导细胞周期进程和抑制细胞凋亡来促进 CRC 细胞增殖。在氧化偶氮甲烷诱导的 CRC 模型中，与野生型小鼠相比，Sqle tg 小鼠的肿瘤发生增加（p<0.01）。综合宏基因组和代谢组学分析揭示了 Sqle tg 小鼠的肠道菌群失调，富集了致病性细菌，这与次级胆汁酸增加有关。与次级胆汁酸的有害作用一致，Sqle tg 小鼠的肠道屏障功能受损，紧密连接蛋白 Jam-c 和闭合蛋白减少。与对照小鼠粪便相比，将 Sqle tg 小鼠的粪便移植到无菌小鼠中会损害肠道屏障功能并刺激细胞增殖。最后，我们证明了 SQLE 抑制剂特比萘芬可以通过与奥沙利铂和 5-氟尿嘧啶协同作用来抑制 CRC 生长，从而被重新用于 CRC 的治疗。
这项研究表明，SQLE 通过细胞内在效应和调节肠道微生物群-代谢物轴来介导致癌作用。SQLE 是 CRC 的治疗靶点和预后标志物。
