SDHC 缺乏通过重编程结直肠癌细胞中的脂肪酸代谢促进转移。
Deficiency of SDHC promotes metastasis by reprogramming fatty acid metabolism in colorectal cancer.
机构信息
Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.
出版信息
J Transl Med. 2024 Jun 6;22(1):544. doi: 10.1186/s12967-024-05361-x.
BACKGROUND
Several studies have demonstrated a strong correlation between impaired Succinate dehydrogenase (SDH) function and the advancement of tumors. As a subunit of SDH, succinate dehydrogenase complex subunit C (SDHC) has been revealed to play tumor suppressive roles in several cancers, while its specific role in colorectal cancer (CRC) still needs further investigation.
METHODS
Online database were utilized to investigate the expression of SDHC in colorectal cancer and to assess its correlation with patient prognosis. Cell metastasis was assessed using transwell and wound healing assays, while tumor metastasis was studied in a nude mice model in vivo. Drug screening and RNA sequencing were carried out to reveal the tumor suppressor mechanism of SDHC. Triglycerides, neutral lipids and fatty acid oxidation were measured using the Triglyceride Assay Kit, BODIPY 493/503 and Colorimetric Fatty Acid Oxidation Rate Assay Kit, respectively. The expression levels of enzymes involved in fatty acid metabolism and the PI3K/AKT signaling pathway were determined by quantitative real-time PCR and western blot.
RESULTS
Downregulation of SDHC was found to be closely associated with a poor prognosis in CRC. SDHC knockdown promoted CRC metastasis both in vitro and in vivo. Through drug screening and Gene set enrichment analysis, it was discovered that SDHC downregulation was positively associated with the fatty acid metabolism pathways significantly. The effects of SDHC silencing on metastasis were reversed when fatty acid synthesis was blocked. Subsequent experiments revealed that SDHC silencing activated the PI3K/AKT signaling axis, leading to lipid accumulation by upregulating the expression of aldehyde dehydrogenase 3 family member A2 (ALDH3A2) and reduction of fatty acid oxidation rate by suppressing the expression of acyl-coenzyme A oxidase 1 (ACOX1) and carnitine palmitoyltransferase 1A (CPT1A).
CONCLUSIONS
SDHC deficiency could potentially enhance CRC metastasis by modulating the PI3K/AKT pathways and reprogramming lipid metabolism.
背景
多项研究表明，琥珀酸脱氢酶（SDH）功能障碍与肿瘤进展之间存在很强的相关性。作为 SDH 的一个亚基，琥珀酸脱氢酶复合体亚基 C（SDHC）已被证实在几种癌症中发挥肿瘤抑制作用，但其在结直肠癌（CRC）中的具体作用仍需进一步研究。
方法
利用在线数据库研究 SDHC 在结直肠癌中的表达情况，并评估其与患者预后的相关性。使用 Transwell 和划痕愈合实验评估细胞转移，在体内裸鼠模型中研究肿瘤转移。进行药物筛选和 RNA 测序以揭示 SDHC 的肿瘤抑制机制。使用甘油三酯测定试剂盒、BODIPY 493/503 和比色法脂肪酸氧化速率测定试剂盒分别测量甘油三酯、中性脂质和脂肪酸氧化。通过定量实时 PCR 和 Western blot 测定参与脂肪酸代谢和 PI3K/AKT 信号通路的酶的表达水平。
结果
SDHC 的下调与 CRC 患者的不良预后密切相关。SDHC 敲低促进了 CRC 在体外和体内的转移。通过药物筛选和基因集富集分析，发现 SDHC 下调与脂肪酸代谢途径显著正相关。当脂肪酸合成被阻断时，SDHC 沉默对转移的影响被逆转。随后的实验表明，SDHC 沉默通过激活 PI3K/AKT 信号轴，上调醛脱氢酶 3 家族成员 A2（ALDH3A2）的表达和降低脂肪酸氧化率来抑制酰基辅酶 A 氧化酶 1（ACOX1）和肉碱棕榈酰转移酶 1A（CPT1A）的表达，导致脂质积累。
结论
SDHC 缺乏可能通过调节 PI3K/AKT 途径和重新编程脂质代谢来增强 CRC 的转移。
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