Oxidized Low-Density Lipoprotein Links Hypercholesterolemia and Bladder Cancer Aggressiveness by Promoting Cancer Stemness

doi:10.1158/0008-5472.CAN-21-0646

	Oxidized Low-Density Lipoprotein Links Hypercholesterolemia and Bladder Cancer Aggressiveness by Promoting Cancer Stemness
	Yang, Lin 2; Sun, Jingya 3; Li, Meiqian 1; Long, Yiming 3,4; Zhang, Dianzheng 5; Guo, Hongqian 2; Huang, Ruimin 3,4; Yan, Jun 6,7
刊名	CANCER RESEARCH
	2021-11-01
卷号	81 期号:22 页码:5720-5732
ISSN号	0008-5472
DOI	10.1158/0008-5472.CAN-21-0646
通讯作者	Guo, Hongqian(dr.ghq@nju.edu.cn) ; Huang, Ruimin(rmhuan@simm.ac.cn) ; Yan, Jun(yan_jun@fudan.edu.cn)
英文摘要	Hypercholesterolemia is a prevalent metabolic disorder that has been implicated in the development of steroid-targeted cancers. However, the link between hypercholesterolemia and urinary bladder cancer (UBC), a non-steroid-targeted cancer, remains unresolved. Here we show that diet-induced and Mir deficiency-induced hypercholesterolemia enhances both UBC sternness and progression. Inhibition of intestinal cholesterol absorption by ezetimibe reversed diet-induced hypercholesterolemia and cancer sternness. As a key component in hypercholesterolemic sera, oxidized low-density lipoprotein (ox-LDL), but not native low-density lipoprotein-cholesterol or metabolite 27-hydroxycholesterol, increased cancer sternness through its receptor CD36. Depletion of CD36, ectopic expression of an ox-LDL binding-disabled mutant form of CD36(K164A), and the neutralization of ox-LDL and CD36 via neutralizing antibodies all reversed ox-LDL-induced cancer sternness. Mechanistically, ox-1,DL enhanced the interaction of CD36 and JAK2, inducing phosphorylation of JAK2 and subsequently activating STAT3 signaling, which was not mediated by JAK1 or Src in UBC cells. Finally, ox-LDL levels in serum predicted poor prognosis, and the ox-LDhigh signature predicted worse survival in patients with UBC. These findings indicate that ox-LDL links hypercholesterolemia with UBC progression by enhancing cancer sternness. Lowering serum ox-LDL or targeting the CD36/JAK2/STAT3 axis might serve as a potential therapeutic strategy for UBCs with hypercholesterolemia. Moreover, elevated ox-LDL may serve as a hiomarker for UBC. Significance: This study demonstrates how hypercholesterolemia-induced oxidized I,DL promotes urinary bladder cancer sternness via a CD36/STAT3 signaling axis, highlighting these factors as biomarkers and potential therapeutic targets of aggressive disease. [GRAPHICS] .
资助项目	National Natural Science Foundation of China[91859106] ; National Natural Science Foundation of China[81771890] ; National Natural Science Foundation of China[81902968] ; National Natural Science Foundation of China[81972388] ; National Natural Science Foundation of China[81772710] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China[2018ZX09711002] ; Shanghai Science and Technology Committee[20S11901400] ; One Hundred Talent Program of Chinese Academy of Sciences ; Shanghai Sailing Program[19YF1456900]
WOS关键词	PROSTATE-CANCER ; CHOLESTEROL ; CELLS ; CD36 ; ATHEROSCLEROSIS ; MACROPHAGES ; ACTIVATION ; EZETIMIBE
WOS研究方向	Oncology
语种	英语
出版者	AMER ASSOC CANCER RESEARCH
WOS记录号	WOS:000719879600015
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/298976]
专题	中国科学院上海药物研究所
通讯作者	Guo, Hongqian; Huang, Ruimin; Yan, Jun
作者单位	1.Nanjing Univ, Model Anim Res Ctr, Nanjing, Jiangsu, Peoples R China 2.Nanjing Univ, Inst Urol, Dept Urol, Drum Tower Hosp,Med Sch, Nanjing, Jiangsu, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai, Peoples R China 4.Univ Chinese Acad Sci, Beijing, Peoples R China 5.Philadelphia Coll Osteopath Med, Dept Biomed Sci, Philadelphia, PA USA 6.Fudan Univ, Dept Lab Anim Sci, Shanghai, Peoples R China 7.Nanjing Univ, Model Anim Res Ctr, MOE Key Lab Model Anim Dis Study, Nanjing, Jiangsu, Peoples R China
推荐引用方式 GB/T 7714	Yang, Lin,Sun, Jingya,Li, Meiqian,et al. Oxidized Low-Density Lipoprotein Links Hypercholesterolemia and Bladder Cancer Aggressiveness by Promoting Cancer Stemness[J]. CANCER RESEARCH,2021,81(22):5720-5732.
APA	Yang, Lin.,Sun, Jingya.,Li, Meiqian.,Long, Yiming.,Zhang, Dianzheng.,...&Yan, Jun.(2021).Oxidized Low-Density Lipoprotein Links Hypercholesterolemia and Bladder Cancer Aggressiveness by Promoting Cancer Stemness.CANCER RESEARCH,81(22),5720-5732.
MLA	Yang, Lin,et al."Oxidized Low-Density Lipoprotein Links Hypercholesterolemia and Bladder Cancer Aggressiveness by Promoting Cancer Stemness".CANCER RESEARCH 81.22(2021):5720-5732.