Pro-protein convertase subtilisin/kexin type 9 promotes intestinal tumor development by activating Janus kinase 2/signal transducer and activator of transcription 3/SOCS3 signaling in Apc(Min/+) mice.
Pro-protein convertase subtilisin/kexin type 9 promotes intestinal tumor development by activating Janus kinase 2/signal transducer and activator of transcription 3/SOCS3 signaling in Apc(Min/+) mice.
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前蛋白转化酶枯草杆菌蛋白酶/kexin 9 型通过激活 ApcMin/ 小鼠的 Janus 激酶 2/信号转导器和转录激活剂 3/SOCS3 信号传导促进肠道肿瘤的发展
DOI：
10.1177/20587384211038345
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发表时间：
2021-01
影响因子：
3.5
通讯作者：
Wang L
中科院分区：
文献类型：
--
作者：
Yang K;Zhu J;Luo HH;Yu SW;Wang L
前蛋白转化酶subtilisin/ keexin type 9 （PCSK9）调节人类脂蛋白稳态。Evolocumab是一种选择性PCSK9抑制剂，可以降低低密度脂蛋白胆固醇（LDLC）水平和降低高胆固醇血症。目前的研究旨在探讨PCSK9是否会增加结直肠癌的风险。首先，我们利用经典肠道肿瘤ApcMin/+小鼠模型和PCSK9敲入（KI）小鼠建立ApcMin/+PCSK9（KI）小鼠。然后，我们通过苏木精和伊红（HE）染色、Western blot和免疫组织化学（IHC）检测，研究了ApcMin/+PCSK9（KI）小鼠中PCSK9过表达和evolocumab抑制PCSK9对体内肠道肿瘤进展的影响。ApcMin/+PCSK9（KI）小鼠的腺瘤数量和大小更高，83.3%的小鼠发生腺癌（ApcMin/+小鼠为16.7%）。然而，在ApcMin/+小鼠中，evolocumab治疗减少了腺瘤的数量和大小，并阻止了腺癌的发展。PCSK9过表达降低肿瘤细胞凋亡、Bax/bcl-2比值和细胞因子信号3蛋白（SOCS3）抑制因子水平，但激活肠道肿瘤中Janus激酶2 (JAK2)/信号转导和转录激活因子3 （STAT3）信号通路。相比之下，evolocumab治疗对ApcMin/+小鼠有相反的效果。PCSK9可能在体内通过激活JAK2/STAT3/SOCS3信号在结直肠癌的发生和进展中起到致癌基因的作用或具有致癌作用。
Pro-protein convertase subtilisin/kexin type 9 (PCSK9) regulates lipoprotein homeostasis in humans. Evolocumab is a selective PCSK9 inhibitor that can reduce low-density lipoprotein cholesterol (LDLC) level and decrease hypercholesterolemia. The current study aimed to explore whether PCSK9 increases the risk of colorectal cancer. First, we utilized the classic intestinal tumor ApcMin/+ mouse model and PCSK9 knock-in (KI) mice to establish ApcMin/+PCSK9(KI) mice. Then, we investigated the effect of PCSK9 overexpression in ApcMin/+PCSK9(KI) mice and PCSK9 inhibition using evolocumab on the progression of intestinal tumors in vivo by hematoxylin and eosin (HE) staining, Western blot, and immunohistochemistry (IHC) assay. ApcMin/+PCSK9(KI) mice had higher numbers and larger sizes of adenomas, with 83.3% of these mice developing adenocarcinoma (vs. 16.7% of ApcMin/+ mice). However, treatment with evolocumab reduced the number and size of adenomas and prevented the development of adenocarcinomas in ApcMin/+ mice. PCSK9 overexpression reduced tumor cell apoptosis, the Bax/bcl-2 ratio, and the levels of cytokine signaling 3 protein (SOCS3) suppressors, but activated Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling in intestinal tumors. In contrast, evolocumab treatment had the opposite effect on ApcMin/+mice. PCSK9 might act as an oncogene or have an oncogenic role in the development and progression of colorectal cancer in vivo via activation of JAK2/STAT3/SOCS3 signaling.
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影响因子：
9.2
作者：
Li Y;Wang J;Ma X;Tan L;Yan Y;Xue C;Hui B;Liu R;Ma H;Ren J
通讯作者：
Ren J
影响因子：
3.1
作者：
Dwivedi, Dhruva J.;Grin, Peter M.;Liaw, Patricia C.
通讯作者：
Liaw, Patricia C.
影响因子：
168.9
作者：
Cunningham, David;Atkin, Wendy;Starling, Naureen
通讯作者：
Starling, Naureen
影响因子：
--
作者：
Hong, Seong Hun;Cha, Jae Myung;Lim, Jun Uk
通讯作者：
Lim, Jun Uk
DOI：
10.1152/ajpgi.00321.2010
发表时间：
2010-11-01
影响因子：
4.5
作者：
Lin, Songbai;Lee, Sei-Jung;Yun, C. Chris
通讯作者：
Yun, C. Chris