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 <sup>Min/+</sup> mice
Kai Yang, Jie Zhu, Huanhua Luo, Shuwen Yu, Lu Wang
Abstract
Introduction 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. Methods First, we utilized the classic intestinal tumor Apc Min/+ mouse model and PCSK9 knock-in (KI) mice to establish Apc Min/+ PCSK9(KI) mice. Then, we investigated the effect of PCSK9 overexpression in Apc Min/+ 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. Results Apc Min/+ PCSK9(KI) mice had higher numbers and larger sizes of adenomas, with 83.3% of these mice developing adenocarcinoma (vs. 16.7% of Apc Min/+ mice). However, treatment with evolocumab reduced the number and size of adenomas and prevented the development of adenocarcinomas in Apc Min/+ 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 Apc Min/+ mice. Conclusion 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.