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

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.