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 ApcMin/+ 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.

Automated summary

The study demonstrated that PCSK9 may have a potential oncogenic role in the development and progression of colorectal cancer in vivo via activation of JAK2/STAT3/SOCS3 signaling pathway. Overexpression of PCSK9 led to increased adenomas and adenocarcinomas in mice, while treatment with evolocumab reduced tumor growth and prevented the development of adenocarcinomas.