The following is a summary of “CircPCNXL2 promotes tumor growth and metastasis by interacting with STRAP to regulate ERK signaling in intrahepatic cholangiocarcinoma,” published in the February 2024 issue of Oncology by Liu et al.

Circular RNAs (circRNAs) are a class of non-coding RNAs that have gained attention in cancer research due to their diverse roles in tumorigenesis and metastasis. In intrahepatic cholangiocarcinoma (ICC), a highly aggressive malignancy arising from the bile duct epithelium, the involvement of circRNAs remains largely unexplored. In this study, circPCNXL2 (has_circ_0016956) was identified as significantly upregulated in ICC tissues and cell lines compared to adjacent non-cancerous tissues. A series of in vitro and in vivo assays were conducted to elucidate its functional significance. Results revealed that circPCNXL2 is critical in promoting ICC progression by enhancing proliferation and metastasis.

Mechanistically, circPCNXL2 was found to interact directly with serine-threonine kinase receptor-associated protein (STRAP), a scaffolding protein implicated in various signaling pathways. This interaction facilitated the recruitment of STRAP to MEK1/2, activating the ERK/MAPK pathway. Activation of this pathway has been associated with increased cell proliferation, survival, and metastatic potential in various cancers, including ICC. Therefore, the interaction between circPCNXL2 and STRAP represents a novel mechanism by which circRNAs regulate tumorigenesis in ICC.

Furthermore, circPCNXL2 was shown to act as a sponge for miR-766-3p, a microRNA known to regulate gene expression by binding to the 3′ untranslated region (UTR) of target mRNAs. By sequestering miR-766-3p, circPCNXL2 relieved the inhibitory effect of miR-766-3p on its target gene, serine/arginine-rich splicing factor 1 (SRSF1). Upregulation of SRSF1, a known oncogene, enhanced ICC growth, providing additional mechanistic insight into the pro-tumorigenic role of circPCNXL2.

Importantly, in vivo experiments demonstrated that circPCNXL2 partially counteracted the anti-tumor effects of trametinib, a MEK1/2 inhibitor commonly used in cancer therapy. This suggests that targeting the circPCNXL2/STRAP/ERK axis may enhance the efficacy of MEK inhibitors in ICC treatment.

Overall, these findings highlight the multifaceted role of circPCNXL2 in ICC progression, involving interactions with STRAP and miR-766-3p to modulate key signaling pathways and oncogenic processes. Understanding the functional significance of circRNAs like circPCNXL2 in ICC may lead to developing novel diagnostic biomarkers and therapeutic strategies for this aggressive cancer.

Source: molecular-cancer.biomedcentral.com/articles/10.1186/s12943-024-01950-y