Researchers have uncovered a previously unrecognized tumor-suppressive circuit that controls stem-like behavior in hepatocellular carcinoma (HCC), the most common form of primary liver cancer. The study, led by scientists at Okayama University in Japan and published (DOI: 10.20892/j.issn.2095-3941.2025.0247) in Cancer Biology & Medicine, reveals how the protein SPRED2 collaborates with p53 and a microRNA to suppress cancer stem cell (CSC) traits. The findings could reshape therapeutic strategies for a disease with five-year recurrence rates as high as 70–80%.
Liver cancer is the fifth most commonly diagnosed cancer and the second leading cause of cancer death worldwide, with HCC accounting for 70–85% of cases. CSCs—a small but aggressive cell population—drive relapse, metastasis, and chemotherapy resistance. SPRED2, known to inhibit Ras/Raf/ERK-MAPK signaling, is downregulated in advanced cancers, but how it controls HCC stemness remained unclear. The new study fills that gap by mapping a complete molecular pathway from SPRED2 to CSC suppression.
Using HepG2, HLE, and Hep3B cell lines, mouse xenograft models, and 40 paired human HCC samples, the team combined multiple techniques to trace the pathway. They found that SPRED2 binds the tumor suppressor p53, enters the nucleus, and activates transcription of miR-506-3p. This microRNA then directly targets KLF4 messenger RNA, reducing KLF4 protein levels. KLF4 emerged as a key pluripotency factor: knocking it down reduced sphere and colony formation, invasion, epithelial–mesenchymal transition, aldehyde dehydrogenase (ALDH) activity, and the percentage of CD44+ and CD90+ cells. It also produced smaller tumors in mice.
SPRED2 overexpression lowered KLF4, c-Myc, and Nanog, while SPRED2 knockout increased them. In human samples, KLF4 and miR-506-3p were negatively correlated, whereas SPRED2 and miR-506-3p were positively correlated. The study also showed that ERK and STAT3 inhibition raised miR-506-3p, linking three signaling pathways to KLF4 suppression. A miR-506-3p mimic reduced stemness traits, while its inhibitor increased them, confirming the microRNA’s central role.
The authors said the findings reveal a tumor-suppressive circuit that connects SPRED2, p53, and microRNA regulation. SPRED2 does not act only by blocking ERK or STAT3 signaling; it also helps p53 drive miR-506-3p, which keeps KLF4 in check. This axis may explain why SPRED2 loss promotes CSC-like behavior and could offer a fresh target for therapies aimed at reducing HCC stemness. Because SPRED2-driven miR-506-3p induction required functional p53, the approach may be most relevant for tumors with intact p53 signaling; HCC cells with mutant or absent p53 may need additional strategies.
Targeting the SPRED2/p53/miR-506-3p/KLF4 axis could lead to new treatments that reduce relapse, metastasis, and chemoresistance. Future studies should test miR-506-3p mimics, SPRED2-stabilizing agents, or combination therapies in preclinical models and define which patients are most likely to benefit. Such work could help translate this newly defined axis into precision approaches for HCC. The study was supported in part by the Japan Society for the Promotion of Science (Grant Nos. 25293095, 90264283, and 22K19562). The full text is freely available through PubMed Central at http://www.ncbi.nlm.nih.gov/pmc/journals/2000/, and additional information about the journal can be found at Cancer Biology & Medicine. For those interested in the innovation ecosystem surrounding such research, Chuanlink Innovations provides a platform where revolutionary ideas meet their true potential.
