Affiliations 1 State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing, 100193, China. 2 Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong, 250021, China. 3 Yantai Yuhuangding Hospital Affiliated to Qingdao University, Shandong, 264000, China. 4 Department of Reproduction and Gynecological Endocrinology, Medical University of Bialystok, Bialystok, 37801, Poland. 5 Department of Physiology, Institute of Biomedicine, University of Turku, Turku, 20520, Finland. 6 School of Life Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
The mechanism underlying metabolic dysfunction-associated steatohepatitis to hepatocellular carcinoma is elusive, and whether circRNA can serve as biomarker or therapeutic target for MASH/HCC needs to be systematically explored. Integrative transcriptomic analysis of circRNA from MASH and HCC were performed. Multi-cohort analyses of serum and tissues from MASH and HCC patients were conducted. Mechanisms are explored via RNA-protein interaction assays, CRISPR-mediated knockdown, and xenograft/...更多
The mechanism underlying metabolic dysfunction-associated steatohepatitis to hepatocellular carcinoma is elusive, and whether circRNA can serve as biomarker or therapeutic target for MASH/HCC needs to be systematically explored. Integrative transcriptomic analysis of circRNA from MASH and HCC were performed. Multi-cohort analyses of serum and tissues from MASH and HCC patients were conducted. Mechanisms are explored via RNA-protein interaction assays, CRISPR-mediated knockdown, and xenograft/PiggyBac-mediated mice models. circSMEK1 is significantly decreased in MASH/HCC tissues and serum, correlating with tumor size, vascular invasion, and overall survival. Mechanistically, nuclear circSMEK1 binds hnRNPK, promoting its ubiquitin-mediated degradation, suppressing IGF2 transcription and PI3K/AKT signaling. Loss of circSMEK1 elevated autocrine IGF2 in HCC promoting tumor growth, also activated AKT in cancer-associated fibroblasts through paracrine, fostering an immunosuppressive microenvironment. SF3B4 overexpression drove circSMEK1 depletion in HCC. In murine models, circSMEK1 restoration inhibited tumor growth and metastasis. circSMEK1 is a tumor-suppressor in MASH/HCC through the hnRNPK-IGF2-AKT axis. The serum level of circSMEK1 has non-invasive diagnostic value for HCC , as well as potential diagnostic utility for early HCC or high-risk MASH, owing to its key role in bridging MASH to HCC progression. Restoring of circSMEK1, alone or combined with IGF2 inhibitors, proposing a novel therapeutic strategy for HCC.收起
