A1 Refereed original research article in a scientific journal
CircSMEK1 Suppresses HCC via the hnRNPK‐IGF2‐AKT Axis: A Diagnostic Biomarker and Therapeutic Target
Authors: Guo, Peilan; Jia, Xiaomeng; Wang, Shenghong; Li, Xinyu; Liu, Yajing; Lin, Lisen; Wang, Zhengkun; Liu, Fujun; Wolczynski, Slawomir; Rahman, Nafis; Gao, Jie; Du, Xuguang; Tsang, Suk‐Ying; Liu, Jiali; Song, Wei; Li, Xiangdong.
Publisher: Wiley
Publication year: 2025
Journal: Advanced Science
Article number: e05267
eISSN: 2198-3844
DOI: https://doi.org/10.1002/advs.202505267
Publication's open availability at the time of reporting: Open Access
Publication channel's open availability : Open Access publication channel
Web address : https://doi.org/10.1002/advs.202505267
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/504738126
The mechanism underlying metabolic dysfunction-associated steatohepatitis (MASH) to hepatocellular carcinoma (HCC) 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 (n = 206) 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 (AUC = 0.790), 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.
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Funding information in the publication:
This work was supported by 1) National Natural Science Foundation of China (Grant No.: 82171854); 2) Medical University of Bialystok, Poland (SUB/1/DN/21/003/1104); 3) The 2115 Talent Development Program of China Agricultural University.
