Ye Wenling, Zhao Yang, Wang Yibo, Wang Yahan, Zhang Huan, Wang Fengling, Chen Weidong
Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Science, Inner Mongolia Medical University, Hohhot 010110, China.
Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Sciences, Henan University, Kaifeng 475001, China.
Int J Mol Sci. 2025 Jan 28;26(3):1122. doi: 10.3390/ijms26031122.
The Farnesoid X receptor (FXR) has recently been identified as being closely associated with the progression of primary hepatocellular carcinoma. Cancer stem cells (CSCs) play a crucial role in tumor initiation, progression, invasion, metastasis, recurrence, and drug resistance. The elucidation of the role and regulatory mechanism of FXR in CSCs is therefore deemed significant. Here, bioinformatics analysis has revealed a downregulation of FXR in hepatocellular carcinoma (HCC), which showed a negative correlation with HCC malignancy. This result was further confirmed through clinical sample analysis. Subsequently, CSCs were isolated from HCC cell lines and exhibited a significant decrease in the expression of FXR. The activation of FXR resulted in a remarkable inhibition of the proliferation, invasion, and tumorigenicity of CSCs. Furthermore, activated FXR prominently upregulated the expression of SOCS3 while suppressing STAT3 phosphorylation in CSCs. To further investigate this discovery, we established a DEN-induced HCC model in mice and observed that FXR-deficient mice exhibited heightened susceptibility to HCC. This was accompanied by decreased expression levels of SOCS3 and elevated expression and phosphorylation levels of STAT3, as well as significantly enhanced HCC CSCs markers and stemness-related genes expression in DEN-induced HCC tissues of FXR-deficient mice. Additionally, we also found a significant upregulation of CSCs markers and stemness-related genes within HCC clinical samples. Based on these findings, we postulated that targeted regulation of SOCS3 by FXR inhibits STAT3 phosphorylation, thereby exerting an inhibitory effect on CSCs.
法尼醇X受体（FXR）最近被确定与原发性肝细胞癌的进展密切相关。癌症干细胞（CSCs）在肿瘤的起始、进展、侵袭、转移、复发和耐药性中起着关键作用。因此，阐明FXR在CSCs中的作用和调控机制具有重要意义。在这里，生物信息学分析显示肝细胞癌（HCC）中FXR表达下调，这与HCC恶性程度呈负相关。通过临床样本分析进一步证实了这一结果。随后，从HCC细胞系中分离出CSCs，其FXR表达显著降低。FXR的激活导致CSCs的增殖、侵袭和致瘤性受到显著抑制。此外，激活的FXR显著上调了CSCs中SOCS3的表达，同时抑制了STAT3的磷酸化。为了进一步研究这一发现，我们在小鼠中建立了二乙基亚硝胺（DEN）诱导的HCC模型，观察到FXR缺陷小鼠对HCC的易感性增加。这伴随着SOCS3表达水平降低，STAT3表达和磷酸化水平升高，以及FXR缺陷小鼠DEN诱导的HCC组织中HCC CSCs标志物和干性相关基因表达显著增强。此外，我们还发现HCC临床样本中CSCs标志物和干性相关基因显著上调。基于这些发现，我们推测FXR对SOCS3的靶向调控抑制了STAT3磷酸化，从而对CSCs发挥抑制作用。
