HBX-induced miR-5188 impairs FOXO1 to stimulate β-catenin nuclear translocation and promotes tumor stemness in hepatocellular carcinoma.

Cancer stem cells (CSCs) are the key factor in determining cancer recurrence, metastasis, chemoresistance and patient prognosis in hepatocellular carcinoma (HCC). The role of miR-5188 in cancer stemness has never been documented. In this study, we investigated the clinical and biological roles of miR-5188 in HCC. Methods: MiRNA expression in HCC was analyzed by bioinformatics analysis and in situ hybridization. The biological effect of miR-5188 was demonstrated in both in vitro and in vivo studies through the ectopic expression of miR-5188. The target gene and molecular pathway of miR-5188 were characterized using bioinformatics tools, dual-luciferase reporter assays, gene knockdown, and rescue experiments. Results: MiR-5188 was shown to be upregulated and confer poor prognosis in HCC patient data from TCGA database. MiR-5188 was subsequently identified as a significant inducer of cancer stemness that promotes HCC pathogenesis. Specifically, the targeting of miR-5188 by its antagomir markedly prolonged the survival time of HCC-bearing mice and improved HCC cell chemosensitivity in vivo. Mechanistic analysis indicated that miR-5188 directly targets FOXO1, which interacts with β-catenin in the cytoplasm to reduce the nuclear translocation of β-catenin and promotes the activation of Wnt signaling and downstream tumor stemness, EMT, and c-Jun. Moreover, c-Jun transcriptionally activates miR-5188 expression, forming a positive feedback loop. Interestingly, the miR-5188-FOXO1/β-catenin-c-Jun feedback loop was induced by hepatitis X protein (HBX) through Wnt signaling and participated in the HBX-induced pathogenesis of HCC. Finally, analyses of transcriptomics data and our clinical data supported the significance of the abnormal expression of the miR-5188 pathway in HCC pathogenesis. Conclusions: These findings present the inhibition of miR-5188 as a novel strategy for the efficient elimination of CSCs to prevent tumor metastasis, recurrence and chemoresistance in patients with hepatocellular carcinoma. Our study highlights the importance of miR-5188 as a tumor stemness inducer that acts as a potential target for HCC treatment.

Lin X ，Zuo S ，Luo R ，Li Y ，Yu G ，Zou Y ，Zhou Y ，Liu Z ，Liu Y ，Hu Y ，Xie Y ，Fang W ，Liu Z ... -  《Theranostics》

Silencing MYH9 blocks HBx-induced GSK3β ubiquitination and degradation to inhibit tumor stemness in hepatocellular carcinoma.

Lin X ，Li AM ，Li YH ，Luo RC ，Zou YJ ，Liu YY ，Liu C ，Xie YY ，Zuo S ，Liu Z ，Liu Z ，Fang WY ... -  《-》

Timeless-Stimulated miR-5188-FOXO1/β-Catenin-c-Jun Feedback Loop Promotes Stemness via Ubiquitination of β-Catenin in Breast Cancer.

MicroRNAs (miRNAs) play an essential role in the self-renewal of breast cancer stem cells (BCCs). Our study aimed to clarify the role of proto-oncogene c-Jun-regulated miR-5188 in breast cancer progression and its association with Timeless-mediated cancer stemness. In the present study, we showed that miR-5188 exerted an oncogenic effect by inducing breast cancer stemness, proliferation, metastasis, and chemoresistance in vitro and in vivo. The mechanistic analysis demonstrated that miR-5188 directly targeted FOXO1, which interacted with β-catenin in the cytoplasm, facilitated β-catenin degradation, and impaired the nuclear accumulation of β-catenin, thus stimulating the activation of known Wnt targets, epithelial-mesenchymal transition (EMT) markers, and key regulators of cancer stemness. Moreover, miR-5188 potentiated Wnt/β-catenin/c-Jun signaling to promote breast cancer progression. Interestingly, c-Jun enhanced miR-5188 transcription to form a positive regulatory loop, and Timeless interacted with Sp1/c-Jun to induce miR-5188 expression by promoting c-Jun-mediated transcription, which further activated miR-5188-FOXO1/β-catenin-c-Jun loop and facilitated breast cancer progression. Importantly, miR-5188 was upregulated in breast cancer and was positively correlated with poor patient prognosis. This study identifies miR-5188 as a novel oncomiR and provides a new theoretical basis for the clinical use of miR-5188 antagonists in the treatment of breast cancer.

Zou Y ，Lin X ，Bu J ，Lin Z ，Chen Y ，Qiu Y ，Mo H ，Tang Y ，Fang W ，Wu Z ... -  《-》

A positive feedback loop involving the LINC00346/β-catenin/MYC axis promotes hepatocellular carcinoma development.

Zhang N ，Chen X 《-》

SPG21, a potential oncogene targeted by miR-128-3p, amplifies HBx-induced carcinogenesis and chemoresistance via activation of TRPM7-mediated JNK pathway in hepatocellular carcinoma.

Chronic hepatitis B virus (HBV) infection is the primary risk factor for the malignant progression of hepatocellular carcinoma (HCC). It has been reported that HBV X protein (HBx) possesses oncogenic properties, promoting hepatocarcinogenesis and chemoresistance. However, the detailed molecular mechanisms are not fully understood. Here, we aim to investigate the effects of miR-128-3p/SPG21 axis on HBx-induced hepatocarcinogenesis and chemoresistance. The expression of SPG21 in HCC was determined using bioinformatics analysis, quantitative real-time PCR (qRT-PCR), western blotting, and immunohistochemistry (IHC). The roles of SPG21 in HCC were elucidated through a series of in vitro and in vivo experiments, including real-time cellular analysis (RTCA), matrigel invasion assay, and xenograft mouse model. Pharmacologic treatment and flow cytometry were performed to demonstrate the potential mechanism of SPG21 in HCC. SPG21 expression was elevated in HCC tissues compared to adjacent non-tumor tissues (NTs). Moreover, higher SPG21 expression correlated with poor overall survival. Functional assays revealed that SPG21 fostered HCC tumorigenesis and invasion. MiR-128-3p, which targeted SPG21, was downregulated in HCC tissues. Subsequent analyses showed that HBx amplified TRPM7-mediated calcium influx via miR-128-3p/SPG21, thereby activating the c-Jun N-terminal kinase (JNK) pathway. Furthermore, HBx inhibited doxorubicin-induced apoptosis by engaging the JNK pathway through miR-128-3p/SPG21. The study suggested that SPG21, targeted by miR-128-3p, might be involved in enhancing HBx-induced carcinogenesis and doxorubicin resistance in HCC via the TRPM7/Ca2+/JNK signaling pathway. This insight suggested that SPG21 could be recognized as a potential oncogene, offering a novel perspective on its role as a prognostic factor and a therapeutic target in the context of HCC.

Zhou P ，Yao W ，Liu L ，Yan Q ，Chen X ，Wei X ，Ding S ，Lv Z ，Zhu F ... -  《-》