CircSCMH1 Accelerates Sorafenib Resistance in Hepatocellular Carcinoma by Regulating HN1 Expression via miR-485-5p.

Sorafenib (SOR) is the first-line chemotherapeutic therapy for hepatocellular carcinoma (HCC) treatment, but SOR resistance is a key factor affecting the therapeutic effect. Emerging studies have suggested that circular RNAs (circRNAs) play an important role in the development of drug resistance in HCC cells. This paper aimed to elucidate the potential role and molecular mechanism of circRNA Scm polycomb group protein homolog 1 (circSCMH1) in SOR-resistant HCC cells. CircSCMH1, microRNA-485-5p (miR-485-5p), and hematological and neurological expressed 1 (HN1) contents were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Cell Counting Kit-8 (CCK8) assay was adopted to detect the SOR sensitivity of cells. Cell proliferation, migration, invasion, and apoptosis were assessed using colony formation, 5-Ethynyl-2'-deoxyuridine (EdU), transwell, and flow cytometry assays. Glucose metabolism was analyzed using commercial kits. HN1, B cell lymphoma-2 (Bcl-2), and Bcl-2-associated X (Bax) protein levels were assessed using western blot. Binding between miR-485-5p and circSCMH1 or HN1 was verified using a dual-luciferase reporter. Xenograft tumor model was used to explore the function of circSCMH1 in vivo. CircSCMH1 expression and HN1 abundances were increased, but the miR-485-5p level was reduced in SOR-resistant HCC tissues and cells. Deficiency of circSCMH1 enhanced SOR sensitivity by suppressing cell proliferation, migration, invasion, and glucose metabolism and inducing cell apoptosis in SOR-resistant HCC cell lines (Huh7/SOR and Hep3B/SOR). Mechanistically, circSCMH1 sponged miR-485-5p to positively regulate HN1 expression. Importantly, circSCMH1 depletion inhibited tumor growth and increased SOR sensitivity in vivo. CircSCMH1 promoted SOR resistance in HCC cells at least partly through upregulating HN1 expression by sponging miR-485-5p. These findings elucidated a new regulatory pathway of chemo-resistance in SOR-resistant HCC cells and provided a possible circRNA-targeted therapy for HCC.

Li M ，Pang X ，Xu H ，Xiao L ... -  《-》

N6-methyladenosine-modified long non-coding RNA KIF9-AS1 promotes stemness and sorafenib resistance in hepatocellular carcinoma by upregulating SHOX2 expression.

Hepatocellular carcinoma (HCC) is a prevalent and aggressive tumor. Sorafenib is the first-line treatment for patients with advanced HCC, but resistance to sorafenib has become a significant challenge in this therapy. Cancer stem cells play a crucial role in sorafenib resistance in HCC. Our previous study revealed that the long non-coding RNA (lncRNA) KIF9-AS1 is an oncogenic gene in HCC. However, the role of KIF9-AS1 in drug resistance and cancer stemness in HCC remains unclear. Herein, we aimed to investigate the function and mechanism of the lncRNA KIF9-AS1 in cancer stemness and drug resistance in HCC. To describe the role of the lncRNA KIF9-AS1 in cancer stemness and drug resistance in HCC and elucidate the underlying mechanism. Tumor tissue and adjacent non-cancerous tissue samples were collected from HCC patients. Sphere formation was quantified via a tumor sphere assay. Cell viability, proliferation, and apoptosis were evaluated via Cell Counting Kit-8, flow cytometry, and colony formation assays, respectively. The interactions between the lncRNA KIF9-AS1 and its downstream targets were confirmed via RNA immunoprecipitation and coimmunoprecipitation. The tumorigenic role of KIF9-AS1 was validated in a mouse model. Compared with that in normal controls, the expression of the lncRNA KIF9-AS1 was upregulated in HCC tissues. Knockdown of KIF9-AS1 inhibited stemness and attenuated sorafenib resistance in HCC cells. Mechanistically, N6-methyladenosine modification mediated by methyltransferase-like 3/insulin-like growth factor 2 mRNA-binding protein 1 stabilized and increased the expression of KIF9-AS1. Additionally, KIF9-AS1 increased the stability and expression of short stature homeobox 2 by promoting ubiquitin-specific peptidase 1-induced deubiquitination. Furthermore, depletion of KIF9-AS1 alleviated sorafenib resistance in a xenograft mouse model of HCC. The N6-methyladenosine-modified lncRNA KIF9-AS1 promoted stemness and sorafenib resistance in HCC by upregulating short stature homeobox 2 expression.

Yu Y ，Lu XH ，Mu JS ，Meng JY ，Sun JS ，Chen HX ，Yan Y ，Meng K ... -  《-》

Exosomal miR-6126 as a novel therapeutic target for overcoming resistance of anti-cancer effect in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) stands as the sixth most prevalent cancer globally, presenting a substantial health challenge, particularly due to late-stage diagnoses that limit treatment effectiveness. Sorafenib, a multi-kinase inhibitor, is the primary chemotherapeutic agent for advanced HCC, but it only extends survival by 2-3 months. However, drug resistance remains a major clinical challenge, necessitating the exploration of new molecular mechanisms, including the role of microRNAs (miRNAs) in sorafenib resistance. In this study, we aimed to identify miRNAs within exosomes derived from sorafenib-resistant HCC cells to elucidate the molecular mechanisms underlying resistance. Sorafenib-resistant cells were generated by culturing the human HCC cell line Huh7 in a medium containing 20 µM sorafenib for six months. Exosomes were isolated from the conditioned medium 24 h before cell harvest using exosome-depleted serum medium. miRNA sequencing and western blotting were used to analyze the expression profiles of exosomal miRNAs and proteins, respectively. pH measurement was performed to assess pH changes in response to sorafenib treatment and miRNA modulation. A total of 180 exosomal miRNAs were found to be dysregulated between sorafenib-treated control Huh7 (Huh7S) and sorafenib-resistant Huh7 (Huh7RS) cells, as well as between untreated control Huh7 and Huh7RS cells. Among these, miR-6126 was significantly downregulated in Huh7RS cells compared to Huh7S cells. Functional studies using 2-dimensional (D) and 3D cell culture systems revealed that miR-6126 overexpression reduced sorafenib resistance in Huh7RS cells, while its inhibition increased resistance in Huh7 cells. miR-6126 downregulated key proteins involved in cancer stem cell maintenance, such as CD44 and HK2. Furthermore, the pH level was elevated in cells overexpressing miR-6126 following sorafenib treatment, whereas inhibiting miR-6126 resulted in a lower pH. Exosomal miR-6126 plays a pivotal role in sorafenib resistance and tumorigenesis, highlighting its potential as a novel therapeutic target for overcoming drug resistance in HCC.

Hwang H ，Kim J ，Kim TH ，Han Y ，Choi D ，Cho S ，Kim S ，Park S ，Park T ，Piccinini F ，Rhee WJ ，Pyun JC ，Lee M ... -  《BMC CANCER》

Long Non-coding RNA 02298 Promotes the Malignancy of HCC by Targeting the miR-28-5p/CCDC6 Pathway.

Hepatocellular carcinoma (HCC) is a malignancy characterized by a high fatality rate. Increasing evidence indicating that long non-coding RNAs (lncRNAs) play a regulatory role in hepatocellular carcinoma (HCC). Among them, the correlation between LINC02298 and HCC remains unknown. The expression and subcellular localization of LINC02298 in HCC tissues and cell lines were detected by real-time quantitative polymerase chain reaction (RT-qPCR). Furthermore, the correlation between the expression of LINC02298 and clinicopathological features of HCC patients was analyzed. The regulatory effects of LINC02298 in HCC were investigated using colony formation, cell count Kit-8(CCK8), Transwell, EDU, cell cycle and apoptosis analysis. In addition, the expression of EMT-related proteins were detected by western blotting. Dual-luciferase reporter, RT-qPCR and rescue assays were employed to validate the involvement of the LINC02298/miR-28-5p/CCDC6 axis in the progression of HCC. The up-regulation of LINC02298 was observed in hepatocellular carcinoma (HCC) tissues and cells, and it was found to be correlated with a negative prognosis in patients with HCC. Overexpression of LINC02298 enhanced the proliferation, migration, invasion, and induction of Epithelial-Mesenchymal Transition (EMT) while suppressing apoptosis in HCC cells. LINC02298 bind to miR-28-5p to regulate the expression of CCDC6. Inhibition of miR-28-5p saved the inhibitory effect of shLINC02298, and knockdown of CCDC6 also saved the inhibitory effect of miR-28-5p on HCC in vitro and in vivo. LINC02298 regulates the expression of CCDC6 by sponging of miR-28-5p, thereby facilitating the the malignancy and EMT of HCC.

Wang J ，Xu B ，Liang L ，Chen Q ... -  《-》

GRHPR, Targeted by miR-138-5p, Inhibits the Proliferation and Metastasis of Hepatocellular Carcinoma Through PI3K/AKT Signaling Pathway.

Yang S ，Liu Y ，Zhang B ，Li J ，Xu F ，Yu M ，Chen Y ，Li C ，Liu T ，Zhao Y ，Zhao Q ，Zhang J ... -  《-》