Dataset Information

MiR-552 Regulates Liver Tumor-Initiating Cell Expansion and Sorafenib Resistance.

ABSTRACT: MicroRNAs (miRNAs) are involved in tumorigenesis, progression, recurrence, and drug resistance of hepatocellular carcinoma (HCC). However, few miRNAs have been identified and entered clinical practice. Herein, we report that microRNA (miR)-552 is upregulated in HCC tissues and has an important function in liver tumor-initiating cells (T-ICs). Functional studies revealed that a forced expression of miR-552 promotes liver T-IC self-renewal and tumorigenesis. Conversely, miR-552 knockdown inhibits liver T-IC self-renewal and tumorigenesis. Mechanistically, miR-552 downregulates phosphatase and tensin homolog (PTEN) via its mRNA 3' UTR and activates protein kinase B (AKT) phosphorylation. Our clinical investigations elucidated the prognostic value of miR-552 in HCC patients. Furthermore, miR-552 expression determines the responses of hepatoma cells to sorafenib treatment. The analysis of patient cohorts and patient-derived xenografts (PDXs) further demonstrated that miR-552 may predict sorafenib benefits in HCC patients. In conclusion, our findings revealed the crucial role of the miR-552 in liver T-IC expansion and sorafenib response, rendering miR-552 an optimal target for the prevention and intervention in HCC.

SUBMITTER: Han T

PROVIDER: S-EPMC7015836 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

miR-552 Regulates Liver Tumor-Initiating Cell Expansion and Sorafenib Resistance.

Han Tao T Zhang Yue Y Yang Xiaodan X Han Lei L Li Hengyu H Chen Tingsong T Zheng Zhendong Z

Molecular therapy. Nucleic acids 20200115

MicroRNAs (miRNAs) are involved in tumorigenesis, progression, recurrence, and drug resistance of hepatocellular carcinoma (HCC). However, few miRNAs have been identified and entered clinical practice. Herein, we report that microRNA (miR)-552 is upregulated in HCC tissues and has an important function in liver tumor-initiating cells (T-ICs). Functional studies revealed that a forced expression of miR-552 promotes liver T-IC self-renewal and tumorigenesis. Conversely, miR-552 knockdown inhibits ...[more]

PMID: 32044726

Similar Datasets

Project description:OBJECTIVE: Sorafenib is effective in hepatocellular carcinoma (HCC), but patients ultimately present disease progression. Molecular mechanisms underlying acquired resistance are still unknown. Herein, we characterize the role of tumor-initiating cells (T-ICs) and signaling pathways involved in sorafenib resistance. DESIGN: HCC xenograft mice treated with sorafenib (n=22) were explored for responsiveness (n=5) and acquired resistance (n=17). Mechanism of acquired resistance were assessed by: 1) Role of T-ICs by in vitro sphere formation and in vivo tumorigenesis assays using NOD/SCID mice, 2) Activation of alternative signaling pathways and 3) Efficacy of anti-FGF and anti-IGF drugs in experimental models. Gene expression (microarray, qRT-PCR) and protein analyses (immunohistochemistry, western blot) were conducted. A novel gene signature of sorafenib resistance was generated and tested in 2 independent cohorts. RESULTS: Sorafenib-acquired resistance tumors showed significant enrichment of T-ICs (164 cells needed to create a tumor) vs. sorafenib-sensitive tumors (13400 cells) and non-treated tumors (1292 cells), p<0.001. Tumors with sorafenib-acquired resistance were enriched with IGF and FGF signaling cascades (FDR<0.05). In vitro, cells derived from sorafenib-acquired resistant tumors and two sorafenib-resistant HCC cell lines were responsive to IGF or FGF inhibition. In vivo, FGF blockade delayed tumor growth and improved survival in sorafenib-resistant tumors. A sorafenib-resistance 175-gene signature was characterized by enrichment of progenitor-cell features, aggressive tumoral traits and predicted poor survival in 2 cohorts (n=442 HCC patients). CONCLUSION: Acquired resistance to sorafenib is driven by tumor initiating cells with enrichment of progenitor markers and activation of IGF and FGF signaling. Inhibition of these pathways would benefit a subset of patients after sorafenib progression. Transcriptomic profile of subcutaneous Huh7 cells-derived tumors treated with sorafenib that developed acquired resistance to the drug (n=4), remain responsive to sorafenib (n=3) or were treated with brivanib after development of resistance (n=3). Gene profiling of hepatospheres generated from tumors with acquired resistance to sorafenib (n=3) and non-treated tumors (n=3) was also analyzed.

Project description:Dysregulation of miRNAs is a hallmark of cancer, modulating oncogenes, tumor suppressors, and drug responsiveness. The multi-kinase inhibitor sorafenib is one of the first-line drugs for advanced hepatocellular carcinoma (HCC), although the outcome for treated patients is heterogeneous. The identification of predictive biomarkers and targets of sorafenib efficacy are sorely needed. Thus, selected top upregulated miRNAs from the C19MC cluster were analyzed in different hepatoma cell lines compared to immortalized liver human cells, THLE-2 as control. MiR-518d-5p showed the most consistent upregulation among them. Thus, miR-518d-5p was measured in liver tumor/non-tumor samples of two distinct cohorts of HCC patients (n = 16 and n = 20, respectively). Circulating miR-518d-5p was measured in an independent cohort of HCC patients receiving sorafenib treatment (n = 100), where miR-518d-5p was analyzed in relation to treatment duration and patient's overall survival. In vitro and in vivo studies were performed in human hepatoma BCLC3 and Huh7 cells to analyze the effect of miR-518d-5p inhibition/overexpression during the response to sorafenib. Compared with healthy individuals, miR-518d-5p levels were higher in hepatic and serum samples from HCC patients (n = 16) and in an additional cohort of tumor/non-tumor paired samples (n = 20). MiR-518d-5p, through the inhibition of c-Jun and its mitochondrial target PUMA, desensitized human hepatoma cells and mouse xenograft to sorafenib-induced apoptosis. Finally, serum miR-518d-5p was assessed in 100 patients with HCC of different etiologies and BCLC-stage treated with sorafenib. In BCLC-C patients, higher serum miR-518d-5p at diagnosis was associated with shorter sorafenib treatment duration and survival. Hence, hepatic miR-518d-5p modulates sorafenib resistance in HCC through inhibition of c-Jun/PUMA-induced apoptosis. Circulating miR-518d-5p emerges as a potential lack of response biomarker to sorafenib in BCLC-C HCC patients.

Project description:HCC (hepatocellular carcinoma) is a major health threat for the Chinese population and has poor prognosis because of strong resistance to chemotherapy in patients. For instance, a considerable challenge for the treatment of HCC is sorafenib resistance. The aberrant glucose metabolism in cancer cells aerobic glycolysis is associated with resistance to chemotherapeutic agents. Drug-resistance cells and tumors were exposed to sorafenib to establish sorafenib-resistance cell lines and tumors. Western blotting and real-time PCR or IHC staining were used to analyze the level of CLCF1 in the sorafenib resistance cell lines or tumors. The aerobic glycolysis was analyzed by ECAR assay. The mechanism mediating the high expression of CLCF1 in sorafenib-resistant cells and its relationships with miR-130-5p was determined by bioinformatic analysis, dual luciferase reporter assays, real-time PCR, and western blotting. The in vivo effect was evaluated by xenografted with nude mice. The relation of CLCF1 and miR-30a-5p was determined in patients' samples. In this study, we report the relationship between sorafenib resistance and increased glycolysis in HCC cells. We also show the vital role of CLCF1 in promoting glycolysis by activating PI3K/AKT signaling and its downstream genes, thus participating in glycolysis in sorafenib-resistant HCC cells. Furthermore, we also show that miR-30a-5p directly targets CLCF1 and that sorafenib-mediated suppression of miR-30a-5p results in the upregulation of CLCF1 in HCC cells resistant to sorafenib. We also found that when a cholesterol modified agomiR-30a-5p was delivered systemically to mice harboring sorafenib-resistant HCC tumors, tumor growth decreased significantly. There is an uncharacterized mechanism of biochemical resistance to hormone therapies orchestrated by the miR-30a-5p/CLCF1 axis to mediate sorafenib resistance and aerobic glycolysis in HCC. Therefore, this study indicates that targeting the miR-30a-5p/CLCF1 axis may hold promise for therapeutic intervention in HCC sorafenib resistance patients.

Dataset Information

MiR-552 Regulates Liver Tumor-Initiating Cell Expansion and Sorafenib Resistance.

Publications

miR-552 Regulates Liver Tumor-Initiating Cell Expansion and Sorafenib Resistance.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets