Downregulation of MUC15 by miR-183-5p.1 promotes liver tumor-initiating cells properties and tumorigenesis via regulating c-MET/PI3K/AKT/SOX2 axis

Han, Tao; Zheng, Hao; Zhang, Jin; Yang, Pinghua; Li, Hengyu; Cheng, Zhangjun; Xiang, Di; Wang, Ruoyu

doi:10.1038/s41419-022-04652-9

Cited by 26 publications

(9 citation statements)

References 38 publications

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“…MUC15 inhibits hepatoma cell self-renewal, malignant proliferation, tumorigenicity, and chemoresistance by interacting with c-Met and subsequently inactivating the PI3K/AKT/SOX2 signaling pathway. The MUC15/c-Met/PI3K/AKT/SOX2 axis determines the responses of hepatoma cells to lenvatinib treatment, as supported by the observation that MUC15 overexpression abrogates lenvatinib resistance [ 160 ]. In addition, miR-552 promotes the proliferation and metastasis of cervical cancer cells by targeting the MUC15 pathway [ 161 ].…”

Section: Genes Associated With Lenvatinib Resistancementioning

confidence: 99%

Evaluation and Application of Drug Resistance by Biomarkers in the Clinical Treatment of Liver Cancer

Huang

Wang

et al. 2023

Cells

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Liver cancer is one of the most lethal cancers in the world, mainly owing to the lack of effective means for early monitoring and treatment. Accordingly, there is considerable research interest in various clinically applicable methods for addressing these unmet needs. At present, the most commonly used biomarker for the early diagnosis of liver cancer is alpha-fetoprotein (AFP), but AFP is sensitive to interference from other factors and cannot really be used as the basis for determining liver cancer. Treatment options in addition to liver surgery (resection, transplantation) include radiation therapy, chemotherapy, and targeted therapy. However, even more expensive targeted drug therapies have a limited impact on the clinical outcome of liver cancer. One of the big reasons is the rapid emergence of drug resistance. Therefore, in addition to finding effective biomarkers for early diagnosis, an important focus of current discussions is on how to effectively adjust and select drug strategies and guidelines for the treatment of liver cancer patients. In this review, we bring this thought process to the drug resistance problem faced by different treatment strategies, approaching it from the perspective of gene expression and molecular biology and the possibility of finding effective solutions.

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Section: Genes Associated With Lenvatinib Resistancementioning

confidence: 99%

Evaluation and Application of Drug Resistance by Biomarkers in the Clinical Treatment of Liver Cancer

Huang

Wang

et al. 2023

Cells

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“…The response of carcinoma cells to lenvatinib is governed by the MUC15/c-MET/PI3K/AKT/SOX2 axis, and MUC15 overexpression can overcome lenvatinib resistance. 77 Takehara et al found in 2020 that long-term exposure to lenvatinib decreases the expression of fibroblast growth factor 19 (FGF19) in HCC cells but that re-expression of FGF19 can increase sensitivity to lenvatinib. ST6 Beta-Galactoside Alpha-2,6-Sialyltransferase 1 (ST6GAL1) is a tumor-derived secretory protein that is positively controlled by FGF19, according to proteomic and secretome studies.…”

Section: Regulation In Cell Signaling Pathwaysmentioning

confidence: 99%

“…Researchers discovered that miR-183-5p.1 specifically targets the 3'-UTR of the unique protein MUC15 in liver tumorinitiating cells (T-ICs) and that the MUC15/c-MET/PI3K/AKT/SOX2 axis controls the responses of hepatoma cells to lenvatinib treatment. 77 In lenvatinib-resistant cells, Sun et al demonstrated that miR-128-3p strongly inhibits the regulation of c-Met. Lenvatinib resistance is caused by miR-128-3p and c-Met, which control the progression of the ERK cell cycle and the AKT apoptotic pathway.…”

Section: Noncoding Rna Regulationmentioning

confidence: 99%

Application and Resistance Mechanisms of Lenvatinib in Patients with Advanced Hepatocellular Carcinoma

Tao¹,

Shi²,

Liao³

et al. 2023

JHC

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Lenvatinib, a multitargeted tyrosine kinase inhibitor (TKI), is one of the preferred targeted drugs for the treatment of advanced hepatocellular carcinoma (aHCC). Since the REFLECT study showed that lenvatinib was noninferior to sorafenib in overall survival (OS), lenvatinib monotherapy has been widely used for aHCC. Moreover, lenvatinib combination therapy, especially lenvatinib combined with immune checkpoint inhibitors (ICIs), has shown more encouraging clinical results. However, drug development and comprehensive treatment have not significantly improved the prognosis, and lenvatinib resistance is often encountered in treatment. The underlying molecular mechanism of lenvatinib resistance is still unclear, and studies to solve drug resistance are ongoing. The molecular mechanisms of lenvatinib resistance in patients with aHCC include the regulation of signaling pathways, the regulation of noncoding RNAs, the impact of the immune microenvironment, tumor stem cell activation and other mechanisms. This review aims to (1) summarize the progress of lenvatinib in treating aHCC, (2) delineate the known lenvatinib resistance mechanisms of current therapy, and (3) describe the development of therapeutic methods intended to overcome these resistance mechanisms.

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“…miR-125b-5p was upregulated in HCC with SOR, and the 50% inhibitory concentration (IC50) of SOR in HCC was signi cantly increased after overexpression of miR-25b-5p, indicating that miR-125b-5p can promote the HCC to SOR [10] . Not only that, miR-183-5p has been identi ed as a potential oncogene associated with various processes, including proliferation, apoptosis, and metastasis, especially resistance [11,12] . Recent studies indicate that elevated miR-183-5p expression levels correlate with poor survival in HCC patients [12] .…”

Section: Introductionmentioning

confidence: 99%

miR-183-5p attenuates the effect of sorafenib on human hepatocellular carcinoma via inhibiting SOCS6/JAK2/STAT3 pathway

Chen,

Zhao,

Song

et al. 2024

Preprint

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Objective: MicroRNA plays a crucial role in the progression of hepatocellular carcinoma (HCC) and the resistance of HCC cells to sorafenib (SOR). Elevation of miR-183-5p is associated with poor survival among patients with HCC. This study aimed to investigate the impact of miR-183-5p on SOR resistance in HCC as well as its related signaling pathway. The objective is to provide new insights, directions, and a theoretical basis for the clinical diagnosis and treatment of HCC. Design: Human normal hepatocytes (LO2) and HCC cell lines (HepG2, Huh7, and MHCC97H) were cultured, and were constructed with miR-183-5p inhibition and SOCS6 overexpression. Biotrust analysis and qRT-PCR were employed to assess the expression of miR-183-5p in liver cancer tissues or cells, respectively. Flow cytometry determined apoptosis rate in each group of cells, while CCK was used for detecting the 50% inhibitory concentration (IC50) of HCC followed SOR treatment. Western blotting was used to detect protein expression changes of SOCS6, p-JAK2, JAK2, p-STAT3, and STAT3. Results: Bioinformatics revealed significantly high expression of miR-183-5p in liver cancer compared to normal tissues. Consistent with this analysis, the expression of miR-183-5p was upregulated in human HCC cell lines, in order of Huh7, HepG2, and MHCC97H, compared to that of non-HCC cells. CCK-8 assays results shown that the IC50 value of sorafenib in Huh7 cells with higher expression levels of miR-183-5p were more high than Hep3B and MHCC97H cells with the relative lower expression levels of miR-183-5p. SOCS6 was elevated with the miR-183-5p inhibition compared to the control. Furthermore, the IC50 value of sorafenib was significantly decreased following miR-183-5p inhibition and increased in the miR-183-5p overexpression compared to the mock treatment. Conversely, the IC50 value of sorafenib in the SOCS6 overexpression group was significantly decreased compared to the control. Conclusions: Dysregulation of the miR-183-5p-SOCS6/JAK2/STAT3 axis plays a critical role in patients' responses to SOR treatment. Manipulation of this axis could potentially enhance the survival of patients with HCC, especially in the context of addressing drug resistance.

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Downregulation of MUC15 by miR-183-5p.1 promotes liver tumor-initiating cells properties and tumorigenesis via regulating c-MET/PI3K/AKT/SOX2 axis

Cited by 26 publications

References 38 publications

Evaluation and Application of Drug Resistance by Biomarkers in the Clinical Treatment of Liver Cancer

Evaluation and Application of Drug Resistance by Biomarkers in the Clinical Treatment of Liver Cancer

Application and Resistance Mechanisms of Lenvatinib in Patients with Advanced Hepatocellular Carcinoma

miR-183-5p attenuates the effect of sorafenib on human hepatocellular carcinoma via inhibiting SOCS6/JAK2/STAT3 pathway

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