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微小RNA-338-3p通过靶向SOX4影响肝癌干细胞及乐伐替尼耐药特性。

miRNA-338-3p influences the liver cancer stem cells and lenvatinib resistance properties by targeting SOX4.

作者信息

Yuan Ying, Li Hui-Fen, Liu Zi-Mei, Yu Li-Ping

机构信息

Department of Oncology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111, Xianxia Road, Shanghai, 200336, China.

Department of Hepatic Surgery & Interventional Radiology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.

出版信息

Sci Rep. 2025 Jul 18;15(1):26137. doi: 10.1038/s41598-025-06805-0.

DOI:10.1038/s41598-025-06805-0
PMID:40681569
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12274585/
Abstract

Cancer stem cells (CSCs) are critical players in the pathogenesis of human-associated cancers. It is well established that the stemness of CSCs is modulated by microRNA (miRNA). In the current study, the miR-338-3p deficiency increased self-renewal and tumor malignancy in hepatic CSCs. Nevertheless, miR-338-3p overexpression suppresses tumorigenesis and self-renewal in liver CSCs. Mechanistically, miR-338-3p specifically targets SOX4 in liver CSCs. Moreover, miR-338-3p-associated downregulation of SOX4 prevents tumorigenesis and self-renewal in the CSCs of the liver. The miR-338-3p overexpression in hepatocellular carcinoma (HCC) cells was responsive to lenvatinib-induced apoptosis and cell progression inhibition. Patients' cohort shows that miR-338-3p may predict Lenvatinib benefits in HCC patients. Furthermore, by decreasing the miR-338-3p overexpression sensitivity to Lenvatinib-induced cell death in HCC cells, SOX4 may be a potential therapeutic candidate. In conclusion, miR-338-3p has a considerable function in liver CSC self-renewal and tumor development, making it a promising therapeutic target against HCC.

摘要

癌症干细胞（CSCs）是人类相关癌症发病机制中的关键参与者。众所周知，CSCs的干性受微小RNA（miRNA）调控。在本研究中，miR-338-3p缺陷增加了肝脏CSCs的自我更新能力和肿瘤恶性程度。然而，miR-338-3p过表达抑制了肝脏CSCs的肿瘤发生和自我更新。机制上，miR-338-3p在肝脏CSCs中特异性靶向SOX4。此外，miR-338-3p介导的SOX4下调可预防肝脏CSCs的肿瘤发生和自我更新。肝细胞癌（HCC）细胞中miR-338-3p过表达对乐伐替尼诱导的细胞凋亡和细胞进展抑制有反应。患者队列研究表明，miR-338-3p可能预测HCC患者对乐伐替尼的疗效。此外，通过降低HCC细胞中miR-338-3p过表达对乐伐替尼诱导的细胞死亡的敏感性，SOX4可能是一个潜在的治疗靶点。总之，miR-338-3p在肝脏CSC自我更新和肿瘤发展中具有重要作用，使其成为对抗HCC的有前景的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5bd/12274585/ce91b95076b9/41598_2025_6805_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5bd/12274585/521e66c12602/41598_2025_6805_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5bd/12274585/18c47173855b/41598_2025_6805_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5bd/12274585/ad9f9492f3ff/41598_2025_6805_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5bd/12274585/ec66618ec5ac/41598_2025_6805_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5bd/12274585/ce91b95076b9/41598_2025_6805_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5bd/12274585/521e66c12602/41598_2025_6805_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5bd/12274585/18c47173855b/41598_2025_6805_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5bd/12274585/ad9f9492f3ff/41598_2025_6805_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5bd/12274585/ec66618ec5ac/41598_2025_6805_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5bd/12274585/ce91b95076b9/41598_2025_6805_Fig5_HTML.jpg

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[1]
miRNA-338-3p influences the liver cancer stem cells and lenvatinib resistance properties by targeting SOX4.

Sci Rep. 2025-7-18

[2]
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[3]
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[4]
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[6]
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[7]
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[9]
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[10]
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本文引用的文献

[1]
N6-Methyladenosine-Mediated Up-Regulation of FZD10 Regulates Liver Cancer Stem Cells' Properties and Lenvatinib Resistance Through WNT/β-Catenin and Hippo Signaling Pathways.

Gastroenterology. 2023-5

[2]
miRNA-338-3p inhibits the migration, invasion and proliferation of human lung adenocarcinoma cells by targeting MAP3K2.

Aging (Albany NY). 2022-8-3

[3]
Downregulation of MUC15 by miR-183-5p.1 promotes liver tumor-initiating cells properties and tumorigenesis via regulating c-MET/PI3K/AKT/SOX2 axis.

Cell Death Dis. 2022-3-2

[4]
Lenvatinib Plus Immune Checkpoint Inhibitors Improve Survival in Advanced Hepatocellular Carcinoma: A Retrospective Study.

Front Oncol. 2021-11-16

[5]
miRNA-338-3p inhibits glioma cell proliferation and progression by targeting MYT1L.

Brain Res Bull. 2022-2

[6]
Nonalcoholic steatohepatitis in hepatocarcinoma: new insights about its prognostic role in patients treated with lenvatinib.

ESMO Open. 2021-12

[7]
Higher intake of whole grains and dietary fiber are associated with lower risk of liver cancer and chronic liver disease mortality.

Nat Commun. 2021-11-4

[8]
Fasting-mimicking diet blocks triple-negative breast cancer and cancer stem cell escape.

Cell Metab. 2021-11-2

[9]
MiRNA-146a/AKT/β-Catenin Activation Regulates Cancer Stem Cell Phenotype in Oral Squamous Cell Carcinoma by Targeting CD24.

Front Oncol. 2021-10-12

[10]
Circulating miR-181 is a prognostic biomarker for amyotrophic lateral sclerosis.

Nat Neurosci. 2021-11

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