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miR-4739 promotes epithelial-mesenchymal transition and angiogenesis in “driver gene-negative” non-small cell lung cancer via activating the Wnt/β-catenin signaling

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Abstract

Purpose

“Driver gene-negative” non-small cell lung cancer (NSCLC) currently has no approved targeted drug, due to the lack of common actionable driver molecules. Even though miRNAs play crucial roles in various malignancies, their roles in “driver gene-negative” NSCLC keep unclear.

Methods

miRNA expression microarrays were utilized to screen miRNAs associated with “driver gene-negative” NSCLC malignant progression. Quantitative real-time PCR (RT-qPCR) and in situ hybridization (ISH) were employed to validate the expression of miR-4739, and its correlation with clinicopathological characteristics was analyzed in tumor specimens using univariate and multivariate analyses. The biological functions and underlying mechanisms of miR-4739 were investigated both in vitro and in vivo.

Results

our research demonstrated, for the first time, that miR-4739 was substantially increased in “driver gene-negative” NSCLC tumor tissues and cell lines, and overexpression of miR-4739 was related to clinical staging, metastasis, and unfavorable outcomes. Functional experiments discovered that miR-4739 dramatically enhanced tumor cell proliferation, migration, and metastasis by promoting the epithelial-to-mesenchymal transition (EMT). Meanwhile, miR-4739 can be transported from cancer cells to the site of vascular epithelial cells through exosomes, consequently facilitating the proliferation and migration of vascular epithelial cells and inducing angiogenesis. Mechanistically, miR-4739 can activate Wnt/β-catenin signaling both in tumor cells and vascular epithelial cells by targeting Wnt/β-catenin signaling antagonists APC2 and DKK3, respectively.

Conclusion

Our work identifies a valuable oncogene, miR-4739, that accelerates malignant progression in “driver gene-negative” NSCLC and serves as a potential therapeutic target for this group of tumors.

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Data availability

All data sets generated during the study are available in the main text or supplementary materials. The raw data of miRNA and mRNA microarray were uploaded to the Gene Expression Omnibus (GEO) Database (GSE229301 and GSE229302, respectively). The data that support the findings of our study are available on request from the corresponding author (Neng Jiang).

Abbreviations

EMT:

epithelial-mesenchymal transition

NSCLC:

non-small cell lung cancer

ICIs:

immune checkpoint inhibitors

CTLA-4:

cytotoxic T-lymphocyte antigen 4

PD-1:

programmed cell death protein 1

PDL-1:

programmed cell death 1 ligand 1

FBS:

fetal bovine serum

NGS:

next-generation sequencing

HUVECs:

human umbilical vein endothelial cells

TVs:

tumor volumes

SD:

standard deviation

OS:

overall survival

CCK8:

cell Counting Kit-8

GSEA:

Gene Set Enrichment Analysis

MVD:

microvessel density

ISH:

in situ hybridization

IHC:

immunohistochemistry

IF:

immunofluorescence

EdU:

5-Ethynyl-2′-deoxyuridine

WB:

western blotting

RT-qPCR:

reverse transcription‑quantitative PCR

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Acknowledgements

We want to thank the State Key Laboratory of Oncology in South China (Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China) for providing guidance and technical assistance in the study.

Funding

This research was supported by the National Nature Science Foundation of China (Nos. 82103271) and the Guangdong Basic and Applied Basic Research Foundation (Nos. 2023A04J2126).

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Authors and Affiliations

  1. State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China

    Wenjian Cen, Qin Yan, Minjie Mao, Qitao Huang, Yaobin Lin & Neng Jiang

  2. Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China

    Wenjian Cen

  3. Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, P. R. China

    Qin Yan, Qitao Huang & Neng Jiang

  4. Department of Gastroenterology and Hepatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, P. R. China

    Wenpeng Zhou

  5. Department of Laboratory Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China

    Minjie Mao

  6. Department of Thoracic Surgery, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, P. R. China

    Yaobin Lin

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  1. Wenjian Cen
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  2. Qin Yan
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  3. Wenpeng Zhou
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Contributions

N.J. and Y. L. designed the manuscript, analyzed the data, and wrote the manuscript. Y.L., W.C., W.Z., Q.Y., M.M., Y.S., and Q.H. collected patient samples, performed experiments, and analyzed the data. N.J. provided financial support. All authors read and approved the manuscript.

Corresponding authors

Correspondence to Yaobin Lin or Neng Jiang.

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Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

All research adhered to the tenets of the Declaration of Helsinki. The Ethics Committee of Sun Yat-Sen University Cancer Center approved this study.

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Patients signed informed consent regarding publishing their data and photographs.

Informed consent

Informed consent was obtained from all subjects involved in the study.

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Wenjian Cen, Qin Yan and Wenpeng Zhou have contributed equally to this work.

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Cen, W., Yan, Q., Zhou, W. et al. miR-4739 promotes epithelial-mesenchymal transition and angiogenesis in “driver gene-negative” non-small cell lung cancer via activating the Wnt/β-catenin signaling. Cell Oncol. 46, 1821–1835 (2023). https://doi.org/10.1007/s13402-023-00848-z

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