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Suppression of exosomal hsa_circ_0001005 eliminates the Vemurafenib resistance of melanoma

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Abstract

Objectives

More and more evidences show that circular RNAs (circRNAs) can be used as miRNA sponge to regulate the drug resistance of malignancies, including melanoma. However, how exosomal circRNAs participate in the therapeutic resistance of melanoma remains ambiguous.

Methods

Vemurafenib-resistant A375 cells were cultured and then the circRNA profile of exosomes from the parental A375 and A375-resistant cells were sequenced. Transmission electron microscopy (TEM), exogenous nanoparticle tracking analysis (NTA) and Western Blot assays were leveraged to confirm the successful collection of exosomes from A375 and A375R cells. Another five published RNA-seq data and microRNA-seq data, and seven miRNA databases were collected to construct a competing endogenous RNA (ceRNA) network. Comprehensive bioinformatic analysis was adopted to identify key molecules related to the drug resistance, including multiscale embedded gene co-expression network analysis (MEGENA). Then, qRT-PCR, cell viability and colony formation were used to estimate the function of hub circRNAs. The role of has_circ_0001005 in vivo was verified via xenograft assay. The Tumor online Prognostic analyses Platform (ToPP) was leveraged to develop the has_circ_0001005-related prognostic models for melanoma patients based on TCGA data.

Results

Compared with parental cells, hsa_circ_0001005 expression was significantly increased in resistant cells and their exosomes. The elevated level of hsa_circ_0001005 was related to the poor clinical prognosis of melanoma patients. Hsa_circ_0001005 found in melanoma was mainly secreted by drug-resistant cells as exosomes. Exosomal hsa_circ_0001005 activated multiple canonical pathways related to drug resistance through sponging four miRNAs, thus suppressing the drug sensitivity of melanoma. Knocking down hsa_circ_0001005 in vitro, we found that the inhibition of hsa_circ_0001005 could hinder the clone formation of melanoma. Further in vivo animal experiments suggested that suppression of hsa_circ_0001005 can increase the sensitivity to Vemurafenib of melanoma cells. Finally, we also constructed the functional regulatory ceRNA network and prognostic risk models for hsa_circ_0001005, and further survival analysis reveals that the regulatory network and prognostic risk models obviously affected the prognosis of melanoma patients.

Conclusions

This study confirmed that the level of hsa_circ_0001005 in exosomes is the key factor affecting drug resistance of melanoma, which provides a new potential therapeutic target for melanoma patients.

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Data availability

All data related to the research are included in the article or uploaded as supplementary information. The raw data used to support the findings of this study are available from the corresponding authors upon reasonable request.

Abbreviations

GO:

Gene ontology

MF:

Molecular function

BP:

Biological process

CC:

Cellular component

MEGENA:

Multiscale embedded gene co-expression network analysis

KEGG:

Kyoto encyclopedia of genes

OS:

Overall survival

RNA-seq:

RNA sequencing

circRNA:

Circular RNA

TCGA:

The Cancer Genome Atlas

ToPP:

Tumor online Prognostic analyses Platform (http://www.biostatistics.online/topp/index.php)

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Funding

This study was funded by New Area Science and Technology Development Fund of Shanghai Pudong (No. PKJ2018-Y01).

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Authors and Affiliations

  1. Institute for Regenerative Medicine, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China

    Xicheng Wang

  2. Department of Dermatology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China

    Qiong Cheng

Authors
  1. Xicheng Wang
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  2. Qiong Cheng
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Contributions

WX analyzed the data and wrote the manuscript. QC designed and directed this project, completed biological experiments, exosome chip sequencing, and participated in the revision and editing of the manuscript.

Corresponding author

Correspondence to Qiong Cheng.

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The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Ethical approval

All animal procedures are approved by Shanghai East Hospital and conform to the policy of Animal Ethics Committee of Shanghai East Hospital on the care, welfare and treatment of experimental animals. All participants consented to participate in the research before participating.

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Wang, X., Cheng, Q. Suppression of exosomal hsa_circ_0001005 eliminates the Vemurafenib resistance of melanoma. J Cancer Res Clin Oncol 149, 5921–5936 (2023). https://doi.org/10.1007/s00432-022-04434-y

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