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Novel exosomal miR-46146 transfer oxaliplatin chemoresistance in colorectal cancer

  • Y. Xu
  • M. ZhuEmail author
Research Article
  • 55 Downloads

Abstract

Purpose

Oxaliplatin (OX) is widely used for patients with advanced colorectal cancer (CRC). However, most of them will turn out to be OX resistant. Therefore, it is necessary to uncover the causes underlying this phenomenon.

Methods

Emerging works have reported that exosomal miRNAs are linked to chemoresistance in many types of cancer. Hence, we separated exosomes from OX sensitive (Exo-S) and resistant CRC cells (Exo-R) by ultracentrifugation and characterized those exosomes by transmission electron microscope and Nanosight NS300. The differentiated miRNAs between Exo-S and Exo-R were identified by small RNA deep sequencing. The expression of miRNA was examined by quantitative real-time PCR (qRT-PCR). The effect of Exo-R and exosomal miR-46146 was determined by CCK-8 assay and flow cytometry (FCM). The target gene of miR-46146 was predicted by computational algorithms and validated by dual luciferase assay.

Results

We found that parental OX sensitive CRC cell acquired increased resistance to the cytotoxicity of OX when they were cocultured with exosomes secreted by OX-resistant CRC. Notably, a novel miRNA miR-46146 was identified and proved to be upregulated in the Exo-R which was internalized by its recipient cells and contributes to the chemoresistance transfer. Furthermore, we demonstrated that PDCD10 was the direct functional target of miR46146 and augmentation of the PDCD10 expression might reverse the effect of Exo-miR-46146-driven chemoresistance.

Conclusions

These results indicate that exosomal miR-46146 functions as a vital mediator of OX resistance by targeting PDCD10 and could be a potential target to re-sensitize CRC cell to OX.

Keywords

Colorectal cancer Chemoresistance miR-46146 Exosomes 

Abbreviations

CRC

Colorectal cancer

OX

Oxaliplatin

miRNAs

MicroRNAs

Exo

Exosomes

HCT116R

Oxaliplatin-resistant HCT116 cells

HT29R

Oxaliplatin-resistant HT29 cells

Exo-S

Exosome from oxaliplatin-sensitive CRC cells

Exo-R

Exosome from oxaliplatin-resistant CRC cells

FCM

Flow cytometry

PI

Propidium iodide

qRT-PCR

Quantitative real-time PCR

TEM

Transmission electron microscope

PDCD10

Programmed cell death 10

UTRs

Untranslated regions

CCM3

Cerebral cavernous malformation 3

NSCLC

Non-small cell lung cancer

Notes

Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (81602126, 81601843), China Postdoctoral Science Foundation Grant (2018M640464), and the young talents program of Jiangsu Cancer Hospital (QL201805).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This work is not a research involving human participants and/or animals.

Informed consent

None.

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Copyright information

© Federación de Sociedades Españolas de Oncología (FESEO) 2019

Authors and Affiliations

  1. 1.Department of Gastroenterology, Nanjing First HospitalNanjing Medical UniversityNanjingChina
  2. 2.Department of Clinical LaboratoryJiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical UniversityNanjingChina

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