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The ATO/miRNA-885-5p/MTPN axis induces reversal of drug-resistance in cholangiocarcinoma

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Abstract

Purpose

Cholangiocarcinoma (CCA) is the second most malignant tumor of the hepatobiliary system. Due to its cumbersome early diagnosis and rapid progression, chemotherapy has become the main treatment option. Primary drug resistance is a major cause of the poor efficacy of chemotherapeutic drugs. Therefore, it is considered urgent to explore new drugs to overcome primary drug resistance of CCA.

Methods

Western blot and qRT-PCR assays were used to assess the expression of myotrophin (MTPN) and microRNA-885-5p (miR-885-5p) in CCA tissues and cells. The viability of CCA cells treated with arsenic trioxide (ATO), 5-fluorouracil (5-Fu) and cisplatin (CDDP) was analyzed using a CCK-8 assay. A luciferase reporter assay was used to assess the interaction between miR-885-5p and MTPN. Kaplan-Meier analyses were used for survival assessments.

Result

We found that ATO can reduce the resistance of CCA cells to 5-Fu and CDDP and promote the killing effect of 5-Fu and CDDP. Low-dose ATO showed an anti-drug-resistance effect through up-regulation of the expression of miR-885-5p. Combined with sequencing results and database predictions, we found that MTPN may serve as a direct target of miR-885-5p. After MTPN knockdown, the sensitivity of CCA cells to 5-FU and CDDP was increased. Finally, we found that ATO can reverse chemotherapy resistance induced by overexpression of MTPN.

Conclusion

Our data indicate that the ATO/miR-885-5p/MTPN axis may serve as a target for improving the sensitivity of CCA cells to chemotherapy.

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Data availability

Not applicable.

Abbreviations

5–:

Fu

5–:

Fluorouracil

ATO:

arsenic trioxide.

CCA:

cholangiocarcinoma.

CDDP:

cisplatin.

miRNAs:

microRNAs.

MTPN:

myotrophin.

ROS:

reactive oxygen species.

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Funding

This work was supported by National 13th Five-Year key Research & Development plan precision medical project subproject (2017YFC 0908304) and the Key Medical Talents of Jiangsu Province.

Author information

Author notes

  1. Yuting Wang, Wen Zhang, Lin Chen, Wei Chen and Shufen Xu contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Center for Digestive Diseases, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, 211166, China

    Yuting Wang, Wen Zhang, Lingyu Tang, Yang Yang, Quanpeng Li & Lin Miao

  2. Department of Gastroenterology, Dongtai People’s Hospital, Yan Chen, 224000, Jiangsu, China

    Lin Chen, Wei Chen & Qi Jiang

  3. Department of Oncology, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, 211166, China

    Shufen Xu

  4. Department of Digestive Diseases Kizilsu Kirghiz, The People’s Hospital of Kizilsu Kirghiz Autonomous Prefecture, Kizilsu Kirghiz, 845350, China

    Quanpeng Li

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  1. Yuting Wang
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Contributions

LM, QL and QJ conceived the research. YW and QL drafted the manuscript. LM, QL and QJ critically reviewed and revised the manuscript. YW, WZ, LC and SX performed the experiments. LT and YY collected the clinical samples and analyzed the data. All authors have read and approved the final version of the manuscript.

Corresponding authors

Correspondence to Quanpeng Li, Qi Jiang or Lin Miao.

Ethics declarations

Ethics approval and consent to participate

This study has been conducted in accordance with ethical standards and according to the Declaration of Helsinki and national and international guidelines, and has been approved by the authors’ institutional review board. The study protocol was approved by the Medical Ethics Committee of Nanjing Medical University.

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Supplementary Information

Fig. S1

The filter of miRNAs: (A) Heatmap of differentially expressed microRNAs (B): Six microRNAs were selected as the detection target of cells and tissues according to the difference multiple.) (PNG 86 kb)

High Resolution (TIF 108 kb)

Fig. S2

The filtered mRNAs (PNG 82 kb)

High Resolution (TIF 123 kb)

Fig. S3

IC50 of the cells transfected with miR-196a-5p inhibitor or not: ((A) RBE and HCCC-9810 were transfected by scrambled or miR-196a-5p inhibitor, IC50 of 5-FU (top) or CDDP (bottom) in them were analyzed.) (PNG 157 kb)

High Resolution (TIF 185 kb)

Fig. S4

The effect of MTPN siRNAs (PNG 52 kb)

High Resolution (TIF 70 kb)

Fig. S5

The primers. (The samples of TCGA were available from: https://www.cancer.gov/about-nci/organization/ccg/research/structural-genomics/tcga) (PNG 20 kb)

High Resolution (TIF 43 kb)

Table S1

The CCA tissue patient group and characteristics. (PNG 20 kb)

High Resolution (TIF 786 kb)

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Wang, Y., Zhang, W., Chen, L. et al. The ATO/miRNA-885-5p/MTPN axis induces reversal of drug-resistance in cholangiocarcinoma. Cell Oncol. 44, 907–916 (2021). https://doi.org/10.1007/s13402-021-00610-3

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