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SHF confers radioresistance in colorectal cancer by the regulation of mitochondrial DNA copy number

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Abstract

Altered mitochondrial function contributes greatly to pathogenesis and progression of colorectal cancer. In this study, we report a functional pool of Src homology 2 domain-containing F (SHF) in mitochondria controlling the response of colorectal cancer cells to radiation therapy. We found that elevated expression of SHF in cancer cells is essential for promoting mitochondrial function by increasing mitochondrial DNA copy number, thus reducing the sensitivity of colorectal cancer cells to radiation. Mechanistically, SHF binds to mitochondrial DNA and promotes POLG/SSBP1-mediated mitochondrial DNA synthesis. Importantly, SHF loss-mediated radiosensitization was phenocopied by depletion of mitochondrial DNA. Thus, our data demonstrate that mitochondrial SHF is an important regulator of radioresistance in colorectal cancer cells, identifying SHF as a promising therapeutic target to enhance radiotherapy efficacy in colorectal cancer.

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Data availability

CRC transcriptome sequencing data and corresponding clinical data set were downloaded from TCGA (https://cancergenome.nih.gov, TCGA-COAD and TCGA-READ).

Abbreviations

CRC:

Colorectal cancer

TCGA:

The Cancer Genome Atlas

OCR:

Oxygen consumption rate

ECAR:

Extracellular acidification rate

MTS:

Mitochondrial targeting signal

NLS:

Nuclear localization sequence

SRB:

Sulforhodamine B

3’ UTR:

3′ Untranslated region

EV:

Empty vector

ddC:

2′,3′-Dideoxycytidine

PDO:

Patient-derived organoid

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Acknowledgements

We thank the TCGA Research Network for providing its platforms and valuable datasets.

Funding

This present study was funded by a grant from the Young Scientists Fund of the National Natural Science Foundation of China (Grant No. 82203425) and a grant from Shandong Province major science and technology innovation project (Grant no. 2019JZZY011008).

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Authors and Affiliations

  1. Gastrointestinal Surgery Ward II, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China

    Zhenyu Zhu, Weipeng Gong, Bishi Wang, Changhao Li, Qingsheng Hou, Hongliang Guo & Jie Guan

  2. Thoracic Surgery Ward II, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China

    Meihua Gong

  3. Gastrointestinal Surgery Ward I, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China

    Jie Chai

  4. Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China

    Yanhan Jia

  5. Radiation Oncology Key Laboratory of Sichuan Province, Chengdu, China

    Yanhan Jia

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  1. Zhenyu Zhu
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  2. Meihua Gong
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Contributions

ZZ, GM, GH, CJ, GJ, and JY were responsible for the concept and design of the original study. ZZ, GM, GH, GJ, and JY analyzed data and illustrated the figures for the manuscript. ZZ, GM, GW, WB, LC, and HQ performed the experiment. ZZ, GM, CJ, GJ, and JY wrote the paper with input from all authors. All authors contributed to the article and approved the submitted version.

Corresponding authors

Correspondence to Jie Guan or Yanhan Jia.

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The authors declare no competing interests.

Ethical approval and consent to participate

The tissue samples from patients used for the generation of organoids were approved by the ethical review committee of Shandong Cancer Hospital and Institute.

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Zhenyu Zhu and Meihua Gong have contributed equally to this work and share first authorship.

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Zhu, Z., Gong, M., Gong, W. et al. SHF confers radioresistance in colorectal cancer by the regulation of mitochondrial DNA copy number. Clin Exp Med 23, 2457–2471 (2023). https://doi.org/10.1007/s10238-022-00969-z

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