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Novel insights into tumorigenesis and prognosis of endometrial cancer through systematic investigation and validation on mitophagy-related signature

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Abstract

In-depth studies on the pathogenesis of endometrial cancer (EC) are critical because of the increasing global incidence of EC. Mitophagy, a mitochondrial quality control process, plays an important role in carcinogenesis and tumor progression. This study aimed to develop a novel mitophagy-based signature to predict the tumorigenesis and prognosis of EC. Data was downloaded from The Cancer Genome Atlas and Gene Expression Omnibus databases, and 29 mitophagy-related genes were downloaded from the Pathway Unification Database. EC patients were classified into two risk groups based on the two-key- gene signature, TOMM40 and MFN1, which were constructed using Cox regression analysis. A better prognosis was noted in the low-risk group. The model was validated for four aspects: clinical features, mutation status, clinical therapeutic response, and immune cell infiltration status. Moreover, according to the contribution to the risk model, TOMM40 was selected for further in vitro experiments. The silencing of TOMM40 inhibited mitochondrial degradation; suppressed cell proliferation; induced cell apoptosis and G1 phase cell cycle arrest; inhibited migration, invasion, and epithelial-mesenchymal transition; and suppressed cell stemness. In conclusion, the mitophagy-related risk score provides a novel perspective for survival and drug selection during the individual treatment of EC patients. TOMM40 serves as an oncogene in EC and promotes tumor progression via a mitophagy-related pathway. Thus, TOMM40 is a potential therapeutic target in EC.

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Data availability

Data generated or analyzed during this study are included in this published article [and its supplementary information files]. Additional data and materials of the study can be obtained from the corresponding authors.

Abbreviations

EC:

Endometrial cancer

MSI-H:

Microsatellite instability hypermutated

CNL:

Copy-number-low

CNH:

Copy-number-high

BNIP3:

Adenovirus E1B 19-kDa interacting protein 3

TCGA:

The cancer genome atlas

TME:

Tumor microenvironment

FPKM:

Fragments per kilobase of transcript per million mapped reads

TPM:

Transcripts per kilobase million

GEO:

Gene expression omnibus

AIC:

Akaike information criterion

MRGs:

Mitophagy-related genes

ROC:

Receiver operating characteristic

IHC:

Immunohistochemistry

mRNAsi:

MRNA expression-based stemness index

OCLR:

One-class logistic regression machine learning algorithm

IC50:

Half-maximal inhibitory concentration

GDSC:

Genomics of drug sensitivity in cancer

RSI:

Radiosensitivity index

ICIs:

Immune-checkpoint inhibitors

IPS:

Immunophenoscore

PMSF:

Phenylmethanesulfonyl fluoride

BCA:

Bicinchoninic acid

siRNA:

Small interfering RNA

RT-qPCR:

Real-time quantitative polymerase chain reaction

CCK8:

Cell counting kit8

OD:

Optical density

SD:

Standard deviation

MFN1:

Mitochondrial fusion protein mitofusin-1

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Funding

The research was supported by the National Natural Science Foundation of China (NSFC:81772778).

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Author notes

  1. Rui Sun and Xiaoyu Zhou have contributed equally to this work and share first authorship.

  2. Chunping Qiu and Jie Jiang have contributed equally to this work and share corresponding authorship.

Authors and Affiliations

  1. Department of Gynecology and Obstetrics, Qilu Hospital of Shandong University, Jinan, China

    Rui Sun, Xiaoyu Zhou, Tong Wang, Yao Liu, Lina Wei, Ziyi Qiu, Chunping Qiu & Jie Jiang

  2. Gynecologic Oncology Key Laboratory of Shandong Province, Qilu Hospital of Shandong University, Jinan, 250012, China

    Rui Sun, Xiaoyu Zhou, Tong Wang, Yao Liu, Lina Wei, Ziyi Qiu, Chunping Qiu & Jie Jiang

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Contributions

JJ and RS designed the study. RS mainly completed public database data analysis and experimental operations. CPQ and XYZ performed data analysis and drafted the manuscript. TW and YL contributed to data collection and interpretation. LNW and ZYQ oversee data quality. All authors contributed to the revision of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Chunping Qiu or Jie Jiang.

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Public data was obtained from the TCGA and GEO databases in accordance with the database policy. Institutional review board approval and informed consent were not required.

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Sun, R., Zhou, X., Wang, T. et al. Novel insights into tumorigenesis and prognosis of endometrial cancer through systematic investigation and validation on mitophagy-related signature. Human Cell 36, 1548–1563 (2023). https://doi.org/10.1007/s13577-023-00920-8

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