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Identification of cancer stem cell-related biomarkers in lung adenocarcinoma by stemness index and weighted correlation network analysis

  • Original Article – Cancer Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Background

Accounting for tumor heterogeneity, cancer stem cells (CSC) are involved in tumor metastasis, relapse, and drug resistance. Genes regulating CSC characteristics in lung adenocarcinoma (LUAD) were explored and validated in this study.

Methods

The mRNA stemness index (mRNAsi) of more than 500 LUAD cases from The Cancer Genome Atlas database were calculated using a one-class logistic regression machine learning algorithm based on the mRNA expression of pluripotent stem cells and their differentiated progeny. mRNAsi-related key genes were identified by weighted correlation network analysis. The expression levels and prognostic roles of key genes were analyzed in Oncomine, PrognoScan, and Kaplan–Meier plotter databases, and validated using data from our center.

Results

The mRNAsi was significantly higher in LUAD compared with normal lung tissues. LUAD patients of advanced stage exhibited a higher mRNAsi and worse overall survival (OS). Eight key genes were identified: heat shock 70 kDa protein 4 (HSPA4), cell division cycle associated 7 (CDCA7), cell division cycle 20 (CDC20), cyclin-dependent kinase 1 (CDK1), CAP-GLY domain containing linker protein 1 (CLIP1), cyclin B1 (CCNB1), H2A histone family, member X (H2AFX), and Bloom syndrome, RecQ helicase-like (BLM). These genes were differentially expressed in various types of malignancies and validated in the LUAD cases. LUAD patients with low expression of CDC20, CDK1, CCNB1, H2AFX, or BLM had a significantly better OS, whereas OS was reduced for patients with low expression of CLIP1. In addition, the expression of CDCA7 did not significantly impact the OS of LUAD patients. The protein–protein interaction networks evaluated by STRING demonstrated strong relationships between these key genes, which were validated in our cases.

Conclusions

The mRNAsi was significantly higher in LUAD compared with normal samples. Eight mRNAsi-related key genes were associated with prognosis and the cell cycle, and were strongly correlated with each other and differentially expressed in tumor and normal samples. We provide a new strategy for exploring stemness-related genes in LUAD cases.

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Abbreviations

LUAD:

Lung adenocarcinoma

CSC:

Cancer stem cells

mRNAsi:

MRNA expression-based-stemness index

OCLR:

One-class logistic regression

WGCNA:

Weighted correlation network analysis

TCGA:

The Cancer Genome Atlas database

OS:

Overall survival

DEGs:

Differentially expressed genes

GS:

Gene significance

MM:

Module membership

GO:

Gene Ontology analysis

KEGG:

Kyoto Encyclopedia of Genes and Genomes analysis

CDCA7:

Heat shock 70 kDa protein 4 (HSPA4), cell division cycle associated 7

CDC20:

Cell division cycle 20

CDK1:

Cyclin-dependent kinase 1

CLIP1:

CAP-GLY domain containing linker protein 1

CCNB1:

Cyclin B1

H2AFX:

H2A histone family, member X

BLM:

Bloom syndrome, RecQ helicase-like

TKI:

Tyrosine kinase inhibitor

NSCLC:

Resistance of non-small cell lung cancer

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Acknowledgements

We would like to thank International Science Editing Co. for the language editing service.

Funding

This work was supported by the National Natural Science Foundation of China (Grant No.: 81672268).

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Author notes

  1. Mengnan Zhao, Zhencong Chen and Yuansheng Zheng contributed equally to this work.

Authors and Affiliations

  1. Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Xuhui District, 180 Fenglin Road, Shanghai, 200032, China

    Mengnan Zhao, Zhencong Chen, Yuansheng Zheng, Jiaqi Liang, Zhengyang Hu, Yunyi Bian, Tian Jiang, Ming Li, Cheng Zhan, Mingxiang Feng & Qun Wang

  2. Eight-Year Program Clinical Medicine, Grade of 2014, Shanghai Medical College, Fudan University, Shanghai, 200032, China

    Ming Li

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  1. Mengnan Zhao
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  2. Zhencong Chen
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Corresponding authors

Correspondence to Cheng Zhan or Mingxiang Feng.

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Conflict of interest

The authors have no conflicts of interest to declare.

Ethics approval

This study was conducted with approval from the Ethics Committee of Zhongshan Hospital, Fudan University, Shanghai, China (Approval No. B2017-042).

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Written informed consent was obtained from all patients.

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Availability of data and material

The RNA-sequencing (RNA-seq) profiles and corresponding clinical phenotypes of human LUAD and normal lung samples were identified from the TCGA database (https://portal.gdc.cancer.gov).

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Zhao, M., Chen, Z., Zheng, Y. et al. Identification of cancer stem cell-related biomarkers in lung adenocarcinoma by stemness index and weighted correlation network analysis. J Cancer Res Clin Oncol 146, 1463–1472 (2020). https://doi.org/10.1007/s00432-020-03194-x

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  • DOI: https://doi.org/10.1007/s00432-020-03194-x

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