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CPVL suppresses metastasis of nasopharyngeal carcinoma through inhibiting epithelial–mesenchymal transition

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Abstract

Purpose

Distant metastasis is the main obstacle to treating nasopharyngeal carcinoma (NPC). Tumor distance metastasis is a complex process involving the jointly participation of multiple oncogenes, tumor suppressor genes, and metastasis-associated genes. Enough accurate prognostic genes for evaluating metastasis risk are lacking. We aimed to identify more precise biomarkers for NPC metastasis.

Methods

We performed weighted gene co-expression network analysis, differentially expressed gene analysis, univariate and multivariate stepwise Cox regression, and Kaplan–Meier (K-M) survival analyses, on data obtained from RNA sequencing of 10 NPC samples and the public database, to identify key genes correlated with NPC metastasis. Wound healing assays, transwell assays, and immunohistochemistry were conducted to validate our bioinformatic conclusions. Western blotting was performed to evaluate and quantify the effect of identified EMT genes on epithelial–mesenchymal transition (EMT) of NPC.

Results

Combined our own RNA sequencing data and public data, we determined carboxypeptidase vitellogenic-like protein (CPVL) as a tumor suppressor for NPC. Pathway enrichment analyses indicated that genes associated with CPVL are involved in EMT. NPC with low CPVL expression had high tumor purity and low levels of immune cells. Experimental results showed that CPVL protein predominantly expressed in cytoplasmic and membranous and it exhibited higher expression levels in NPC tissues without distant metastasis than those with distant metastasis. CPVL inhibits the migration and invasive capability of NPC cells. Overexpression of CPVL upregulates E-cadherin and ZO-1, whereas it downregulates vimentin, suggesting that CPVL suppresses tumor metastasis by inhibiting EMT.

Conclusion

CPVL inhibits migration and invasion of NPC cells and is associated with tumor metastasis suppression through upregulating epithelial marker and inhibiting mesenchymal marker expression and could be a prognostic biomarker for metastasis risk evaluation in NPC.

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Data availability

The NPC dataset (GSE102349) can be downloaded from Gene Expression Omnibus (GEO) public database (https://www.ncbi.nlm.nih.gov/geo/).

Abbreviations

NPC:

Nasopharyngeal carcinoma

LR:

Local recurrence

DM:

Distant metastasis

PFS:

Progression-free survival

mRNA:

Messenger RNA

EMT:

Epithelial–mesenchymal transition

NPC-DM:

NPC with distant metastasis occurred within five years

NPC-NM:

NPC without tumor progression more than five years

STUMCCH:

Shantou University Medical College Cancer Hospital

GEO:

Gene Expression Omnibus

WGCNA:

Weighted gene correlation network analysis

Mes:

Module eigengenes

MM:

Module membership

GS:

Gene significance

DEGs:

Differentially expressed genes

GO:

Gene Ontology

KEGG:

Kyoto encyclopedia of genes and genomes pathways

MsigDB:

Molecular signatures database

TILs:

Tumor-infiltrating lymphocytes

TIICs:

Tumor-infiltrating immune cells

TME:

Tumor microenvironment

ROC:

Receiver operating characteristic

K-M:

Kaplan–Meier

DMFS:

Distant metastasis-free survival

AUC:

Area under curve

CPVL-L:

Low CPVL expression

CPVL-H:

High CPVL expression

IHC:

Immunohistochemistry

NC:

Negative control

GC:

Gastric cancer

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Acknowledgements

We sincerely appreciate the support of public data with GEO database and contribution from NPC patients received biopsy. This research was funded by Science and Technology Special Fund of Guangdong Province of China (190829105556145).

Funding

This research was funded by Science and Technology Special Fund of Guangdong Province of China (190829105556145).

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Author notes

  1. Xiao Wang and Linxin Chen contributed equally to this article.

Authors and Affiliations

  1. Department of Radiation Oncology, Cancer Hospital of Shantou University Medical College, 7 Raoping Road, Shantou, 515000, Guangdong, China

    Xiao Wang, Kaichun Huang, Yinbing Lin, Yingji Hong & Zhixiong Lin

  2. Eye Hospital, School of Ophthalmology and Optometry, School of Biomedical Engineering, State Key Laboratory of Ophthalmology, Optometry and Vision Science, Wenzhou Medical University, 270 Xuanyuanxi Road, Wenzhou, 325027, Zhejiang, China

    Linxin Chen

  3. Nasopharyngeal Carcinoma Research Center, Shantou University Medical College, Shantou University, 7 Raoping Road, Shantou, 515000, Guangdong, China

    Xiao Wang, Kaichun Huang, Yinbing Lin, Yingji Hong & Zhixiong Lin

  4. Shantou University Medical College, 22 Xinling Road, Shantou, 515000, Guangdong, China

    Xiao Wang & Yinbing Lin

Authors
  1. Xiao Wang
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  2. Linxin Chen
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  3. Kaichun Huang
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Contributions

All authors contributed to the study conception and design. XW contributed to conceptualization and visualization; KC and XW were involved in methodology and experiments design and implementation; KC and KH contributed to formal analysis; YL was involved in writing—original draft preparation; KC contributed to writing—review and editing; and YH and ZL were involved in supervision. All authors have read and agreed to the published version of the manuscript.

Corresponding authors

Correspondence to Yingji Hong or Zhixiong Lin.

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Conflict of interest

All authors state that there are no commercial interactions that may be considered as a possible conflict of interest during the study.

Ethical approval

This study received ethical approval from the ethics board of Shantou University Medical College Cancer Hospital (ethical approval number: 2022154). All adults provided written informed consent including written informed consent for genetic studies, while minors provided written assent, with written informed consent obtained from a parent.

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Wang, X., Chen, L., Huang, K. et al. CPVL suppresses metastasis of nasopharyngeal carcinoma through inhibiting epithelial–mesenchymal transition. J Cancer Res Clin Oncol 149, 16473–16488 (2023). https://doi.org/10.1007/s00432-023-05340-7

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