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Molecular Characterization of Cuproptosis-related lncRNAs: Defining Molecular Subtypes and a Prognostic Signature of Ovarian Cancer

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Abstract

Cuproptosis, a newly discovered form of programmed cell death, relies on mitochondrial respiration, the chain of which has been found to be altered in ovarian cancer (OC). The current work probed into the effects of Cuproptosis on the prognosis, immune microenvironment and therapeutic response of OC based on Cuproptosis-related lncRNAs. Data on OC gene expression and clinical characteristics were collected from TCGA, ICGC and GEO databases, and mRNA and lncRNA were distinguished. Cuproptosis-related lncRNAs were screened for consensus clustering analysis. Differentially expressed lncRNAs (DElncRNAs) were identified between clusters, and least absolute shrinkage and selection operator (LASSO) and Cox regression analysis were performed to establish a prognostic signature. Its potential value in OC was evaluated by Gene Set Enrichment Analysis (GSEA), tumor cell mutation and immune microenvironment analysis, and response to immunotherapy and antineoplastic drugs. According to the classification scheme of Cuproptosis-related lncRNAs, OC was divided into four molecular subtypes, which were different in survival time, immune characteristics and somatic mutation. The prognostic signature between subtypes included 10 lncRNAs, which were significantly correlated with the prognosis, immune microenvironment related indexes, the expression of immune checkpoint molecules and the sensitivity of antineoplastic drug Paclitaxel and Gefitinib of OC. We examined the expression of ten LncRNAs in OC cell lines and found that LINC00189, ZFHX4-AS1, RPS6KA2-IT1 and C9orf106 were expressed elevated in OC cell lines, and LINC00861, LINC00582, DEPDC1-AS1, LINC01556, LEMD1-AS1, TYMSOS expression was decreased in OC cell lines. The results of CCK8 showed that the cell viability of OC cells decreased after inhibition of C9orf106, whereas the cell viability of OC cells increased after inhibition of LEMD1-AS1. This work revealed new Cuproptosis-related lncRNA molecular subtypes exhibiting tumor microenvironment (TME) heterogeneity for OC and proposed a prognostic signature that may have benefits in understanding the prognosis, pathological features and immune microenvironment of OC patients.

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Data Availability

The datasets generated and/or analyzed during the current study are available in the [GSE102073] repository, [https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE102073].

Abbreviations

OC:

Ovarian cancer

DElncRNAs:

Differentially expressed Long non-coding RNAs

LASSO:

Least absolute shrinkage and selection operator

GSEA:

Gene Set Enrichment Analysis

RNA-seq:

RNA sequencing

TCGA:

The Cancer Genome Atlas

GEO:

Gene Expression Omnibus

FPKM:

Fragments per kilobase of exon model per million mapped fragments

SNV:

Single nucleotide variation

CNV:

Copy number variation

ICGC:

International Cancer Genome Consortium

TPM:

Transcripts per kilobase

ROC:

Receiver operating characteristic

AUC:

Area under the curve

TME:

Tumor microenvironment

Fges:

Functional gene expression signatures

MATH:

Mutant-allele tumor heterogeneity

TMB:

Tumor mutational burden

HRD:

Homologous recombination DNA repair deficiency

GSEA:

Gene Set Enrichment Analysis

TIDE:

Tumor Immune Dysfunction and Exclusion

ICI:

Immune checkpoint inhibitor

GDSC:

Genome of Drug Sensitivity in Cancer

IC50:

Half maximal inhibitory concentration

MDSCs:

Myeloid-derived suppressor cells

CAFs:

Cancer-associated fibroblasts

TAMs:

Tumor-associated macrophages

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Funding

This research was supported by Guangxi Medical high-level and sub backbone talents training “139” program (No. G202003005), the Key Research and Development Program of Guangxi (No. GuikeAB18126056) and Liuzhou Science and Technology Bureau Project (No. 2018BJ10301, No. 2019BJ10604), Guangxi Science and Technology Plan Project (Guangxi Clinical Research Center for Obstetrics and Gynecology, GuiKe AD22035223) and Guangxi Self-Financing Research Program of Guangxi Region Health Commission (No. Z20210518, No. Z-B20221595).

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Author notes

  1. Nan Li, Kai Yu and Delun Huang equally contributed to this paper.

Authors and Affiliations

  1. Reproductive Medicine Center, Liuzhou Maternity and Child Health Care Hospital, Liuzhou, 545001, China

    Nan Li, Shu Li, Jingjing Li & Li Fan

  2. Liuzhou Institute of Reproduction and Genetics, Liuzhou, 545001, China

    Nan Li, Shu Li, Jingjing Li & Li Fan

  3. Affiliated Maternity Hospital and Affiliated Children’s Hospital of Guangxi, University of Science and Technology, Liuzhou, 545001, China

    Nan Li, Shu Li, Dingyuan Zeng, Jingjing Li & Li Fan

  4. Guangxi Health Commission Key Laboratory of Birth Cohort Study in Pregnant Women of Advanced Age, Liuzhou, 545001, China

    Nan Li, Shu Li, Jingjing Li & Li Fan

  5. College of Animal Science and Technology, Guangxi University, Nanning, 530004, China

    Kai Yu

  6. Department of Physiology, Guangxi University of Chinese Medicine, Nanning, 530001, China

    Delun Huang

  7. The Department of Obstetrics and Gynecology, Liuzhou Maternity and Child Health Care Hospital, Liuzhou, 545001, China

    Dingyuan Zeng

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  1. Nan Li
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Contributions

All authors contributed to this present work: [NL] and [KY] designed the study; [DLH] and [SL] acquired the data; [DYZ] drafted the manuscript; [JJL] and [LF] revised the manuscript. All authors read and approved the manuscript.

Corresponding authors

Correspondence to Jingjing Li or Li Fan.

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Li, N., Yu, K., Huang, D. et al. Molecular Characterization of Cuproptosis-related lncRNAs: Defining Molecular Subtypes and a Prognostic Signature of Ovarian Cancer. Biol Trace Elem Res 202, 1428–1445 (2024). https://doi.org/10.1007/s12011-023-03780-3

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