Tropomodulin 3 Overexpression as a Marker for Platinum Resistance and Immune Infiltration in Ovarian Cancer

Summary

Tropomodulin 3 (TMOD3) has been increasingly studied in tumors in recent years. This study is the first to report that TMOD3 is highly expressed in ovarian cancer and is closely associated with platinum resistance and immune infiltration. These results could help improve the therapeutic outcomes for ovarian cancer.

Abstract

The cytoskeleton plays an important role in platinum resistance in ovarian cancer. Tropomodulin 3 (TMOD3) is critical in the development of many tumors, but its role in the drug resistance of ovarian cancer remains unexplored. By analyzing data from the Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), and Clinical Proteomic Tumor Analysis Consortium (CPTAC) databases, this study compared TMOD3 expression in ovarian cancer and normal tissues, and examined the expression of TMOD3 after platinum treatment in platinum-sensitive and platinum-resistant ovarian cancers. The Kaplan-Meier method was used to assess the effect of TMOD3 on overall survival (OS) and progression-free survival (PFS) in ovarian cancer patients. microRNAs (miRNAs) targeting TMOD3 were predicted using TargetScan and analyzed using the TCGA database. Tumor Immune Estimation Resource (TIMER) and an integrated repository portal for tumor-immune system interactions (TISIDB) were used to determine the relationship between TMOD3 expression and immune infiltration. TMOD3 coexpression networks in ovarian cancer were explored using LinkedOmics, the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), and The Database for Annotation, Visualization, and Integrated Discovery (DAVID) Bioinformatics. The results showed that TMOD3 was highly expressed in ovarian cancer and was associated with the grading, staging, and metastasis of ovarian cancer. TMOD3 expression was significantly reduced in platinum-treated ovarian cancer cells and patients. However, TMOD3 expression was higher in platinum-resistant ovarian cancer cells and tissues compared to platinum-sensitive ones. Higher TMOD3 expression was significantly associated with lower OS and PFS in ovarian cancer patients treated with platinum-based chemotherapy. miRNA-mediated post-transcriptional regulation is likely responsible for high TMOD3 expression in ovarian cancer and platinum-resistant ovarian tissues. The expression of TMOD3 mRNA was associated with immune infiltration in ovarian cancer. These findings indicate that TMOD3 is highly expressed in ovarian cancer and is closely associated with platinum resistance and immune infiltration.

Introduction

Ovarian cancer is the second-highest in the mortality rate of gynecologic tumors worldwide¹. It can be classified into three types based on histopathology: germ cell, gonadal mesenchymal, and epithelial tumors, of which 90% of patients are epithelial ovarian cancer. Risk factors associated with ovarian cancer include persistent ovulation, increased gonadotropin exposure, and inflammatory cytokines². More than 75% of ovarian cancer cases are not detected until advanced stages, resulting in their lack of effective treatment. Patients with advanced ovarian cancer have a poor prognosis, with less than 20% of the 5-year survi....

Protocol

1. Gene Expression Omnibus (GEO)

NOTE: TMOD3 expression in ovarian cancer, in ovarian cancer treated with platinum drugs, and in drug-resistant ovarian cancer were derived from the GEO datasets. The study type of all datasets was expression profiling by array, and the organisms were Homo sapiens.

1. Go to the GEO database (see Table of Materials), and input keywords such as TMOD3, ovarian cancer, and .......

Discussion

The cytoskeleton has been considered essential in the development and progression, treatment, and prognosis of various tumors⁵². Compared with TMOD1, which is restricted to erythrocytes and the cardiovascular system⁵³, and TMOD2, which is restricted to the nervous system⁵⁴, TMOD3 has a ubiquitous distribution, which makes the study of TMOD3 in systemic tumors more popular^14,15,

Materials

Name	Company	Catalog Number	Comments
cBioportal	Memorial Sloan Kettering Cancer Center		Correlation analysis of  TMOD3 with targeted miRNAs (https://www.cbioportal.org)
CTD database	North Carolina State University		To analyze the relationships between chemistry, genes, phenotype, disease, and environment (https://ctdbase.org/)
Cytoscape	National Institute of General Medical Sciences of the National Institutes of Health		Network Data Integration, Analysis, and Visualization (www.cytoscape.org/)
DAVID	Frederick National Laboratory for Cancer Research		A comprehensive set of functional annotation tools for investigators to understand the biological meaning behind large lists of genes(https://david.ncifcrf.gov/)
GEO	NCBI		Gene expression analysis (https://www.ncbi.nlm.nih.gov/geo/ )
HPA	Knut & Alice Wallenberg foundation		The Human Protein Atlas (HPA) database helped analyze the distribution of TMOD3 in various immune cells (https://www.proteinatlas.org/)
KM-plotter	Department of Bioinformatics of the Semmelweis University		Prognostic Analysis (https://kmplot.com/analysis/)
LinkedOmics	Baylor College of Medicine		A platform for biologists and clinicians to access, analyze and compare cancer multi-omics data within and across tumor types (http://www.linkedomics.org/)
PubChem database	U.S. National Library of Medicine		To determine the definitive molecular structure of the drug
ROC Plotter	Department of Bioinformatics of the Semmelweis University		Validation of the interest gene as a predictive marker (http://www.rocplot.org/)
STRING	Swiss Institute of Bioinformatics		Coexpression networks analysis(https://string-db.org)
TargetScan	Whitehead Institute for Biomedical Research		Prediction of miRNA targets (www.targetscan.org/)
TIMER	Harvard University		Systematical analysis of immune infiltrates across diverse cancer types (https://cistrome.shinyapps.io/timer/)
TISIDB	The University of Hong Kong		A web portal for tumor and immune system interaction(http://cis.hku.hk/TISIDB/)
TNMplot	Department of Bioinformatics of the Semmelweis University		Gene expression analysis (https://www.tnmplot.com/ )
UALCAN	The University of ALabama at Birmingham		Gene expression analysis (http://ualcan.path.uab.edu)