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Published on: May 20, 2014
THBS1 Contributes to Chemoresistance in Ovarian Clear Cell Carcinoma via Promoting Epithelial-Mesenchymal Transition
Dongdong Ye1, Yunyun Liu1,2,3,4, Aoshuang Cheng1,2,3
1Department of Gynecological Oncology, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, China.
Objective:
Ovarian clear cell carcinoma (OCCC) is prone to primary platinum resistance and has a poor prognosis in advanced stages. Understanding the mechanisms underlying chemoresistance is essential to improving treatment outcomes. This study aimed to identify and validate molecular targets linked to platinum sensitivity in OCCC and explore their clinical and biological relevance.
Methods:
The mRNA sequencing was performed on fresh-frozen tumor tissues from six OCCC patients (three platinum-resistant and three platinum-sensitive). Differentially expressed genes (DEGs) were identified using edgeR and DESeq2. A random forest model ranked candidate genes by their predictive value, and prognostic associations with progression-free survival (PFS) and overall survival (OS) were assessed via the database of the Cancer Science Institute of Singapore (CSIOVDB). The protein expression of THBS1 was compared between groups using immunohistochemistry. Functional effects of THBS1 knockdown were assessed through CCK-8, colony formation, wound healing, transwell assays, and tube formation assays using HUVECs.
Results:
A total of 1592 DEGs were identified, with 43 overlapping with GSEA-defined platinum resistance pathways. Enrichment analysis indicated significant enrichment of cancer-related signaling pathways and biological processes were enriched in the platinum-resistant group. Gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA) highlighted the platelet-associated biological processes and immune relative pathway. The immune infiltration landscape indicated a prominent immunosuppressive microenvironment in the platinum-resistant group. THBS1 ranked highly in the random forest model and was associated with shorter PFS (p = 0.0012) and OS (p = 0.0046) in CSIOVDB analysis. Immunohistochemistry confirmed elevated THBS1 expression in the platinum-resistant group (p < 0.0001). In vitro, THBS1 knockdown reduced cell migration, invasion, angiogenesis, and cisplatin resistance. It also downregulated E-cadherin while upregulating N-cadherin and vimentin, suggesting EMT pathway involvement.
Conclusion:
THBS1 promotes platinum resistance in OCCC through EMT activation and may serve as a prognostic biomarker and therapeutic target.
Insights
This study identifies Thrombospondin-1 (THBS1) as a key driver of platinum resistance in ovarian clear cell carcinoma (OCCC). Lowering THBS1 levels may improve treatment outcomes for OCCC patients.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Ovarian clear cell carcinoma (OCCC) frequently exhibits primary platinum resistance, leading to poor prognoses in advanced stages.
- Understanding the molecular mechanisms of chemoresistance is critical for developing effective treatment strategies.
Purpose of the Study:
- To identify and validate molecular targets associated with platinum sensitivity in OCCC.
- To explore the clinical and biological relevance of these targets.
Main Methods:
- mRNA sequencing of platinum-resistant and -sensitive OCCC tumors to identify differentially expressed genes (DEGs).
- Random forest modeling to rank candidate genes by predictive value.
- Prognostic association analysis using the CSIOVDB database.
- Immunohistochemistry to assess THBS1 protein expression.
- In vitro functional assays (CCK-8, colony formation, wound healing, transwell, tube formation) to evaluate THBS1 knockdown effects.
Main Results:
- 1592 DEGs were identified; 43 overlapped with platinum resistance pathways.
- Enrichment analyses highlighted cancer-related pathways, platelet functions, and immune suppression in resistant tumors.
- THBS1 was highly ranked, associated with shorter progression-free survival (PFS) and overall survival (OS) (p<0.01).
- THBS1 expression was elevated in platinum-resistant OCCC (p<0.0001).
- THBS1 knockdown reduced cell migration, invasion, angiogenesis, and cisplatin resistance, suggesting epithelial-mesenchymal transition (EMT) involvement.
Conclusions:
- THBS1 promotes platinum resistance in OCCC by activating the EMT pathway.
- THBS1 serves as a potential prognostic biomarker and therapeutic target for OCCC.
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