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Updated: Jun 21, 2025
MicroRNA In situ Hybridization for Formalin Fixed Kidney Tissues
Published on: November 30, 2013
Significance and Possible Biological Mechanism for CLDN8 Downregulation in Kidney Renal Clear Cell Carcinoma Tissues
Han Chu Ji1,2, Jian Di Li3,2, Guan Lan Zhang3
1Department of Urology, Guigang People's Hospital, The Eighth Affiliated of Guangxi Medical University, Guigang 537100, Guangxi Zhuang Autonomous Region, China.
Background:
The clinical role of claudin 8 (CLDN8) in kidney renal clear cell carcinoma (KIRC) remains unclarified. Herein, the expression level and potential molecular mechanisms of CLDN8 underlying KIRC were determined.
Methods:
High-throughput datasets of KIRC were collected from GEO, ArrayExpress, SRA, and TCGA databases to determine the mRNA expression level of the CLDN8. In-house tissue microarrays and immunochemistry were performed to examine CLDN8 protein expression. A summary receiver operating characteristic curve (SROC) and standardized mean difference (SMD) forest plot were generated using Stata v16.0. Single-cell analysis was conducted to further prove the expression level of CLDN8. A clustered regularly interspaced short palindromic repeats knockout screen analysis was executed to assess the growth impact of CLDN8. Functional enrichment analysis was conducted using the Metascape database. Additionally, single-sample gene set enrichment analysis was implied to explore immune cell infiltration in KIRC.
Results:
A total of 17 mRNA datasets comprising 1,060 KIRC samples and 452 non-cancerous control samples were included in this study. Additionally, 105 KIRC and 16 non-KIRC tissues were analyzed using in-house immunohistochemistry. The combined SMD was -5.25 (95% confidence interval (CI): -6.13 to -4.37), and CLDN8 downregulation yielded an SROC area under the curve (AUC) close to 1.00 (95% CI: 0.99 - 1.00). CLDN8 downregulation was also confirmed at the single-cell level. Knocking out CLDN8 stimulated KIRC cell proliferation. Lower CLDN8 expression was correlated with worse overall survival of KIRC patients (hazard ratio of CLDN8 downregulation = 1.69, 95% CI: 1.2 - 2.4). Functional pathways associated with CLDN8 co-expressed genes were centered on carbon metabolism obstruction, with key hub genes ACADM, ACO2, NDUFS1, PDHB, SDHD, SUCLA2, SUCLG1, and SUCLG2.
Conclusions:
CLDN8 is downregulated in KIRC and is considered a potential tumor suppressor. CLDN8 deficiency may promote the initiation and progression of KIRC, potentially in conjunction with metabolic dysfunction.
Insights
Claudin 8 (CLDN8) is downregulated in kidney renal clear cell carcinoma (KIRC), acting as a potential tumor suppressor. CLDN8 deficiency may promote KIRC initiation and progression, possibly linked to metabolic dysfunction.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The specific role of claudin 8 (CLDN8) in kidney renal clear cell carcinoma (KIRC) is not well understood.
- Investigating CLDN8's expression and molecular functions in KIRC is crucial for understanding its clinical significance.
Purpose of the Study:
- To determine the expression level of CLDN8 in KIRC.
- To elucidate the potential molecular mechanisms and clinical implications of CLDN8 in KIRC pathogenesis.
Main Methods:
- Analysis of high-throughput datasets (GEO, ArrayExpress, TCGA) for CLDN8 mRNA expression.
- Immunohistochemistry on tissue microarrays to assess CLDN8 protein levels.
- Single-cell analysis, CRISPR knockout screens, and functional enrichment analysis (Metascape) to evaluate CLDN8's impact on KIRC cells and patient survival.
Main Results:
- CLDN8 is significantly downregulated in KIRC tissues compared to non-cancerous controls (SMD = -5.25).
- CLDN8 downregulation correlates with poorer patient survival and promotes KIRC cell proliferation.
- Functional analysis revealed pathways related to carbon metabolism obstruction associated with CLDN8 co-expressed genes.
Conclusions:
- CLDN8 functions as a potential tumor suppressor in KIRC.
- CLDN8 deficiency may contribute to KIRC initiation and progression, potentially through metabolic dysregulation.
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