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MicroRNA-30a-5pme: a novel diagnostic and prognostic biomarker for clear cell renal cell carcinoma in tissue and urine samples.

ABSTRACT: BACKGROUND:The rising incidence of renal cell carcinomas (RCC) constitutes a significant challenge owing to risk of overtreatment. Because aberrant microRNA (miR) promoter methylation contributes to cancer development, we investigated whether altered miR-30a-5p expression associates with DNA promoter methylation and evaluated the usefulness as clear cell RCC (ccRCC) diagnostic and prognostic markers. METHODS:Genome-wide methylome and RNA sequencing data from a set of ccRCC and normal tissue samples from The Cancer Genome Atlas (TCGA) database were integrated to identify candidate CpG loci involved in cancer onset. MiR-30a-5p expression and promoter methylation were quantitatively assessed by PCR in a tissue set (Cohort #1) and urine sets (Cohorts #2 and 3) from IPOPorto and Homburg University Hospital. Non-parametric tests were used for comparing continuous variables. MiR-30a-5p promoter methylation (miR-30a-5pme) performance as diagnostic (receiver operator characteristics [ROC] - validity estimates) and prognostic [metastasis-free (MFS) and disease-specific survival (DSS)] biomarker was further validated in urine samples from ccRCC patients by Kaplan Meier curves (with log rank) and both univariable and multivariable analysis. RESULTS:Two significant hypermethylated CpG loci in TCGA ccRCC samples, correlating with miR-30a-5p transcriptional downregulation, were disclosed. MiR-30a-5pme in ccRCC tissues was confirmed in an independent patient's cohort of IPOPorto and associated with shorter time to relapse. In urine samples, miR-30a-5pme levels identified cancer both in testing and validation cohorts, with 83% sensitivity/53% specificity and 63% sensitivity/67% specificity, respectively. Moreover, higher miR-30a-5pme levels independently predicted metastatic dissemination and survival. CONCLUSION:To the best of our knowledge, this is the first study validating the diagnostic and prognostic potential of miR-30a-5pme for ccRCC in urine samples, providing new insights for its clinical usefulness as non-invasive cancer biomarker.

SUBMITTER: Outeiro-Pinho G

PROVIDER: S-EPMC7323611 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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MicroRNA-30a-5p<sup>me</sup>: a novel diagnostic and prognostic biomarker for clear cell renal cell carcinoma in tissue and urine samples.

Outeiro-Pinho Gonçalo G Barros-Silva Daniela D Aznar Elena E Sousa Ana-Isabel AI Vieira-Coimbra Márcia M Oliveira Jorge J Gonçalves Céline S CS Costa Bruno M BM Junker Kerstin K Henrique Rui R Jerónimo Carmen C

Journal of experimental & clinical cancer research : CR 20200601 1

<h4>Background</h4>The rising incidence of renal cell carcinomas (RCC) constitutes a significant challenge owing to risk of overtreatment. Because aberrant microRNA (miR) promoter methylation contributes to cancer development, we investigated whether altered miR-30a-5p expression associates with DNA promoter methylation and evaluated the usefulness as clear cell RCC (ccRCC) diagnostic and prognostic markers.<h4>Methods</h4>Genome-wide methylome and RNA sequencing data from a set of ccRCC and nor ...[more]

PMID: 32487203

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Project description:Background: Apolipoprotein C1 (APOC1) has been proved to play a critical role in gastric, breast, lung, and pancreatic cancer. However, the relationship between APOC1 and urinary tumors remains unclear. This study aimed to assess the diagnostic and prognostic value of APOC1 in urinary tumors. Methods: We performed a pan analysis of APOC1 mRNA expression in urinary cancer using the Gene Expression Profiling Interactive Analysis (GEPIA) database. To further investigate the prognostic value of APOC1 expression in urinary cancers, the Kaplan-Meier plotter database was used. Furthermore, we collected the tumor and adjacent normal samples of 32 ccRCC patients to perform qRT-PCR and western blotting assays. A total of 72 cases with ccRCC were analyzed using tissue microarrays (TMAs). Results: Our results based on Kaplan-Meier plotter database indicated that a high expression of APOC1 may lead to poor overall survival (OS, p = 0.0019) in patients with ccRCC. Furthermore, the cancer stages and tumor grade of ccRCC appeared to be strongly linked with APOC1 expression according to UALCAN database. Hence, we reached a preliminary conclusion that APOC1 may play a key role in the tumorigenesis and progression of ccRCC. Furthermore, the Kaplan-Meier survival curve analyses of 72 clinical patients indicated that high expression of APOC1 was associated with poor progression-free survival (PFS, p = 0.007) and OS (p = 0.022). In addition, univariate Cox regression analysis confirmed the significant relationship between APOC1 expression and survival (p = 0.038). The TMAs analysis in combination with the patients' clinicopathological features was also performed. The expression of APOC1 was found to be significantly correlated with the tumor size (p = 0.018) and histological grade (p = 0.016). Conclusions: In conclusion, the findings of our study suggest that APOC1 may serve as a novel diagnostic and prognostic biomarker for ccRCC. Further evidence on the mechanism of APOC1 promoting tumor progression may transform it to a new therapeutic target for the treatment of ccRCC.

Project description:Genetic alterations in lipid metabolism genes are correlated with progression and poor prognosis of Clear cell renal cell carcinoma (ccRCC). PPARα play a critical role in lipid metabolism. This study aimed to identify that PPARα is a diagnosis and prognostic biomarker in ccRCC by integrated bioinformatics analysis. UALCAN database was used to explore the differential expression status and prognostic value of PPARα gene in various tumor types, qRT-PCR and immunohistochemical staining experiments were utilized for validation. Next, ccRCC data were obtained from TCGA. Correlation between PPARα expression levels and patients' clinicopathological characteristics was assessed, and the clinically diagnosis and prognostic value of PPARα were explored in ccRCC. According to the gene set enrichment analysis (GSEA) analysis, PPARα gene associated biological pathways were identified. PPARα has prognostic significance only in ccRCC tumors. Expression of PPARα was associated with ccRCC stages. PPARα was significantly down-regulated in ccRCC and associated with survival. Gender, tumor dimension, grade and stage showed a significant relevance with PPARα expression. Lower PPARα expression revealed significantly poorer survival and progression compared with higher PPARα expression. Adjusted by other clinical risk factors, PPARα remained an independent prognostic factor. Moreover, Low PPARα expression was a potential diagnostic biomarker of ccRCC. A nomogram was constructed based on PPARα expression and other clinicopathological risk factors, and it performed well in predict patients survival. GSEA analysis showed that PPARα gene associated biological pathways were enriched in mTOR pathway, AKT pathway, IGF1-mTOR pathway and Wnt signaling pathways. In conclusion, PPARα expression was decreased in ccRCC tumors. Lower expression of PPARα is closely correlated with poorer survival. It can be used as a clinically diagnosis and prognostic biomarker in ccRCC.

Project description:Background and Objectives: Calcium-binding protein 39-like (CAB39L) has been reported to be downregulated and possessed diagnostic and prognostic values in several types of cancer. However, the clinical value and mechanism of CAB39L in kidney renal clear cell carcinoma (KIRC) remain unclear. Materials and Methods: Bioinformatics analysis was conducted using different databases including TCGA, UALCAN, GEPIA, LinkedOmics, STRING, and TIMER. One-way variance analysis and t-test were chosen to investigate the statistical differences of CAB39L expression in KIRC tissues with different clinical characteristics. The receiver operating characteristic (ROC) curve was chosen to assess the discriminatory capacity of CAB39L. Kaplan-Meier curves were employed for assessing the influence of CAB39L on the progression-free survival (PFS), disease-specific survival (DSS), and overall survival (OS) of KIRC patients. The independent prognostic significance of clinical parameters for OS such as CAB39L expression in KIRC patients was estimated by Cox analysis. A series of in vitro functional experiments and Western blot (WB) and immunohistochemistry (IHC) were used to validate the relative protein expression and function of CAB39L. Results: The mRNA and protein levels of CAB39L were relatively downregulated in KIRC samples. Meanwhile, hypermethylation of the CAB39L promoter region was possibly associated with its low expression in KIRC. The ROC curve showed that the mRNA expression of CAB39L had a strong diagnostic value for both early and late KIRC. Kaplan-Meier survival curves indicated that a higher mRNA level of CAB39L predicted good PFS, DSS, and OS. The mRNA expression of CAB39L was an independent prognostic factor (hazard ratio = 0.6, p = 0.034) identified by multivariate Cox regression analysis. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analysis exhibited that CAB39L was mainly associated with substance and energy metabolism. Finally, overexpression of CAB39L impaired the proliferation and metastasis of KIRC cells in vitro. Conclusions: CAB39L possesses prognostic and diagnostic capacity in KIRC.

Dataset Information

MicroRNA-30a-5pme: a novel diagnostic and prognostic biomarker for clear cell renal cell carcinoma in tissue and urine samples.

Publications

MicroRNA-30a-5p<sup>me</sup>: a novel diagnostic and prognostic biomarker for clear cell renal cell carcinoma in tissue and urine samples.

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