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Evaluating the Urinary Exosome microRNA Profile of von Hippel Lindau Syndrome Patients with Clear Cell Renal Cell
Beatriz Walter-Rodriguez1, Christopher J Ricketts2, W Marston Linehan2
1Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Introduction:
Renal cell carcinoma is one of the ten more common malignant tumors worldwide, with a high incidence and mortality rate. Kidney cancer frequently presents at an advanced stage, and it is almost invariably fatal. Much progress has been made in identifying molecular targets for therapy in the hope of improving survival rates, but still, we have no good markers for early detection or progression of the disease. Von Hippel Lindau syndrome (VHL) is an autosomal dominant cancer hereditary syndrome in which affected individuals are at risk of developing bilateral and multifocal renal cell carcinomas (RCC) as well as other tumors. These patients provide an ideal platform to investigate the potential of urinary exosomal miRNA biomarkers in the early development of ccRCC, as these patients are regularly imaged and tumors are actively monitored until the tumor reaches 3 cm before surgical excision. This allows for pre- and post-surgical urine collection and comparison to excised tumor tissues. Studying different biomarkers in urine can provide comprehensive molecular profiling available to patients and physicians and can be a great source of additional tumor genetic information.
Methods:
Pre- and postoperative urine samples were obtained from a cohort of VHL patients undergoing surveillance and surgical excision of ccRCCs, and exosomes were extracted. MicroRNA-Seq analysis was performed on miRNA extracted from both urine-derived exosomes and FFPE material from excised ccRCCs.
Results:
MicroRNA-Seq analysis highlighted a significant difference in the urinary exosome-derived miRNA expression profiles between VHL patients and normal control individuals. This included decreased expression of the miR-320 family, such as miR-320a, known to be decreased in sporadic ccRCC and suppressed by the HIF1α transcription factor activated by the loss of the VHL gene. MiR-542-5p represented a potential marker of VHL-associated ccRCC that was lowly expressed in normal control urinary exosomes, significantly increased in the preoperative urinary exosomes of tumor-bearing VHL patients, and subsequently reduced to normal levels of expression after tumor excision. In concordance with this, the expression of miR-542-5p was increased in the VHL-associated ccRCC in comparison to the normal kidney.
Conclusions:
This study shows the potential for miRNA profiling of exosomes from readily available biofluids to both distinguish VHL patient urine from normal control urine microRNAs and to provide biomarkers for the presence of VHL syndrome-associated ccRCC. Further validation studies are necessary to demonstrate the utility of urinary exosome-derived miRNAs as biomarkers in kidney cancer.
Insights
Urinary exosomal microRNAs show promise as biomarkers for early detection of kidney cancer in Von Hippel Lindau syndrome patients. Profiling these microRNAs can help distinguish VHL patients from healthy individuals and identify ccRCC presence.
Area of Science:
- Molecular Biology
- Oncology
- Biomarker Discovery
Background:
- Renal cell carcinoma (RCC) is a prevalent and often fatal malignancy with limited early detection markers.
- Von Hippel Lindau (VHL) syndrome patients develop multifocal RCC, offering a unique model for studying early disease development.
- Urinary exosomal microRNAs (miRNAs) are emerging as non-invasive biomarkers for various cancers.
Purpose of the Study:
- To investigate the potential of urinary exosomal miRNAs as biomarkers for early detection and monitoring of clear cell renal cell carcinoma (ccRCC) in VHL patients.
- To compare miRNA expression profiles in urine exosomes from VHL patients with and without ccRCC against healthy controls.
Main Methods:
- Collected pre- and post-operative urine samples from VHL patients undergoing ccRCC surveillance and surgical excision.
- Extracted exosomes from urine and performed microRNA sequencing (miRNA-Seq) on exosomal RNA.
- Compared miRNA profiles from urine exosomes and Formalin-Fixed Paraffin-Embedded (FFPE) ccRCC tissues.
Main Results:
- Significant differences in urinary exosome-derived miRNA expression were observed between VHL patients and healthy controls.
- Decreased expression of the miR-320 family was noted, consistent with findings in sporadic ccRCC.
- miR-542-5p showed significantly increased expression in preoperative urine exosomes of tumor-bearing VHL patients, decreasing post-excision, and was elevated in ccRCC tissue.
Conclusions:
- Urinary exosome-derived miRNA profiling can differentiate VHL patients from healthy controls.
- Specific miRNAs, like miR-542-5p, show potential as non-invasive biomarkers for VHL-associated ccRCC.
- Further validation is required to establish the clinical utility of these urinary exosomal miRNAs in kidney cancer diagnostics.
