Loss of MIR503HG facilitates papillary renal cell carcinoma associated lymphatic metastasis by triggering NOTCH1/VEGFC signaling.

Clinical lymphatic metastasis indicates an extremely poor prognosis. Patients with papillary renal cell carcinoma (pRCC) have a high probability of progressing to lymphatic metastasis. However, the molecular mechanism of pRCC-associated lymphatic metastasis has not been elucidated. In this study, we found a downregulated long non-coding RNA (lncRNA) MIR503HG in pRCC primary tumor tissues due to hypermethylation at the CpG islands within its transcriptional start site. Decreased MIR503HG expression could stimulate tube formation and migration of human lymphatic endothelial cell (HLEC) and play a central role to promote lymphatic metastasis in vivo by enhancing tumor lymphangiogenesis. MIR503HG, located in the nucleus, bound with histone variant H2A.Z and affected the recruitment of histone variant H2A.Z to chromatin. Subsequently, increasing the H3K27 trimethylation caused by MIR503HG-overexpression epigenetically downregulated the NOTCH1 expression, which ultimately resulted in decreasing VEGFC secretion and lymphangiogenesis. Additionally, downregulated MIR503HG facilitated the HNRNPC expression, which ultimately promoted the maturation of NOTCH1 mRNA. Notably, upregulating MIR503HG expression might decrease pRCC resistance to the mTOR inhibitor. Together, these findings highlighted a VEGFC-independent mechanism of MIR503HG-mediated lymphatic metastasis. MIR503HG, identified as a novel pRCC-suppressor, would serve as the potentially biomarker for lymphatic metastasis.

Serum extracellular vesicles derived hsa-miR-320d as an indicator for progression of clear cell renal cell carcinoma.

BACKGROUND: Renal cell carcinoma (RCC) is a prevalent malignancy with a rising incidence in developing countries. Clear cell renal cell carcinoma (ccRCC) constitutes 70% of RCC cases and is prone to metastasis and recurrence, yet lacks a liquid biomarker for surveillance. Extracellular vesicles (EVs) have shown promise as biomarkers in various malignancies. In this study, we investigated the potential of serum EV-derived miRNAs as a biomarker for ccRCC metastasis and recurrence. MATERIALS AND METHODS: Patients diagnosed with ccRCC between 2017 and 2020 were recruited in this study. In the discovery phase, high throughput small RNA sequencing was used to analyze RNA extracted from serum EVs derived from localized ccRCC (LccRCC) and advanced ccRCC (AccRCC). In the validation phase, qPCR was employed for quantitative detection of candidate biomarkers. Migration and invasion assays were performed on ccRCC cell line OSRC2. RESULTS: Serum EVs derived hsa-miR-320d was significantly up-regulated in patients with AccRCC than in patients with LccRCC (p < 0.01). In addition, Serum EVs derived hsa-miR-320d was also significantly up-regulated in patients who experienced recurrence or metastasis (p < 0.01). Besides, hsa-miR-320d enhances the pro-metastatic phenotype of ccRCC cells in vitro. CONCLUSIONS: Serum EVs derived hsa-miR-320d as a liquid biomarker exhibits significant potential for identifying the recurrence or metastasis of ccRCC, as well as hsa-miR-320d promotes ccRCC cells migration and invasion.

Predictive genomic biomarkers of therapeutic effects in renal cell carcinoma.

BACKGROUND: In recent years, there have been great improvements in the therapy of renal cell carcinoma. Nevertheless, the therapeutic effect varies significantly from person to person. To discern the effective treatment for different populations, predictive molecular biomarkers in response to target, immunological, and combined therapies are widely studied. CONCLUSION: This review summarized those studies from three perspectives (SNPs, mutation, and expression level) and listed the relationship between biomarkers and therapeutic effect, highlighting the great potential of predictive molecular biomarkers in metastatic RCC therapy. However, due to a series of reasons, most of these findings require further validation.