Dissecting lncRNA Roles in Renal Cell Carcinoma Metastasis and Characterizing Genomic Heterogeneity by Single-cell RNA-seq.

Long non-coding RNAs (lncRNAs) have recently emerged as important regulators in cancer cell proliferation and metastasis. However, the role of lncRNAs in metastatic clear cell renal cell carcinoma (ccRCC) remains unclear. Here, single-cell RNA sequencing (RNA-seq) data was analyzed from primary renal cell carcinoma (pRCC) and paired metastatic renal cell carcinoma (mRCC) specimens, and characterized the expression profiles of over 10,000 genes, including 1874 lncRNAs. Further analysis revealed that lncRNAs exhibit cancer type- and tissue-specific expression across ccRCC cells. Interestingly, a number of lncRNAs (n=173) associated with ccRCC metastasis, termed ccRCC metastasis associated lncRNAs (CMAL). Moreover, functional analysis based on a CMAL-PCG co-expression network revealed that CMALs contribute to cell adhesion, immune response and cell proliferation. In combination with survival analysis, 12 CMALs were identified that participate in TNF and HIF-1 signaling to promote ccRCC metastasis. Further investigation on intratumoral heterogeneity showed that some CMALs are selectively expressed in different subpopulations.

IMPLICATIONS: To explore ccRCC metastasis, the current study performed a global dissection of lncRNAs and a complex genomic analysis of ccRCC tumor heterogeneity. The data shed light on the discovery of potential lncRNA biomarkers and lncRNA therapeutic targets.