Penile cancer with inguinal lymph node metastases is a clinically challenging condition with poor prognosis, yet the molecular mechanisms driving its metastatic progression remain unclear. This study conducted a comprehensive transcriptomic analysis to identify and characterize differentially expressed genes (DEGs) and pathways distinguishing metastatic and non-metastatic penile cancer. Heatmaps, correlation analyses, and principal component analysis (PCA) revealed distinct transcriptomic clusters between metastatic and non-metastatic samples in our cohort, underscoring divergent molecular landscapes. RNA-seq compared metastatic and non-metastatic penile cancer tissues to identify DEGs and enriched pathways. Functional validation was performed by shRNA-mediated knockdown of ENSG00000270077 in Penl1 cells, followed by migration and invasion assays with statistical analysis. A total of 218 DEGs were identified, including 82 upregulated and 136 downregulated genes in metastatic cases. Among these, the novel long non-coding RNA (lncRNA) ENSG00000270077 exhibited significant upregulation in metastatic samples. Functional enrichment analyses of DEGs highlighted key biological processes such as immune modulation, RNA processing, and extracellular interactions, while KEGG pathway enrichment revealed significant alterations in antigen processing, ribosome, and proteasome pathways. Gene set enrichment analysis (GSEA) further emphasized downregulation of ribosomal and proteasomal activity and upregulation of herpes simplex virus 1 infection pathways in metastatic samples. Functional validation using short hairpin RNA (shRNA)-mediated knockdown of ENSG00000270077 in penile cancer cell lines demonstrated significant reductions in migration and invasion capabilities. These findings unveil ENSG00000270077 as a novel functional regulator of metastatic behavior, highlighting a previously unknown player in penile cancer progression, offering novel insights and a candidate for future therapeutic investigation.
Xie et al. (Sun,) studied this question.