PDRG1 sustains the proliferative and invasive phenotypes of tumor cells in oral squamous cell carcinoma

PDRG1 (p53 and DNA damage-regulated gene 1) promotes proliferation and invasion in multiple carcinomas. However, it has been quantified only in bulk tissue, its intratumoral heterogeneity has not been definitively established, and whether it is associated with the immune contexture remains unknown. Here, compartment- and region-resolved immunohistochemistry was performed in 91 oral squamous cell carcinoma (OSCC) tissues, scoring tumor cells (TCs), fibroblast-like cells and tumor-infiltrating lymphocytes separately in tumor center (TCs-Center) and invasive front (TCs-Front) from the same section (n = 81), together with single-cell and pan-cancer transcriptomics, siRNA knockdown with RNA sequencing, peripheral immunocyte phenotyping by flow cytometry (n = 56) and survival analysis. PDRG1 mainly localizes to tumor cells, with higher expression at the invasive front than at tumor center, and PDRG1 expression in TCs-Front correlated highly with TNM stage and lymph node metastasis. PDRG1 knockdown in HSC3 and HN6 cell lines reduced proliferation, migration and invasion, down-regulated cell division gene scores and partial epithelial-mesenchymal transition. In TCGA, PDRG1 correlated negatively with junction-related genes and positively with proliferation and invasion markers. However, PDRG1 showed no links to immune infiltration, and both circulating percentage and counts of CD4 + T cells, CD8 + T cells, CD19 + B cells and CD56 + NK cells were unchanged, indicating that its effect is not mediated by anti-tumor immunity. High PDRG1 in tumor cells indicated shorter overall, metastasis-free and disease-free survival. Taken together, PDRG1 may be a novel therapeutic target via regulating tumor proliferation and invasion of OSCC.