Mar Martinez-Lozano

Specific targeting of the pseudogene RPSAP52 reduces ovarian tumor growth in patient-derived orthoxenograft models

The RPSAP52 pseudogene is transcribed in the opposite direction to the oncofetal gene HMGA2 and is reexpressed in various human cancers. Here, we investigate the impact of RPSAP52 in ovarian cancer (OC) and explore the potential therapeutic application of GapmeR antisense oligonucleotides against RPSAP52 in preclinical models. RPSAP52 and HMGA2 expression were investigated in TCGA for OC and further explored in a panel of orthotopic PDXs and commercial cell lines by RT-qPCR. The Kaplan-Meier method was used to estimate survival associated with RPSAP52 expression in a dataset within the OC TCGA cohort. The effect of specific silencing of RPSAP52 on tumor growth in vitro and in vivo was evaluated by lentiviral-mediated depletion and antisense LNA GapmeRs against RPSAP52. The pseudogene RPSAP52 was overexpressed in epithelial OC in both patient samples and OC preclinical models coinciding with the overexpression of HMGA2. Elevated expression levels of RPSAP52 in the early stages of OC were associated with poorer clinical outcomes and could stratify patients in stages I and II. The specific depletion of RPSAP52 led to a reduction in OC tumor growth in vitro and in vivo. Furthermore, the treatment with antisense LNA GapmeRs against RPSAP52 showed significant antitumoral effect in OC cell lines and in a PDOX model (without evident toxicity). Our findings demonstrate that RPSAP52 displays pro-growth features in OC, underscoring the significance of pseudogenes in cancer pathophysiology. This pseudogene has potential utility as therapeutic target in OC and as valuable prognostic biomarker for the early stages of this disease.