Endocrine Abstracts

JOINT1986

New diagnostic, prognostic and therapeutic strategies for different endocrine-related cancers are urgency required, especially in highly common types of malignancies affecting millions of subjects worldwide. Prostate cancer (PCa) represents a major endocrine health issue, with its progression influenced by intricate molecular factors, being the acquisition of an androgen-independent phenotype by prostate cancer cells a death sentence for patients [metastatic PCa (mPCa)]. In this context, recent evidence from our group indicates a profound dysregulation in the RNA-Exosome complex (REC), a molecular machinery responsible for 3′-5′ RNA processing and degradation, in PCa vs. non-tumoral samples which might be implicated in driving oncogenic processes associated with tumour progression and aggressiveness. This study focuses on characterizing the levels and pathophysiological role of a REC component (REC-C) in PCa. Analysis of seven independent cohorts of patients with PCa and/or mPCa (three internal and four external) revealed that REC-C was consistently up-regulated in PCa and mPCa vs. control tissues, being this overexpression directly correlated with different clinical features of aggressiveness, including high Gleason scores, recurrence, and metastasis. Functional studies in different preclinical models, both in vitro [using normal-like prostate (PNT-2) and mPCa (LNCaP, DU145, and 22Rv1) cells] and in vivo (xenografted mice) demonstrated the impact of REC-C silencing in critical cancer hallmarks, including significant reductions in cell proliferation, migration, colonies or tumourspheres formation and tumor growth. Mechanistically (employing RNAseq and phosphoarray approaches), REC-C actions were mediated through the modulation of key inflammatory-related RNAs (e.g., interferon-gamma response) and critical oncogenic signalling pathways (e.g., MAPK and TGFβ). Remarkably, microscopy studies indicated that REC-C was predominantly localised in the nucleolus of normal and low-aggressiveness mPCa cells, whereas it was found to be enriched in the nucleoplasm of highly aggressive mPCa cells suggesting a cellular localization-dependent role of REC-C in prostate cells. In fact, this study demonstrated that the general expression and nucleoplasmic-guided accumulation of REC-C in the PNT2 normal prostate cell model induced metastasis-associated morphological changes (e.g. loss of nucleolar circularity) and increased cellular aggressiveness, including enhanced migration and invasion capacity. Finally, cross-linking and analysis of cDNA (CRAC) technique revealed that the enhanced aggressiveness features linked to REC-C might be associated to its potential interaction with critical long non-coding RNAs. These findings underscore REC-C as a driving force behind prostate cancer progression and as a promising therapeutic target for PCa/advance-state PCa.

Funding

MICINN (PID2022-1381850B-I00; PRE2020-094225)