Abstract
Prostate cancer (PCa) is one of the leading causes of cancer-related deaths among
men. Consequently, the identification of novel molecular targets for treatment is
urgently needed to improve patients’ outcomes. Our group recently reported that some
elements of the cellular machinery controlling alternative-splicing might be useful
as potential novel therapeutic tools against advanced PCa. However, the presence and
functional role of RBM22, a key spliceosome component, in PCa remains unknown. Therefore,
RBM22 levels were firstly interrogated in 3 human cohorts and 2 preclinical mouse
models (TRAMP/Pbsn-Myc). Results were validated in in silico using 2 additional cohorts. Then, functional effects in response to RBM22 overexpression
(proliferation, migration, tumorspheres/colonies formation) were tested in PCa models
in vitro (LNCaP, 22Rv1, and PC-3 cell-lines) and in vivo (xenograft). High throughput methods (ie, RNA-seq, nCounter PanCancer Pathways Panel)
were performed in RBM22 overexpressing cells and xenograft tumors. We found that RBM22
levels were down-regulated (mRNA and protein) in PCa samples, and were inversely associated
with key clinical aggressiveness features. Consistently, a gradual reduction of RBM22
from non-tumor to poorly differentiated PCa samples was observed in transgenic models
(TRAMP/Pbsn-Myc). Notably, RBM22 overexpression decreased aggressiveness features
in vitro, and in vivo. These actions were associated with the splicing dysregulation of numerous genes
and to the downregulation of critical upstream regulators of cell-cycle (i.e., CDK1/CCND1/EPAS1). Altogether, our data demonstrate that RBM22 plays a critical pathophysiological
role in PCa and invites to suggest that targeting negative regulators of RBM22 expression/activity
could represent a novel therapeutic strategy to tackle this disease.
Graphical Abstract
Graphical Abstract
Abbreviation:
AR (androgen receptor), BPH (benign prostatic hyperplasia), FDR (false discovery rate), FFPE (formalin-fixed, paraffin-embedded), GS (gleason score), IHC (immunohistochemistry), IPA (ingenuity pathway analysis), MD-PCa (moderately differentiated prostate cancer), N-TAR (non-tumor adjacent region), PCa (prostate cancer), PD-PCa (poorly differentiated prostate cancer), PI3K (phosphoInositide 3-kinase), PIN (prostatic intraepithelial neoplasia), RBM22 (RNA binding motif protein 22), RRM (rna recognition motif), TRAMP (transgenic adenocarcinoma of mouse prostate model)To read this article in full you will need to make a payment
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Article info
Publication history
Published online: September 08, 2022
Accepted:
August 24,
2022
Received in revised form:
August 7,
2022
Received:
June 17,
2022
Footnotes
Juan M. Jiménez-Vacas and Antonio J. Montero-Hidalgo contributed equally to this work and should be considered co-first authors.
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