Profile of chimeric RNAs and TMPRSS2-ERG e2e4 isoform in neuroendocrine prostate cancer

Abstract

Purpose Specific gene fusions and their fusion products (chimeric RNA and protein) have served as ideal diagnostic markers and therapeutic targets for cancer. However, few systematic studies for chimeric RNAs have been conducted in neuroendocrine prostate cancer (NEPC). In this study, we explored the landscape of chimeric RNAs in different types of prostate cancer (PCa) cell lines and aimed to identify chimeric RNAs specifically expressed in NEPC. Methods To do so, we employed the RNA-seq data of eight prostate related cell lines from Cancer Cell Line Encyclopedia (CCLE) for chimeric RNA identification. Multiple filtering criteria were used and the candidate chimeric RNAs were characterized at multiple levels and from various angles. We then performed experimental validation on all 80 candidates, and focused on the ones that are specific to NEPC. Lastly, we studied the clinical relevance and effect of one chimera in neuroendocrine process. Results Out of 80 candidates, 15 were confirmed to be expressed preferentially in NEPC lines. Among them, 13 of the 15 were found to be specifically expressed in NEPC, and four were further validated in another NEPC cell line. Importantly, in silico analysis showed that tumor malignancy may be correlated to the level of these chimeric RNAs. Clinically, the expression of TMPRSS2-ERG (e2e4) was elevated in tumor tissues and indicated poor clinical prognosis, whereas the parental wild type transcripts had no such association. Furthermore, compared to the most frequently detected TMPRSS2-ERG form (e1e4), e2e4 encodes 31 more amino acids and accelerated neuroendocrine process of prostate cancer. Conclusions In summary, these findings painted the landscape of chimeric RNA in NEPC and supported the idea that some chimeric RNAs may represent additional biomarkers and/or treatment targets independent of parental gene transcripts.

The regulatory process and practical significance of non-coding RNA in the dissemination of prostate cancer to the skeletal system

“…Hence, circRNA could possess possibilities in the detection and surveillance of PCa bone metastasis. Furthermore, chimeric RNA could be another important type of ncRNA ( 113 ), and could influence the migration/invasion of PCa ( 114 ) although relevant studies are lacking.…”

Antitarget, Anti-SARS-CoV-2 Leads, Drugs, and the Drug Discovery–Genetics Alliance Perspective

“…Although only preliminary results have been obtained with SARS-CoV-2, human TMPRSS2 genotypic variants (already present in some cancer tissues) further enrich the knowledge of the role of this protease on viral entry. 165,166 Entry Inhibitors Targeting Cathepsin L. As the endosomal pathway requires the intervention of cathepsin L (CTSL) for endolysosomal escape, the inhibition of this cysteine exopeptidase implicated in cell growth, matrix regulation, and neovascularization represents a target for the development of antivirals targeting β-coronaviruses and other viruses such as the Ebola one. 100 Cathepsin L inhibition in vivo treatment decreased entry of SARS-CoV-1 and SARS-CoV-2 pseudovirions into 293/hACE2 by over 76%, suggesting cathepsin L, but not cathepsin B nor calpain, is responsible for an endosomal S1/S2 spike cleavage.…”

“…It is worth noting that TMPRSS2 also proved to be involved in proteolytic activation of some influenza A viruses, promoting their infectivity, and that the HA10 subtype of the avian influenza A virus (AIV) was unable to infect the TMPRSS2 knockout mice, since the enzyme is indispensable for the proteolytic cleavage of the viral hemagglutinin (HA). Although only preliminary results have been obtained with SARS-CoV-2, human TMPRSS2 genotypic variants (already present in some cancer tissues) further enrich the knowledge of the role of this protease on viral entry. , …”

Chimeric RNAs and their implication in prostate cancer

“…The most typical example is TMPRSS2-ERG (e1e4), which can be detected in about 50% of PCa cases and is reported to be the product of intra-chromosomal deletion or insertional gene rearrangement. 3 However, with the development of advanced deep sequencing technologies, novel types of non-canonical chimeric RNAs have been discovered to be generated from intergenic splicing without genomic aberrations. 2 These chimeric RNAs can be formed through trans-splicing or cis-splicing between adjacent genes (cis-SAGe) mechanisms.…”