The secret identities of TMPRSS2: Fertility factor, virus trafficker, inflammation moderator, prostate protector and tumor suppressor.
Tumour Biol
; 43(1): 159-176, 2021.
Article
in English
| MEDLINE | ID: covidwho-1369645
ABSTRACT
The human TMPRSS2 gene is pathogenetically implicated in both coronaviral lung infection and prostate cancer, suggesting its potential as a drug target in both contexts. SARS-COV-2 spike polypeptides are primed by the host transmembrane TMPRSS2 protease, triggering virus fusion with epithelial cell membranes followed by an endocytotic internalisation process that bypasses normal endosomal activation of cathepsin-mediated innate immunity; viral co-opting of TMPRSS2 thus favors microbial survivability by attenuating host inflammatory responses. In contrast, most early hormone-dependent prostate cancers express TMPRSS2ERG fusion genes arising from deletions that eliminate the TMPRSS2 coding region while juxtaposing its androgen-inducible promoter and the open reading frame of ERG, upregulating pro-inflammatory ERG while functionally disabling TMPRSS2. Moreover, inflammatory oxidative DNA damage selects for TMPRSS2ERG-fused cancers, whereas patients treated with antiinflammatory drugs develop fewer of these fusion-dependent tumors. These findings imply that TMPRSS2 protects the prostate by enabling endosomal bypass of pathogens which could otherwise trigger inflammation-induced DNA damage that predisposes to TMPRSS2ERG fusions. Hence, the high oncogenic selectability of TMPRSS2ERG fusions may reflect a unique pro-inflammatory synergy between androgenic ERG gain-of-function and fusogenic TMPRSS2 loss-of-function, cautioning against the use of TMPRSS2-inhibitory drugs to prevent or treat early prostate cancer.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Prostatic Neoplasms
/
Serine Endopeptidases
/
Genes, Tumor Suppressor
/
Fertility
/
COVID-19
/
Inflammation
Type of study:
Observational study
/
Prognostic study
Limits:
Humans
/
Male
Language:
English
Journal:
Tumour Biol
Journal subject:
Neoplasms
Year:
2021
Document Type:
Article
Affiliation country:
TUB-211502
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