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The secret identities of TMPRSS2: Fertility factor, virus trafficker, inflammation moderator, prostate protector and tumor suppressor.
Epstein, Richard J.
  • Epstein RJ; New Hope Cancer Center, Beijing United Hospital, Jiangtai Xi Rd 9-11, Chaoyang, Beijing, China.
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.
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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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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