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Human endogenous retrovirus onco-exaptation counters cancer cell senescence through calbindin. | LitMetric

AI Article Synopsis

  • Increased levels and variety of human endogenous retrovirus (HERV) transcription are found in many cancer types and are associated with disease outcomes, although the mechanisms are not fully understood.
  • The study identified that higher transcription of HERVH in lung squamous cell carcinoma (LUSC) is linked to patient survival and is driven by a CALB1 isoform influenced by HERVH, which begins to express in early preinvasive stages.
  • While calbindin (the protein encoded by CALB1) promotes growth in LUSC, its absence triggers cellular senescence and affects the cancer environment by altering the secretion of factors like CXCL8, leading to increased neutrophil presence and poorer patient prognosis in advanced tumors

Article Abstract

Increased levels and diversity of human endogenous retrovirus (HERV) transcription characterize most cancer types and are linked with disease outcomes. However, the underlying processes are incompletely understood. Here, we show that elevated transcription of HERVH proviruses predicted survival of lung squamous cell carcinoma (LUSC) and identified an isoform of CALB1, encoding calbindin, ectopically driven by an upstream HERVH provirus under the control of KLF5, as the mediator of this effect. HERVH-CALB1 expression was initiated in preinvasive lesions and associated with their progression. Calbindin loss in LUSC cell lines impaired in vitro and in vivo growth and triggered senescence, consistent with a protumor effect. However, calbindin also directly controlled the senescence-associated secretory phenotype (SASP), marked by secretion of CXCL8 and other neutrophil chemoattractants. In established carcinomas, CALB1-negative cancer cells became the dominant source of CXCL8, correlating with neutrophil infiltration and worse prognosis. Thus, HERVH-CALB1 expression in LUSC may display antagonistic pleiotropy, whereby the benefits of escaping senescence early during cancer initiation and clonal competition were offset by the prevention of SASP and protumor inflammation at later stages.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10348765PMC
http://dx.doi.org/10.1172/JCI164397DOI Listing

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