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Dysregulation of piRNA biogenesis-associated proteins in cancer: mechanisms; evidence; and translational constraints
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DOI：10.3389/fmolb.2026.1906635.png)
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Abstract
En 中文
PIWI-interacting RNAs (piRNAs); PIWI proteins; and piRNA biogenesis-associated proteins form a conserved RNA network that protects germline genome integrity and is increasingly linked to cancer biology. Most cancer reviews have emphasized altered piRNA abundance or PIWI expression; whereas the upstream machinery that generates; loads; trims; and stabilizes piRNAs has received less critical attention. For the RNA Networks and Biology section; this Review re-evaluates piRNA biogenesis proteins as RNA-network regulators rather than as isolated tumor biomarkers. We summarize the biochemical logic of precursor selection; mitochondrial processing; PIWI loading; 3-end maturation; and effector complex assembly; focusing on PIWIL1-4; PLD6/MitoPLD; MOV10L1; DDX4/VASA; GASZ; TDRKH; PNLDC1; HENMT1; Tudor-domain proteins; HSP90; and MAEL. We then assess cancer evidence by distinguishing direct perturbation studies from expression associations; animal-germline mechanisms; and computational inference. Current evidence supports tumor-context-specific roles for PIWIL1; PIWIL2; DDX4; TDRD1; MAEL; and emerging PLD6 biology in selected tumors; whereas several canonical maturation or scaffold proteins remain underexplored in human cancer. We propose that dysregulated piRNA biogenesis proteins may influence cancer through piRNA-dependent small-RNA imbalance and piRNA-independent reactivation of germline RNA-processing; epigenetic; metabolic; and immune programs. Finally; we discuss biomarker and therapeutic opportunities while emphasizing unresolved controversies; technical limitations in piRNA detection; reproductive toxicity; and the need for causal validation in human tumor models.
Keywords:
cancer
non-coding RNA
piRNA
PIWI proteins
piRNA biogenesis
RNA network
DDX4
PLD6
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