Piwil2, also known as Mili, belongs to the PIWI gene subfamily. Classically, it regulates reproduction by binding to piRNA. It is involved in various biological processes, and its dysregulation is associated with numerous diseases. In the context of cancer, it has been linked to oncogenic pathways, and in the brain, it is associated with neurogenesis-related pathways [1,2,3,4,5,6,7,8,9,10].

In cancer research, a meta-analysis of 10 studies with 2116 patients across 8 solid cancers showed that higher Piwil2 expression was associated with shorter overall survival, disease-free/recurrence-free/metastasis-free survival, and cancer-specific survival. It was also correlated with more lymph node metastasis [1]. In cervical epithelial lesions, Piwil2, when restored by human papillomavirus integration, upregulates PDK1 via the LIN28/let-7 axis, promoting metabolic reprogramming and tumor-initiating cell stemness [2]. In esophageal squamous cell carcinoma, Piwil2 binds to IKK, promoting its phosphorylation and inhibiting apoptosis and autophagy, and mouse xenograft models showed it promotes tumor growth in an IKK-dependent manner [3]. In colorectal cancer, overexpression of Piwil2 in SW480 cells promoted cell proliferation, colony formation, and inhibited apoptosis [6]. Also, dexmedetomidine promoted colorectal cancer progression via activating the Nrf2/Piwil2/Siah2 pathway [7]. In thyroid cancer, Piwil2 inhibited cancer progression by sponging miR-146a-3p [5]. In hepatocellular carcinoma, PIWIL2 was significantly higher in cancer cases compared to controls [9].

In the brain, depletion of Piwil2 in the adult hippocampus impaired neural progenitor cell differentiation, induced senescence, and generated reactive glia [8]. Hypoxic post-conditioning downregulated Piwil2 in the CA1 region after transient global cerebral ischemia, and silencing Piwil2 decreased apoptosis-related proteins and exerted neuroprotective effects [10].

In summary, Piwil2 has diverse functions in different biological processes. In cancer, it often acts as an oncogene, promoting tumor growth, metastasis, and inhibiting apoptosis. In the brain, it is crucial for maintaining proper neurogenesis and preventing cellular senescence. Studies using mouse models, such as xenograft models in cancer research and gene manipulation in the hippocampus, have been instrumental in revealing these functions, providing insights into potential therapeutic targets for cancer treatment and understanding brain-related physiological and pathological processes.