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  • Circulating piRNAs in Colorectal Cancer: From Biomarker Discovery to Clinical Monitoring

  • Kimia Sadat Nazemi,1 Marziyeh Etesami,2,*
    1. Department of Cellular and Molecular Biology, TeMS.C., Islamic Azad University, Tehran, Iran.
    2. Department of Genetics and Biotechnology, VaP.C, Islamic Azad University, Varamin, Iran.


  • Introduction: Colorectal cancer (CRC) is among the commonest cancer types found across the globe and is also a leading cancer cause of death. It is vital to identify this disease early for successful treatment and good outcomes. Colonoscopy, an invasive procedure that can be used to detect CRC, demands development of less invasive means to diagnose the cancer. It resulted in growing interest in discovering biomarkers of CRC in body fluids. In recent years, small non-coding RNAs (snRNAs), particularly PIWI-interacting RNAs (piRNAs), have gained considerable attention. These 26–31 nucleotide RNAs play important roles in transposon silencing and genome stability. They can not only serve as biomarkers for cancer but also participate in the development and progression of cancer, particularly CRC. The aim of this narrative review is to investigate the possible functions of circulating piRNAs in CRC, including their potential as biomarkers for diagnosis, prognosis, and clinical monitoring.
  • Methods: The present review was based on a literature search conducted via PubMed and Google Scholar. The inclusion criteria included articles published in English and studies in which circulating piRNAs were measured in CRC cases. The publication period of the studies ranged from 2018 to 2026. The exclusion criteria included articles outside the scope of the study and outside the specified time period.
  • Results: The reviewed studies exhibited both upregulation and downregulation of circulating piRNAs in patients with CRC. Notably, combinations of piRNAs with the two commonly used biomarkers, carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9), demonstrated higher diagnostic potential than these conventional biomarkers alone. One study reported diagnostic value in early-stage CRC02, with an AUC of 0.819. In another study, a five-member piRNA signature, including piR-001311, piR-004153, piR-017723, piR-017724, and piR-020365, achieved an AUC of 0.867 in the training set and showed better diagnostic performance than CEA. In addition, low levels of piR-017724 were associated with poorer overall survival (OS) and progression-free survival (PFS). In contrast, serum levels of piR-020619 and piR-020450 were increased in CRC patients. Their combined panel showed higher diagnostic performance than CEA and CA19-9. Serum levels of piR-54265 in CRC patients were significantly higher than those in the control group, showing diagnostic potential with an AUC of 0.896. Its serum levels decreased after surgery but increased with disease recurrence. In contrast, in another study, serum levels of piR-5937 and piR-28876 increased after surgery, which may indicate their potential for monitoring treatment response. Another study found increased piR-823 expression in both serum and tumor tissues. It showed promising diagnostic performance, with an AUC of 0.933. Higher piR-823 levels were also associated with advanced disease stages, poor tumor differentiation, and lymph node metastasis. Finally, in a recent study, the oncogenic piR-37524 was identified through small RNA sequencing analysis, and its increased expression was reported in the serum of CRC patients. Functional studies also showed that it promotes cell proliferation through the TNFAIP3/NF-κB/EMT axis.
  • Conclusion: The findings suggest that circulating piRNAs can serve as promising biomarkers for the diagnosis, prognosis, and treatment monitoring of CRC. Some of them have shown good diagnostic performance, while others have been associated with survival or changes after treatment. In addition, evaluating the diagnostic and prognostic potential of piRNAs as combination panels could help increase sensitivity and improve diagnostic performance. However, further clinical studies are necessary before these biomarkers can be used in routine clinical practice.
  • Keywords: Colorectal cancer; piRNAs; Biomarkers; Diagnosis; Treatment monitoring

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