November 21, 2019

Cancer including degradation of transposons in association with PIWI-proteins

Cancer is a major public health problem and recognized as one of the leading cause of increasing mortality worldwide (doi: 10.3322/caac.21387).  Among human malignant tumors, Fibrosarcomas are rare soft tissue sarcoma originating from the intra- and intermuscular fibrous tissues, fascia and tendons with an extensively high division rate and display highly aggressive behaviors (PMC4774566). Regardless of the advancement in understanding of Fibrosarcoma, treatment options are stagnant for the past few decades because of their rarity, genetic complexities, and late diagnosis. They are also notorious for their ability to metastasize early (DOI:10.1016/j.yexcr.2017.04.017). The standard therapy comprises surgical resection and adjuvant chemotherapy become unavailable due to local recurrence and distant metastasis (doi: 10.1007/s11864-011-0145-5) (PMC2517216). Although  combined therapy of doxorubicin and ifosfamide having greater efficacy and shown improvements in overall survival, but unfortunately this treatment is associated with severe short- and long- term toxicities, including cumulative cardiotoxicity, myelotoxicity, renal impairment, bladder toxicity, central encephalopathy and bone marrow suppression (DOI: 10.1016/S1470-2045(14)70063-4). Therefore, it is an urgency to explore new therapeutic strategies like targeted therapies and development of new diagnostic biomarkers possibly by harnessing the potential role of small non-coding RNAs (ncRNAs) such as microRNAs (miRNAs) and PIWI-interacting RNAs (piRNAs) to handle this aggressive  early-metastatic tumor (PMC3376845) (PMC5216777) (PMC4412036).

Non-coding RNAs, especially the small non-coding RNAs (ncRNAs) have recently emerged as useful biomarkers for prognosis and diagnosis of different cancers.  Recently, the PIWI-interacting RNA pathway was identified in the mammalian testicular germline cells and established as a highly conserved, evolutionarily pathway in animals (PMC4988489). The PIWI-interacting RNAs (piRNAs) pathway was discovered  in 2006 simultaneously by five groups in mammalian testicular germline cells ( PMC1522070) (PMC1522066) (DOI:10.1038/nature04917) (DOI:10.1038/nature04916) (DOI:10.1126/science.1130164). piRNAs are 26-32 nucleotides in length, characterized by a 3-terminal 2´-O-methylation, and most of the piRNAs are only expressed in the germline cells, where they are crucial for fertility by maintaining genome stability (12062093) (14736746). In germline cells, the key role of piRNAs is the suppression of transposons, therefore prevent mutations caused by mobile genetic elements. piRNAs regulate transposons in germline at different levels, including degradation of transposons in association with PIWI-proteins 17346786 (PMC4265212) (DOI:10.1016/j.cell.2007.03.026) and the regulation of transposon expression by histone-modification and DNA-methylation (doi:10.1038/nrg3355). Besides transposon silencing piRNAs also play an important role in some biological processes such as gametogenesis, developmental transitions, and sex determination by regulating key mRNAs in these pathways at the post transcriptional level (PMC4185416).

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The initial studies of PIWI-protein/piRNAs axis mainly focused on testicular germ cell development, but recent studies using high-throughput small RNA sequencing showed widespread expression of piRNAs in the somatic tissues (PMC3159465) (doi: 10.1073/pnas.1320965111), which demonstrated new regulatory functions of the piRNAs in the somatic tissues in addition to their roles in the development of gonads and maintaining genome integrity (PMC4714483). Recently our lab reported the expression of piRNAs in human brain (HB) and Alzheimer’s disease (AD)-affected brain using next-generation small RNA sequencing, and elucidated some dysregulated piRNAs (piR-38240, piR-34393, and piR-40666) and their potential targets (CYCS, KPNA6, and RAB11A) enriched in biological pathways of AD-affected brain (DOI:10.1039/c6mb00699j). To date, only a few piRNAs (piR-651, piR-20365, piR-021285, piR-932, and piR-823) have been identified in different cancer/tumor including lung cancer, pancreatic cancer, ovarian cancer, colorectal cancer, breast cancer and classical Hodgkin lymphoma, and their role in tumorigenesis/cancer well studied (23992744) (27431575) (27329591) (26210741) (28618124). However, the precise prognostic and diagnostic impact of piRNAs in cancer/tumor remains to be elucidated.

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