Abstract
TAR-DNA-binding protein-43 (TDP-43) is a member of hnRNP family and acts as both RNA and DNA binding regulator, mediating RNA metabolism and transcription regulation in various diseases. Currently, emerging evidence gradually elucidates the crucial role of TDP-43 in human cancers like it is previously widely researched in neurodegeneration diseases. A series of RNA metabolism events, including mRNA alternative splicing, transport, stability, miRNA processing, and ncRNA regulation, are all confirmed to be closely involved in various carcinogenesis and tumor progressions, which are all partially regulated and interacted by TDP-43. Herein we conducted the first overall review about TDP-43 and cancers to systematically summarize the function and precise mechanism of TDP-43 in different human cancers. We hope it would provide basic knowledge and concepts for tumor target therapy and biomarker diagnosis in the future.
Highlights
TAR-DNA-binding protein-43 (TDP-43, named TARDBP) was first cloned (43 kDa) in 1995, and its name was derived from the characteristics of binding to human immunodeficiency virus type 1 (HIV-1) TAR DNA sequence motifs [1]
To investigate the mechanism of TDP-43 in regulating lung cancer-associated miRNA biogenesis, Chen et al used miRNA sequencing after knocking down TDP-43 and found that TDP-43 knockdown affected the expression of many miRNAs and altered the patterns of different isoforms of miRNAs and miRNA arm Dysregulation Associated Downstream factor
As a member of hnRNP family RNA binding protein (RBP), TDP-43 plays a significant role in RNA metabolism in various diseases, especially the cancers discussed here
Summary
TAR-DNA-binding protein-43 (TDP-43, named TARDBP) was first cloned (43 kDa) in 1995, and its name was derived from the characteristics of binding to human immunodeficiency virus type 1 (HIV-1) TAR DNA sequence motifs [1]. TDP-43 is well confirmed by previous studies to mainly regulate RNA metabolism, like biogenesis, processing, decay, and transport, in various diseases We stated these tumor-associated molecular mechanisms with several parts in detail as discussed in the following paragraphs (Figures 1B–D). A novel miR-NID1 (miR-8485) transcribed from NRXN1 intron 5 could interact with AGO and together transported by TDP-43 to the nucleus for further regulation (see the details in Figure 1C) [51] These genes have been confirmed by previous studies to be crucial for various cancers. In contrast to RNA metabolism like mRNA splicing and miRNA processing, more research proposed the direct interaction between TDP-43 and mature miRNAs or lncRNA to cooperatively regulate downstream, which further extends the function and mechanism complexity of TDP-43. One recent paper suggested that mutations in the tumor suppressor SPOP were linked to specific phase separation defects, which induced the upregulation of various protooncogenic proteins targeted by normal SPOP-mediated protein proteasomal degradation [75]
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