# Pathogenic Roles of RNA-Binding Proteins in Sarcomas
## 2 Regulations of RNA Metabolism by RBPs
### Noncoding RNA Processing  
No-coding RNAs (ncRNAs) are commonly expressed RNAs in human cells that lack protein-coding ability. In the research results of FANTOM and ENCODE, two large genome projects, 80% of the human genome has transcriptional activity, while only 2% of the human genome codes for proteins. The noncoding regions of the human genome (98%) are primarily responsible for regulating gene expression [51; 52]. RBPs also bind to noncoding RNAs such as microRNAs (miRNA), transfer RNAs (tRNA), siRNA, telomerase RNA, small nucleolar RNA (snoRNA), and splicing small nucleolar RNA (snRNA), which regulates multiple molecular processes including RNA splicing and modification, protein localization, and chromosomal remodeling [53]. The interactions between noncoding RNAs and RBPs are increasingly recognized as one of the basic mechanisms of gene regulation and plays a crucial role in cancer [54]. RBPs are key regulators of miRNA biogenesis and maturation. They promote or inhibit miRNA processing mainly through their effects on typical proteins such as Drosha and Dicer. Altered functions in such RBPs result in the impairment of miRNA processing, which in turn affects expression of cancer-associated genes [55].  
The RBP LIN28 is one of the four factors sufficient to reprogram human somatic cells into induced pluripotent stem cells, which upregulates or inhibits the maturation of different members of the let-7 microRNA family in many cancer cells [56]. LIN28A binds to the terminal ring of precursor let-7 (pre-let-7) and enforces terminal uridine transferase (TUTase) ZCCHC11, which can acidify pre-let-7 polyuridine, thereby blocking miRNA biogenesis and tumor suppressor function. For LIN28B, the exact mechanism that causes let-7 inhibition remains controversial. Functionally, the reduction in let-7 miRNA leads to the overexpression of its oncogenic targets such as MYC, RAS, HMGA2, and BLIMP1 [57]. In addition to let-7, other miRNAs (miR8-9, -107, -143, -200C, -370, and -638) containing the same tetranucleotide sequence motif (GGAG) as pre-let-7 undergo the same process. Most of these miRNAs have been identified as tumor suppressors, suggesting that LIN28 may promote cancer metastasis by inhibiting multiple metastasis-associated miRNAs [6].  
CircRNAs are covalently closed RNA molecules, usually derived from precursor mRNA (pre-mRNA) through reverse splicing events, where the downstream 5\({}^{\prime}\) splicing donor is reversely spliced to the upstream 3\({}^{\prime}\) splicing receptor [58]. Recent evidence suggests that abnormal circRNA expression exists in almost all cancer types and plays an indispensable role in cancer pathogenesis as oncogenes or tumor suppressors [59]. CircRNA can act as a protein scaffold or antagonist that interacts with RBPs. For example, circACC1 acts as a protein scaffold to enhance the enzyme activity of the AMP-activated protein kinase (AMPK) holoenzyme by directly binding AMPK \(\beta\) and \(\gamma\) subunits. [60], CircRHOBTB3 also inhibits metastasis in colorectal cancer by interacting with HuR, which in turn degrades HuR to reduce the expression level of the downstream target PTBP1 [61].