RNA-binding proteins in tumor progression

Abstract

RNA-binding protein (RBP) has a highly dynamic spatiotemporal regulation process and important biological functions. They are critical to maintain the transcriptome through post-transcriptionally controlling the processing and transportation of RNA, including regulating RNA splicing, polyadenylation, mRNA stability, mRNA localization, and translation. Alteration of each process will affect the RNA life cycle, produce abnormal protein phenotypes, and thus lead to the occurrence and development of tumors. Here, we summarize RBPs involved in tumor progression and the underlying molecular mechanisms whereby they are regulated and exert their effects. This analysis is an important step towards the comprehensive characterization of post-transcriptional gene regulation involved in tumor progression.

Keywords: Polyadenylation; RNA splicing; RNA-binding proteins; mRNA localization carcinoma; mRNA stability.

Fig. 1

Currently, more than 50 domains of RBPs have been discovered. Here, we select the common RBP domains. Different domains are represented by colored boxes: RNA recognition motif (RRM), K homology (KH) domain, tyrosine-rich domain, arginine-glycine-glycine (RGG) motif, cold-shock domain (CSD), zinc fingers of the CCCH, CCHC, ZZ type etc

Fig. 2

RBPs can interact with rRNAs, ncRNAs, snRNAs, miRNAs, mRNAs, tRNAs, and snoRNAs by binding to specific RNA-binding domains to perform specific biological functions

Fig. 3

The whole process of RBP analysis

Fig. 4

Signal pathways and metabolic pathways involved in abnormal RBP. HnRNP A1 /A2 is involved in the synthesis of M-type pyruvate kinase (PKM2), thereby enhancing the Warburg effect and let-7a-5p/Stat3/hnRNP-A1/PKM2 forms a cyclically regulated aerobic glycolysis. HuR regulates the PI3K/AKT/NF-κB signaling pathway. RNPC1 promotes the STARD13-mediated ceRNA network, thereby inhibiting the occurrence of EMT. The transcription factor ZEB1 protein can inhibit the mRNA level of epithelial splicing regulator protein 1 (ESRP1), resulting in the upregulation of the alternative spliceosome in the cell surface antigen CD44

Fig. 5

The LIN28/let-7 two-way negative feedback mechanism is involved in the processing of let-7 precursor miRNA into mature miRNA and combines with some cytokines (such as the SCR family, MYC family, and NF-κB) to form a complex factor regulatory system involved in cancer occurrence

Fig. 6

RBP post-translational modifications (PTMs) (acetylation, phosphorylation, methylation, and ubiquitination) are involved in important biological processes. Different PTMs regulate the abundance of RBP, subcellular localization, and different protein kinases and signal transduction pathways. Abnormal PTM promotes carcinogenesis, apoptosis, tumorigenesis and cancer progression by changing the binding ability of IGF2BPs to mRNA, and regulating the protein activity, stability, and localization of hnRNPE1, RBM15 and Sam68

Fig. 7

In addition to producing protein-encoding mRNA, genomic DNA also produces many non-coding RNAs, including long non-coding RNA (lncRNA) and miRNA, many of which are directly involved in transcription control. The occurrence of RNA transcription regulation involves multiple RNA-binding proteins (SRSF2, RBFox2, NONO). The abnormal function of typical splicing regulators in transcription is closely related to the pathogenesis of cancer

Fig. 8

Alternative splicing contributes to protein diversity and mRNA stability. Abnormal or erroneous splicing of RBPs is one of the causes of cancer. Some RBPs can form complexes with core proteins and combine with splicing, increase or decrease the activity of spliceosomes and jointly control the splicing of tumor cell molecules. SF3B1, hnRNP, and SR proteins are selective splicing regulators. They recognize spliceosomes by binding to spliceosomes, which in turn regulates splicing. Abnormalities in alternative splicing regulators are often associated with tumorigenesis

Fig. 9

APA makes the miRNA binding site missing by a cleavage complex (CFIm), which makes the mRNA more stable, the translation efficiency is higher, and the transcription of the mRNA is out of control, thereby promoting the migration and invasion of tumor cells

Fig. 10

HUR, PTPB, or other RNA binding proteins enhance the stabilization of BCL2, MCL1, c-myc, cyclin E1, BLxL, and ZEB1 PTEN-related mRNAs by binding to the ARE sequence elements of mRNA in 3′UTR, thereby increasing the expression of cancer-related proteins and promoting tumor angiogenesis, migration, invasion and drug resistance

Fig. 11

DNA is transcribed into RNA. With the help of hnRNA, pre-mRNA is transported to the cytoplasm. RBP binds to pre-mRNA and participates in splicing and splicing to form mRNA. Then hnRNA enters the cytoplasm and becomes mRNPs, which becomes a substrate for mRNA localization, and subsequently to be deadenylated so as to ensure that the mRNA can be effectively located to a specific position and efficiently synthesize protein

Fig. 12

The mRNA translation process is mainly the 5′cap structure of the eIF4F cap-binding complex that recognizes and binds to the mRNA. When the 43S pre-initiation complex-mediated cap binding and ribosome binding, translation starts from the AUG. Abnormal mRNA translation of eIF4E, XIAP and LAMB1 is closely related to the occurrence of cancer. In addition, the binding of PUM and miRNAs to 3′UTR can inhibit the translation of E2F3, JUN, and NRAS mRNA and its overexpression is related to tumor development

Fig. 13

RBPs participate in the entire physiological process of RNA and play a key role in the function of RNA. In tumor cells, the abnormal function of RBPs makes tumor cells be highly heterogeneous