Fine-tuning p53 activity by modulating the interaction between eukaryotic translation initiation factor eIF4E and RNA-binding protein RBM38.

p53 is critical for tumor suppression but also elicits detrimental effects when aberrantly overexpressed. Thus, multiple regulators, including RNA-binding protein RBM38, are found to tightly control p53 expression. Interestingly, RBM38 is unique in that it can either suppress or enhance p53 mRNA translation via altered interaction with eIF4E potentially mediated by serine-195 (S195) in RBM38. Thus, multiple RBM38/eIF4E knock-in (KI) cell lines were generated to investigate the significance of eIF4E-RBM38 interaction in controlling p53 activity. We showed that KI of RBM38-S195D or -Y192C enhances, whereas KI of RBM38-S195K/R/L weakens, the binding of eIF4E to p53 mRNA and subsequently p53 expression. We also showed that KI of eIF4E-D202K weakens the interaction of eIF4E with RBM38 and thereby enhances p53 expression, suggesting that D202 in eIF4E interacts with S195 in RBM38. Moreover, we generated an Rbm38 S193D KI mouse model in which human-equivalent serine-193 is substituted with aspartic acid. We showed that S193D KI enhances p53-dependent cellular senescence and that S193D KI mice have a shortened life span and are prone to spontaneous tumors, chronic inflammation, and liver steatosis. Together, we provide in vivo evidence that the RBM38-eIF4E loop can be explored to fine-tune p53 expression for therapeutic development.

LncRNA CALML3-AS1 suppresses papillary thyroid cancer progression via sponging miR-20a-5p/RBM38 axis.

BACKGROUND: The incidence and mortality of thyroid cancer (TC) has been steadily rising in the past decades. It is imperative to have a better understanding of the molecular mechanisms underlying TC development and identify novel therapeutic targets. This study characterized the role of lncRNA CALML3-AS1 (CALML3-AS1) in the development of papillary thyroid cancer (PTC). METHOD: Related mRNAs expression were validated in the tumor and adjacent normal tissues from 52 PTC patients and PTC cell lines by qRT-PCR. Expression of RBM38 was detected by Western blot. We have also conducted CCK-8 and colony formation assays were used to detect the effect of CALML3-AS1 on cell proliferation, Transwell assay was utilized to evaluate cell migration and invasion, apoptosis detected by flow cytometry assay, RNA pull-down and luciferase assays were performed to validate gene predictions. RESULTS: The results indicated that the expression of both CALML3A-S1 and RBM38 were significantly downregulated in PTC tissues (p < 0.01), while the expression of miR-20a-5p was increased in PTC (p < 0.01). Functionally, CALML3-AS1 overexpression inhibited PTC cell proliferation in vitro and in vivo. Mechanistically, CALML 3-AS1 sponged miR-20a-5p, which in turn leads to the suppression of RBM38 expression and PTC progression. CONCLUSIONS: CALML3-AS1 functions as a ceRNA for miR-20a-5p in the regulation of the expression of RBM38 in PTC. Higher level of CALML3-AS1 serves as a good prognostic indicator of survival in PTC patients. Targeting CALML3-AS1/ miR-20a-5p/RBM38 axis may represent a novel therapeutic strategy in the treatment of PTC.

Structural basis for mRNA recognition by human RBM38.

RNA-binding protein RBM38 was reported to bind the mRNA of several p53-related genes through its RRM domain and to up-regulate or down-regulate protein translation by increasing mRNA stability or recruitment of other effector proteins. The recognition mechanism, however, for RNA-binding of RBM38 remains unclear. Here, we report the crystal structure of the RRM domain of human RBM38 in complex with a single-stranded RNA. Our structural and biological results revealed that RBM38 recognizes G(U/C/A)GUG sequence single-stranded RNA in a sequence-specific and structure-specific manner. Two phenylalanine stacked with bases of RNA were crucial for RNA binding, and a series of hydrogen bonds between the base atoms of RNA and main-chain or side-chain atoms of RBM38 determine the sequence-specific recognition. Our results revealed the RNA-recognition mechanism of human RBM38 and provided structural information for understanding the RNA-binding property of RBM38.

RNA-binding protein RBM38 inhibits colorectal cancer progression by partly and competitively binding to PTEN 3'UTR with miR-92a-3p.

RNA-binding motif protein 38 (RBM38) belongs to the RNA recognition motif family of RNA-binding proteins (RBPs). RBM38 was previously identified to suppress tumorigenesis in colorectal cancer (CRC). RBM38 was also reported to bind to the 3'UTR of phosphatase and tensin homolog gene on chromosome 10 (PTEN), a tumor suppressor involved in many cellular processes, to stabilize PTEN transcripts. In the present study, we investigated the mechanisms underlying the regulation of RBM38 in CRC. Reverse transcription quantitative polymerase chain reaction and western blotting detected the expression of RBM38, PTEN, and miR-92a-3p. Colony formation, EdU, sphere formation, Transwell invasion, and in vivo assays examined the influence of RBM38 on CRC progression. Furthermore, RNA immunoprecipitation (RIP) assay determined the binding site of RBM38 on PTEN 3'UTR. The binding of miR-92a-3p or RBM38 on PTEN 3'UTR was assessed by luciferase reporter and RIP assays. We discovered that RBM38 was downregulated in CRC cells and tissues. RBM38 repressed CRC progression in vitro and in vivo. Furthermore, RBM38 upregulated and stabilized PTEN expression. Interestingly, the overexpression of PTEN reversely attenuated the promotion of RBM38 depletion on CRC progression. Additionally, RBM38 competed with miR-92a-3p in binding to PTEN 3'UTR. In conclusion, RBM38 inhibits CRC progression by competitively binding to PTEN 3'UTR with miR-92a-3p.

Glycogen synthase kinase 3 promotes p53 mRNA translation via phosphorylation of RNPC1.

The RNPC1 RNA-binding protein, also called Rbm38, is a target of p53 and a repressor of p53 mRNA translation. Thus, the p53-RNPC1 loop is critical for modulating p53 tumor suppression, but it is not clear how the loop is regulated. Here, we showed that RNPC1 is phosphorylated at Ser195 by glycogen synthase kinase 3 (GSK3). We also showed that GSK3 promotes p53 mRNA translation through phosphorylation of RNPC1. Interestingly, we found that the phosphor-mimetic mutant S195D and the deletion mutant Δ189-204, which lacks the GSK3 phosphorylation site, are unable to repress p53 mRNA translation due to loss of interaction with eukaryotic translation factor eIF4E on p53 mRNA. Additionally, we found that phosphorylated RNPC1, RNPC1-S195D, and RNPC1(Δ189-204) promote p53 mRNA translation through interaction with eukaryotic translation factor eIF4G, which then facilitates the assembly of the eIF4F complex on p53 mRNA. Furthermore, we showed that upon inhibition of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway, GSK3 is activated, leading to increased RNPC1 phosphorylation and increased p53 expression in a RNPC1-dependent manner. Together, we postulate that the p53-RNPC1 loop can be explored to increase or decrease p53 activity for cancer therapy.

Serine 195 phosphorylation in the RNA-binding protein Rbm38 increases p63 expression by modulating Rbm38's interaction with the Ago2-miR203 complex.

The p63 transcription factor, a p53 family protein, regulates genes involved in various cellular processes, including cell growth and differentiation. We previously showed that RNA-binding motif protein (Rbm38) is a p63 target and, in turn, regulates p63α mRNA stability by binding to the AU/U-rich element in its 3'UTR. Interestingly, Rbm38 can be phosphorylated at serine 195, altering its ability to regulate mRNA translation. However, whether the Ser-195 phosphorylation affects Rbm38's ability to destabilize p63 mRNA remains unclear. Here, using MCF7 and HaCaT cells, we showed that ectopic expression of phosphomimetic Rbm38-S195D increases, whereas WT Rbm38 and nonphosphorylatable Rbm38-S195A decrease p63α protein and transcript levels. We also found that upon activation of glycogen synthase kinase 3ß (GSK3ß), phosphorylation of Rbm38 at Ser-195 is increased, enhancing p63α expression in an Rbm38-dependent manner. To confirm this, we generated mouse embryo fibroblasts (MEFs) in which Ser-193 in mouse Rbm38 (equivalent to Ser-195 in human Rbm38) was substituted with aspartic acid (Rbm38S193D/S193D ) or alanine (Rbm38S193A/S193A ). We observed that the p63 transcript level was increased in Rbm38S193D/S193D MEFs, but decreased in Rbm38S193A/S193A MEFs. Mechanistically, we found that WT Rbm38, but not Rbm38-S195D, is required for p63 mRNA degradation mediated by microRNA 203 (miR203). Furthermore, we noted that Argonaute 2 (Ago2), a key regulator in microRNA-mediated mRNA decay, associates with WT Rbm38, and this association was reduced by Ser-195 phosphorylation. Together, our results reveal a critical mechanism by which Ser-195 phosphorylation in Rbm38 increases p63 expression by attenuating the association of Rbm38 with the Ago2-miR203 complex.

RBM38 induces SIRT1 expression during hypoxia in non-small cell lung cancer cells by suppressing MIR34A expression.

OBJECTIVE: The study is to research how miR-34-SIRT1 is regulated during hypoxia in lung cancer cells. RESULTS: Analysis of publicly available datasets from patients with NSCLC did not reveal significant genomic alterations in RBM38, SIRT1, HIF1A, MIR34A, MIR34B, and MIR34C, but expectedly revealed alterations in TP53. Overall survival in NSCLC patients with or without alterations in these genes was not significantly different. When expanded to include all lung cancer patients, overall survival was significantly lower in patients with genomic alterations in these genes. CONCLUSIONS: Cumulatively, our results reveal a novel mechanism of RBM38-mediated regulation of the HIF1A/miR-34a/SIRT1/p53 axis under hypoxia in NSCLC cells.

Rbm38 Reduces the Transcription Elongation Defect of the SMEK2 Gene Caused by Splicing Deficiency.

Pre-mRNA splicing is an essential mechanism for ensuring integrity of the transcriptome in eukaryotes. Therefore, splicing deficiency might cause a decrease in functional proteins and the production of nonfunctional, aberrant proteins. To prevent the production of such aberrant proteins, eukaryotic cells have several mRNA quality control mechanisms. In addition to the known mechanisms, we previously found that transcription elongation is attenuated to prevent the accumulation of pre-mRNA under splicing-deficient conditions. However, the detailed molecular mechanism behind the defect in transcription elongation remains unknown. Here, we showed that the RNA binding protein Rbm38 reduced the transcription elongation defect of the SMEK2 gene caused by splicing deficiency. This reduction was shown to require the N- and C-terminal regions of Rbm38, along with an important role being played by the RNA-recognition motif of Rbm38. These findings advance our understanding of the molecular mechanism of the transcription elongation defect caused by splicing deficiency.

The expression of RNA-binding protein RBM38 decreased in renal cell carcinoma and represses renal cancer cell proliferation, migration, and invasion.

RBM38, a member of RNA recognition motif family of RNA-binding proteins, can regulate the expression of diverse targets by influencing their messenger RNA stability and play a vital role in cancer development. RBM38 may act as an oncogene or suppressor gene in several human tumors. However, its role in human renal cell carcinoma remains unclear. In this study, we found that the expression of RBM38 was lower in renal cell carcinoma tissues and cell lines. Moreover, overexpression of RBM38 could reduce, whereas knockdown of RBM38 could accelerate renal cell carcinoma cell lines growth rate and number of colonies formation of renal cell carcinoma cell lines. Furthermore, RBM38 inhibited renal cell carcinoma cell lines migration and invasion through epithelial-mesenchymal transition suppression by up-regulating E-cadherin and down-regulating ß-catenin and vimentin. For in vivo assays, we found that the RBM38-positive group CAKI-1-RBM38 formed smaller tumors in nude mice compared with the control group. Kaplan-Meier analysis showed that renal cell carcinoma patients with lower expression of RBM38 had a significantly shorter survival time than those with higher expression of RBM38 ( p = 0.028). All these suggested that RBM38 acts as a tumor suppressor in renal cell carcinoma, which has the potential value for the prediction of renal cell carcinoma prognosis.

Mice deficient in Rbm38, a target of the p53 family, are susceptible to accelerated aging and spontaneous tumors.

RNA-binding motif protein 38 (Rbm38), also called RNPC1 [RNA-binding region (RNP1, RRM) containing 1], is a target of the p53 family and modulates p53 expression via mRNA translation. To investigate the biological function of Rbm38 in vivo, we generated an Rbm38-null mouse model. We showed that mice deficient in Rbm38 exhibit signs of accelerated aging and are prone to hematopoietic defects and spontaneous tumors. To determine the biological significance of the p53-Rbm38 loop, we showed that Rbm38 deficiency enhances accumulation of p53 induced by ionizing radiation (IR) and sensitizes mice to IR-induced lethality in a p53-dependent manner. Most importantly, Rbm38 deficiency markedly decreases the tumor penetrance in mice heterozygous for p53 via enhanced p53 expression. Interestingly, we found that Rbm38 deficiency shortens the life span of, and promotes lymphomagenesis in, mice deficient in p53. These results provide genetic evidence that Rbm38 is necessary for normal hematopoiesis and for suppressing accelerated aging and tumorigenesis. Thus, the p53-Rbm38 axis might be explored for extending longevity and for tumor suppression.

Identification of novel proteins binding the AU-rich element of α-prothymosin mRNA through the selection of open reading frames (RIDome).

We describe here a platform for high-throughput protein expression and interaction analysis aimed at identifying the RNA-interacting domainome. This approach combines the selection of a phage library displaying "filtered" open reading frames with next-generation DNA sequencing. The method was validated using an RNA bait corresponding to the AU-rich element of α-prothymosin, an RNA motif that promotes mRNA stability and translation through its interaction with the RNA-binding protein ELAVL1. With this strategy, we not only confirmed known RNA-binding proteins that specifically interact with the target RNA (such as ELAVL1/HuR and RBM38) but also identified proteins not previously known to be ARE-binding (R3HDM2 and RALY). We propose this technology as a novel approach for studying the RNA-binding proteome.

CREB3 suppresses hepatocellular carcinoma progression by depressing AKT signaling through competitively binding with insulin receptor and transcriptionally activating RNA-binding motif protein 38.

cAMP responsive element binding protein 3 (CREB3), belonging to bZIP family, was reported to play multiple roles in various cancers, but its role in hepatocellular carcinoma (HCC) is still unclear. cAMP responsive element binding protein 3 like 3 (CREB3L3), another member of bZIP family, was thought to be transcription factor (TF) to regulate hepatic metabolism. Nevertheless, except for being TFs, other function of bZIP family were poorly understood. In this study, we found CREB3 inhibited growth and metastasis of HCC in vitro and in vivo. RNA sequencing indicated CREB3 regulated AKT signaling to influence HCC progression. Mass spectrometry analysis revealed CREB3 interacted with insulin receptor (INSR). Mechanistically, CREB3 suppressed AKT phosphorylation by inhibiting the interaction of INSR with insulin receptor substrate 1 (IRS1). In our study, CREB3 was firstly proved to affect activation of substrates by interacting with tyrosine kinase receptor. Besides, CREB3 could act as a TF to transactivate RNA-binding motif protein 38 (RBM38) expression, leading to suppressed AKT phosphorylation. Rescue experiments further confirmed the independence between the two functional manners. In conclusion, CREB3 acted as a tumor suppressor in HCC, which inhibited AKT phosphorylation through independently interfering interaction of INSR with IRS1, and transcriptionally activating RBM38.

TRIM17-mediated ubiquitination and degradation of RBM38 promotes cisplatin resistance in non-small cell lung cancer.

Cisplatin (CDDP)-based chemotherapy is commonly used to treat advanced non-small cell lung cancer (NSCLC). However, the efficacy is limited by the development of drug resistance. Tripartite motif (TRIM) proteins typically have E3 ubiquitin ligase activities and modulate protein stability. In the present study, we screened for chemosensitivity-regulating TRIM proteins using CDDP-resistant NSCLC cell lines. We show that TRIM17 is upregulated in CDDP-resistant NSCLC cells and tumors compared to CDDP-sensitive counterparts. NSCLC patients with high TRIM17 expression in tumors have shorter progression-free survival than those with low TRIM17 expression after CDDP chemotherapy. Knockdown of TRIM17 increases the sensitivity of NSCLC cells to CDDP both in vitro and in vivo. In contrast, overexpression of TRIM17 promotes CDDP resistance in NSCLC cells. TRIM17-mediated CDDP resistance is associated with attenuation of reactive oxygen species (ROS) production and DNA damage. Mechanistically, TRIM17 interacts with RBM38 and promotes K48-linked ubiquitination and degradation of RBM38. TRIM17-induced CDDP resistance is remarkably reversed by RBM38. Additionally, RBM38 enhances CDDP-induced production of ROS. In conclusion, TRIM17 upregulation drives CDDP resistance in NSCLC largely by promoting RBM38 ubiquitination and degradation. Targeting TRIM17 may represent a promising strategy for improving CDDP-based chemotherapy in NSCLC.

RBM38 Reverses Sorafenib Resistance in Hepatocellular Carcinoma Cells by Combining and Promoting lncRNA-GAS5.

BACKGROUND: Hepatocellular carcinoma (HCC) is a life-threatening human malignancy and the fourth leading cause of cancer-related deaths worldwide. Patients with HCC are often diagnosed at an advanced stage with a poor prognosis. Sorafenib is a multikinase inhibitor used as the first-line treatment for patients with advanced HCC. However, acquired resistance to sorafenib in HCC leads to tumor aggression and limits the drug's survival benefits; the underlying molecular mechanisms for this resistance remain unclear. METHODS: This study aimed to examine the role of the tumor suppressor RBM38 in HCC, and its potential to reverse sorafenib resistance. In addition, the molecular mechanisms underlying the binding of RBM38 and the lncRNA GAS5 were examined. The potential involvement of RBM38 in sorafenib resistance was examined using both in vitro and in vivo models. Functional assays were performed to assess whether RBM38: binds to and promotes the stability of the lncRNA GAS5; reverses the resistance of HCC to sorafenib in vitro; and suppresses the tumorigenicity of sorafenib-resistant HCC cells in vivo. RESULTS: RBM38 expression was lower in HCC cells. The IC50 value of sorafenib was significantly lower in cells with RBM38 overexpression than in control cells. RBM38 overexpression improved sorafenib sensitivity in ectopic transplanted tumors and suppressed the growth rate of tumor cells. RBM38 could bind to and stabilize GAS5 in sorafenib-resistant HCC cells. In addition, functional assays revealed that RBM38 reversed sorafenib resistance both in vivo and in vitro in a GAS5-dependent manner. CONCLUSIONS: RBM38 is a novel therapeutic target that can reverse sorafenib resistance in HCC by combining and promoting the lncRNA GAS5.

RNA-Binding motif protein 38 (RBM38) mediates HBV pgRNA packaging into the nucleocapsid.

The binding of HBV polymerase (Pol) and the epsilon stem loop (ε) on the 5' terminal region of pgRNA is required for pgRNA packaging and HBV replication. Previous research has demonstrated that RNA binding motif protein 24 (RBM24) is involved in pgRNA packaging by mediating the interaction between HBV polymerase (Pol) and the ε element. Here, we demonstrate that RBM38 interacts with ε, pol, RBM24 and HBV core which mediate pgRNA packaging. RBM38 directly binds to the lower bulge of ε via RNA recognition submotifs (RNPs) and interacts with HBV Pol in an RNA-independent manner. RBM38 interacts with RBM24 and forms heterogeneous oligomers, which mediate Pol-ε binding and the formation of the Pol-RBM38/RBM24-ε complex. More important, RBM38 also binds to the HBV core via the C-terminal region (ARD domain), which facilitates the combination of Pol-ε with the HBV core protein. In conclusion, RBM38 facilitates the Pol-ε interaction and mediates Pol-ε in combining with the HBV core, triggering pgRNA packaging for reverse transcription and DNA synthesis. This study provides new insights into pgRNA encapsidation.

Immune Landscape and an RBM38-Associated Immune Prognostic Model with Laboratory Verification in Malignant Melanoma.

BACKGROUND: Current studies have revealed that RNA-binding protein RBM38 is closely related to tumor development, while its role in malignant melanoma remains unclear. Therefore, this research aimed to investigate the function of RBM38 in melanoma and the prognosis of the disease. METHODS: Functional experiments (CCK-8 assay, cell colony formation, transwell cell migration/invasion experiment, wound healing assay, nude mouse tumor formation, and immunohistochemical analysis) were applied to evaluate the role of RBM38 in malignant melanoma. Immune-associated differentially expressed genes (DEGs) on RBM38 related immune pathways were comprehensively analyzed based on RNA sequencing results. RESULTS: We found that high expression of RBM38 promoted melanoma cell proliferation, invasion, and migration, and RBM38 was associated with immune infiltration. Then, a five-gene (A2M, NAMPT, LIF, EBI3, and ERAP1) model of RBM38-associated immune DEGs was constructed and validated. Our signature showed superior prognosis capacity compared with other melanoma prognostic signatures. Moreover, the risk score of our signature was connected with the infiltration of immune cells, immune-regulatory proteins, and immunophenoscore in melanoma. CONCLUSIONS: We constructed an immune prognosis model using RBM38-related immune DEGs that may help evaluate melanoma patient prognosis and immunotherapy modalities.

Optimization of eIF4E-Binding Peptide Pep8 to Disrupt the RBM38-eIF4E Complex for Induction of p53 and Tumor Suppression.

Interaction of RNA-binding protein RBM38 with eIF4E on p53 mRNA is known to suppress p53 mRNA translation, which can be disrupted by an 8-amino acid peptide (Pep8-YPYAASPA) derived from RBM38, leading to induction of p53 and tumor suppression. Here, we rationally designed multiple Pep8 derivatives and screened for their binding affinities towards eIF4E in silico. We showed that several key residues within Pep8 are necessary for its structure and function. We identified a shortened 7-amino acid peptide (Pep7-PSAASPV) that has the highest affinity towards eIF4E and is the most potent inducer of p53 expression. We found that iRGD is an effective vehicle to deliver Pep7 inside of cells for induction of p53 expression and growth suppression as compared to other cell penetrating peptides (Penetratin and Pep-1). We found that peptide cyclization enhances Pep8 affinity for eIF4E, induction of p53 and tumor cell growth suppression. We also found that the ability of Pep7 to induce p53 expression and growth suppression is conserved in cells derived from canine osteosarcoma, a spontaneous tumor model frequently used for testing the feasibility of a therapeutic agent for human cancer. Moreover, we showed that both human and canine osteosarcoma cells, which are notoriously resistant to radiation therapy, were sensitized by Pep7 to radiation-induced growth suppression and cell death. Together, our data suggest that Pep7 may be explored to sensitize tumors to radiation therapy.

The RNA-binding protein RBM24 regulates lipid metabolism and SLC7A11 mRNA stability to modulate ferroptosis and inflammatory response.

Lipids play a critical role in many cellular processes by serving as structural components of cell membranes or functioning as energy fuel and signaling molecules. The RNA-binding proteins RBM24 and RBM38 share an identical RNA-binding domain and thereby, regulate a group of same targets, such as p21. However, it is not certain whether RBM24 and RBM38 participates in lipid homeostasis. Here, lipidomic analysis showed that a deficiency in RBM24 or RBM38 leads to altered lipid metabolism, with more profound alteration by loss of RBM24 in MCF7 cells. We also showed that mice deficient in RBM24 were prone to chronic inflammation and liver steatosis, but not spontaneous tumors. These data let us speculate whether RBM24 regulates ferroptosis, a programmed cell death that links inflammation and liver steatosis via lipid peroxidation. Indeed, we found that over-expression of RBM24 protected, whereas knockout of RBM24 sensitized, cells to Erastin-induced ferroptosis by modulating the mRNA stability of SLC7A11, a ferroptosis inhibitor. Moreover, we showed that knockdown of SLC7A11 reversed the effect of RBM24 on ferroptosis. Together, our study revealed that RBM24 regulates lipid metabolism and SLC7A11 mRNA stability to modulate ferroptosis and inflammatory response.

miR-125a-5p increases cellular DNA damage of aging males and perturbs stage-specific embryo development via Rbm38-p53 signaling.

An increasing number of men are fathering children at an older age than in the past. While advanced maternal age has long been recognized as a risk factor for adverse reproductive outcomes, the influence of paternal age on reproduction is incompletely comprehended. Herein, we found that miR-125a-5p was upregulated in the sperm of aging males and was related to inferior sperm DNA integrity as an adverse predictor. Moreover, we demonstrated that miR-125a-5p suppressed mitochondrial function and increased cellular DNA damage in GC2 cells. We also found that miR-125a-5p perturbed embryo development at specific morula/blastocyst stages. Mechanistically, we confirmed that miR-125a-5p disturbed the mitochondrial function by targeting Rbm38 and activating the p53 damage response pathway, and induced a developmental delay in a p21-dependent manner. Our study revealed an important role of miR-125a-5p in sperm function and early embryo development of aging males, and provided a fresh view to comprehend the aging process in sperm.

RNA-Binding Motif Protein 38 as a Potential Biomarker and Therapeutic Target in Cancer.

RNA-binding proteins (RBPs) act as a key factor in gene regulation by governing RNA metabolism. They contribute to the expression and functions of most RNAs by binding to them and forming complexes. RNA-binding motif protein 38 (RBM38), a member of the RBP family, alters the stability and translation of targeted mRNAs to affect various biological processes, such as cell proliferation, cell cycle arrest, and myogenic differentiation. RBM38 contains a highly conserved RNA recognition motif (RRM) consisting of two subunits, RNP1 and RNP2, which specifically bind to RNAs. Recent studies have revealed that RBM38 regulates the mRNA stability of several tumor-related genes, such as p53, mdm2, p63, p73, p21, and c-Myc, by binding to their 3' untranslated regions (3' UTRs); thus, RBM38 modulates targeted gene expression and affects the biological processes of tumors. In addition, abnormal RBM38 expression in some malignant tumors and its correlation with prognosis have been documented in many studies, indicating its value for potential clinical applications. In this review, we present an overview of RBM38, specifically highlighting its relationship with tumor manifestation and development. A brief overview of the potential use of RBM38 in cancer therapy is also included to provide ideas for further research on RBM38.