1. RBM24 in Cancer Development
1.1. RBM24 in Hepatocellular Carcinoma
Hepatocellular carcinoma (HCC) represents the most common form of liver cancer
[1]. Large-scale analysis of transcriptome alterations indicates that RBM24 expression is frequently downregulated in HCC, which may trigger or sustain an undifferentiated state of tumor cells
[2]. This suggests that RBM24 normally functions to inhibit HCC proliferation by promoting cell differentiation. Indeed, recent studies indicate that RBM24 shows reduced expression in liver cancer cell lines (HepG2, Hep3B, and Huh7) and exerts tumor-suppressive functions in HCC cells through several post-transcriptional mechanisms
[3][4]. Overexpression of RBM24 prevents tumor cell growth and induces sorafenib sensitivity by indirectly reducing the expression level of
p63 mRNA likely through inhibition of β-catenin nuclear translocation
[3]. Moreover, RBM24 can mediate the tumor suppressor function of ncRNAs by activating apoptotic tumor cell death. For example, the ncRNA
TPRG1-AS1 (tumor protein p63 regulated 1, antisense 1) has been shown to exert a tumor-suppressing property through stabilization of RBM24 expression by sequestrating its inhibitory
miR-3659 and
miR-4691-5p [4]. These observations suggest that RBM24 displays potential tumor suppressor function in liver cancer. However, another study shows that RBM24 exhibits increased expression in HCC and can prevent the inhibitory effect of the E3 ubiquitin ligase TRIM56 (tripartite motif containing 56) on the proliferation of Huh7 and Bel-7402 cells, implying that it may exert an oncogenic function
[5]. Further investigation will be necessary to clarify these apparent opposing results on RBM24 functions in HCC cells. In vivo functional assays, such as xenografts derived from RBM24-overexpressing or RBM24-deficient HCC cells combined with characterization of RBM24 target genes, should help to determine how it modulates HCC progression.
Chronic infection by hepatitis viruses represents the main risk factors for HCC development
[6]. Several in vitro studies show that RBM24 can function as a host factor that interacts with RNAs of hepatitis B virus and hepatitis C virus to regulate their replication
[7][8][9]. It appears that an appropriate level of RBM24 is required for hepatitis B virus replication in host cells, while either overexpression or knockdown of RBM24 can prevent virus replication
[8]. These observations suggest that RBM24 may contribute to hepatitis virus infection and represent a potential target for developing antiviral strategies.
1.2. RBM24 in Gastrointestinal Cancers
Gastrointestinal cancers account for 26% of the total cancer incidence and 35% of all cancer-related mortality
[10]. Colorectal cancer (CRC) represents the second most common cause of cancer death worldwide
[11]. Dysregulation of several important signaling pathways including Wnt/β-catenin, Hedgehog, Notch, TGF-β and MAPK/PI3K are involved in gastrointestinal carcinogenesis
[12]. Evidence is accumulating that RBM24 plays an important role in gastrointestinal cancers through different post-transcriptional mechanisms. One study demonstrates that RBM24 expression is strongly downregulated in colorectal tumor tissues from human patients and that spontaneous colorectal adenomas appear in
RBM24-knockout mice
[13]. This suggests that RBM24 has potential tumor suppressor function. Consistently, overexpression of RBM24 can inhibit metastasis of CRC cells and xenografts. Mechanistically, RBM24 promotes the accumulation of PTEN protein, a tumor suppressor and a negative regulator of PI3K (phosphoinositide 3-kinase) signaling, by directly binding to the 3′-UTR and increasing the stability of
PTEN mRNA
[13]. These results show that RBM24 can repress CRC progression by promoting the expression of tumor suppressor proteins. However, in gastric cancer, RBM24 expression seems to be associated with tumor cell migration or invasion
[14]. Systematic profiling of splicing landscape of epithelial–mesenchymal transition (EMT) subtypes of gastric tumors indicates that RBM24 is upregulated in the tumor subtype displaying mesenchyme-specific alternative splicing, which is correlated with a poor prognosis in patients from The Cancer Genome Atlas (TCGA) clinical data
[15]. In addition, the upregulation of RBM24 is positively correlated with the expression of the EMT activator ZEB1 (zinc finger E-box binding homeobox 1; previously known as TCF8), which impacts tumorigenesis by promoting migration, invasion, and metastasis
[15][16]. This post-transcriptional activity is consistent with the function of RBM24 in alternative splicing during embryonic development
[17]. However, the precise role of RBM24 in gastric cancer EMT remains unclear, and further identification of RBM24-regulated alternative splicing events will be necessary in order to understand how it modulates EMT in tumor progression and whether it exerts pro-tumor or anti-tumor activity in this cancer.
1.3. Tumor Suppressor Function of RBM24 in Nasopharyngeal Carcinoma
Expression profiling indicates that RBM24 and CELF4 are among the few RBPs that show frequent downregulation in nasopharyngeal carcinoma (NPC) tumor tissues and various NPC cell lines
[18]. In functional assays, overexpression of RBM24 inhibits tumor growth in xenografts and suppresses migration and invasion of NPC cells, while knockdown of RBM24 produces the opposite effects, suggesting that it exerts anti-tumor activity in NPC
[18]. Moreover, the tumor suppressor function of RBM24 appears to be mediated by
miR-25, which is the most upregulated miRNAs in RBM24-induced cells and suppresses NPC progression by targeting the oncogenic lncRNA
MALAT1 (metastasis associated with lung adenocarcinoma transcript 1) for degradation
[18]. These observations provide a mechanistic insight into the inhibitory role of RBM24 on NPC growth and viability. Further investigation will be necessary to analyze the clinical significance of RBM24 expression in NPC diagnosis and treatment. It is also of interest to determine how it functions in other types of head and neck cancers.
1.4. RBM24 Expression and Function in Lung Cancer
Lung cancer is one of the most common malignant tumors and a leading cause of cancer-related death worldwide
[11]. Non-small cell lung cancer (NSCLC) represents a large majority of all lung cancer subtypes. It frequently displays advanced or distant metastasis at the time of diagnosis
[19], which is associated with the process of EMT
[20]. RBM24 may play a role in lung cancer development, but how it functions to modulate progression of this type of cancer remains unclear. There are conflicting reports on its expression and activity in NSCLC. One study shows that RBM24 exhibits reduced expression in NSCLC tissues. Functional assays using NSCLC cell lines suggest that it mediates the tumor suppressor activity of the circRNA
SMARCA5 to inhibit tumor growth and induce apoptosis
[21]. By contrast, another study indicates that RBM24 protein shows increased expression in lung cancer tissues in a majority of cases, which may be correlated with a decreased chemosensitivity of lung adenocarcinoma (LUAD) cells and a reduced overall survival rate of patients with NSCLC
[14]. Due to these discrepancies and the lack of detailed mechanistic analyses, the exact role of RBM24 in lung cancer awaits further functional investigation. Moreover, it is also important to identify RBM24-regulated targets and understand how it is involved in LUAD cell proliferation, migration and invasion. In this regard, it is worth mentioning that ZEB1 has been shown to play an important role in EMT and malignant progression
[22]. Given the possible link between RBM24 and ZEB1 in gastric cancer
[15], it will be also of interest to examine whether and how RBM24 modulates ZEB1 expression and EMT in lung cancer.
1.5. Pro-Tumor Activity of RBM24 in Bladder Cancer
RBM24 has been shown to display increased expression in bladder cancer tissues and appears to play an oncogenic role by promoting cell proliferation. Its upregulation is correlated with a poor prognosis in bladder cancer patients
[23]. In addition, high expression of RBM24 appears to be associated with low overall survival and disease-free survival
[24]. Functional analyses using human bladder carcinoma cells indicate that RBM24 stabilizes
RUNX1T1 mRNA and increases the expression of RUNX1T1 protein, which in turn positively regulates RBM24 expression by suppressing the transcription of its inhibitory
miR-625-5p [23]. This positive feedback loop may represent a mechanism by which RBM24 participates in bladder cancer progression, but in vivo functional assays will be necessary to further determine its implication in tumor growth.
1.6. RBM24 in Other Cancers
RBM24 expression also appears to be dysregulated in several other cancer types, but functional and molecular analyses of its activity in tumor progression are still lacking. Bioinformatic analyses provide correlative evidence for a possible involvement of RBM24 in the development of several cancers. For example, survival analyses suggest that RBM24 may be a potential prognostic biomarker for head and neck squamous cell carcinoma (HNSCC) and skin cutaneous melanoma (SKCM) patients
[25][26]. In triple negative breast cancer (TNBC) patients, RBM24 is upregulated during the disease-free interval (DFI) and is correlated with poor prognosis
[27]. In medulloblastoma (MB), RBM24 represents one of the few reliable biomarkers that can be used for diagnosis and prognosis of group 4 tumors
[28]. However, these correlative data require further experimental validation to determine how RBM24 regulates cell proliferation and tumor metastasis in these cancers. In particular, functional analyses using animal models associated with systematic identification of target genes will be necessary to understand its function in the development or recurrence of these cancers.
1.7. Possible Roles of RBM24 in the Progression of Other Diseases
RBM24 exhibits strongly restricted expression in skeletal muscle and in the heart during vertebrate development
[29]. It also shows cytoplasm-to-nucleus translocation during myogenesis and dynamic post-transcriptional functions during muscle regeneration mediated by muscle stem cells
[30]. In several animal models, loss of RBM24 activity has been shown to inhibit myogenic differentiation
[29][31] and impair cardiogenesis
[17][32][33][34][35] and vasculogenesis
[33]. At present, no skeletal muscle disease has been directly associated with dysfunction of the
RBM24 gene. However, its altered expression has been observed in dystrophic muscular cells
[36][37]. Of note, mouse models for muscular dystrophy are prone to myogenic tumors
[38] and human patients with Duchenne muscular dystrophy present high susceptibility of developing rhabdomyosarcoma
[39]. There is also evidence that muscle stem cells can give rise to rhabdomyosarcoma in dystrophic mice
[40]. Thus, it will be of interest to examine whether dysregulation of RBM24 in muscle progenitor or stem cells impacts the occurrence of different myogenic tumors.
The most obvious phenotype resulting from loss of RBM24 is cardiogenic defects. RBM24-deficient mice develop dilated cardiomyopathy due to disrupted muscle-specific splicing of a large number of genes associated with cardiogenesis and sarcomere organization
[17][35]. In addition, mutant embryos die at E13.5 due to endocardial cushion defect and growth retardation at least in part as a consequence of aberrant activation of p53-dependent apoptosis
[32]. These observations suggest a possible involvement of RBM24 in heart disease and heart failure.
2. Regulation of RBM24 Expression and Activity in Cancers
It seems that RBM24 displays either decreased or increased expression as well as anti-tumor or pro-tumor activity, depending on the cancer type (
Table 1). In several cancers, RBM24 functions as a tumor suppressor, and its low expression can lead to tumorigenesis. On the contrary, increased expression of RBM24 in other cancers may be associated with cell proliferation and tumor progression, resulting in poor prognosis and low overall survival. Thus, the challenge is to understand how the expression and activity of RBM24 are dysregulated during malignant transformation. There is evidence that the
RBM24 gene represents a transcriptional target of the tumor suppressor p53, which binds to
RBM24 promoter region and induces its expression in tumor cells independently of DNA damage
[41]. The upregulation of RBM24 can, in turn, repress tumor progression by stabilizing mRNAs encoding tumor suppressor proteins. This is consistent with its anti-tumor activity in several cancer types. However, when the serine residue within the elF4E-binding motif is not phosphorylated, RBM24 can also inhibit p53 expression by interacting with elF4E and preventing the assembly of translation initiation complex
[32]. In this situation, it may exert a potential pro-tumor function. These observations raise the intriguing possibility that RBM24 may have context-dependent activity and that the oncogenic or anti-oncogenic potential of RBM24 in different cancers may be modulated by phosphorylation. Accordingly, the elF4E-binding motif may represent a potential therapeutic target for cancer treatment. Indeed, disrupting the interaction between RBM24 and elF4E can effectively convert RBM24 into an activator of
p53 mRNA translation
[32]. Therefore, it will be interesting to determine the phosphorylation status of RBM24 and identify possible kinases that are potentially involved in its post-translational modifications in different cancer tissues. In this regard, it is worth mentioning that GSK3β and Stk38 may play a role in RBM24 phosphorylation to regulate its function and stability
[42][43].
Inappropriate epigenetic modifications can also contribute to dysregulation of RBM24 expression in cancers. It has been reported that cancer-related genes display differential methylation between tumor and normal tissues
[44]. This mechanism can lead to overexpression of RBM24 in HCC cells and in HCC specimen. The reactivation of RBM24 expression is a consequence of increased demethylation in its enhancer but not in its promoter, and deletion of the enhancer region reduces its transcriptional level in Huh7 HCC cells but not in non-tumorigenic hepatocytes
[44]. This raises a possibility that the decrease or increase in RBM24 expression during cancer progression may be dependent on its epigenetic modifications. There is also evidence that the function of RBM24 in cancers may be subjected to post-transcriptional regulation. As aforementioned, ncRNAs such as
TPRG1-AS1 and
circSMARCA5 can positively or negatively modulate the post-transcriptional expression of RBM24 in HCC and LUAD
[4][21]. Altogether, RBM24 expression and function can be regulated at transcriptional, post-transcriptional and post-translational levels. Future studies will be necessary to provide further insights into the mechanisms underlying RBM24 dysregulation during malignant transformation and determine its activity in specific cancer cells.