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 Table of Contents  
REVIEW ARTICLE
Year : 2013  |  Volume : 9  |  Issue : 7  |  Page : 129-134

The function of the RNA-binding protein hnRNP in cancer metastasis


Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China

Date of Web Publication30-Nov-2013

Correspondence Address:
Mengxian Zhang
Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.122506

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 > Abstract 

Heterogeneous ribonucleoproteins (hnRNPs) are involved in a variety of key cellular functions and are most likely involved in different steps of pre-mRNA processing. Over the past decades, the central roles of hnRNPs have been detected, which show that they are involved in RNA splicing, telomere biogenesis, DNA repair, cell signaling, and in transcription and translation. Mounting evidence suggests that they are involved in the regulation of mRNA stability and translation in many cancer types. The hnRNPs have a variety of potential roles in inhibition of apoptosis, angiogenesis, cell invasion, and epithelial-mesenchymal transition (EMT). It is thus suggested that hnRNP might be a novel and promising therapeutic target and a marker for treatment response and prognostic evaluation. The aims of this review are to survey the existing evidence and discuss the diverse functions of hnRNPs in cancer metastasis.

Keywords: Apoptosis, cancer, epithelial-mesenchymal transition, HnRNP, metastasis


How to cite this article:
Han N, Li W, Zhang M. The function of the RNA-binding protein hnRNP in cancer metastasis. J Can Res Ther 2013;9, Suppl S2:129-34

How to cite this URL:
Han N, Li W, Zhang M. The function of the RNA-binding protein hnRNP in cancer metastasis. J Can Res Ther [serial online] 2013 [cited 2019 Sep 16];9:129-34. Available from: http://www.cancerjournal.net/text.asp?2013/9/7/129/122506


 > Introduction Top


RNA-binding proteins (RBPs) are proteins that bind to the double- or single-stranded RNA in cells and participate in forming ribonucleoprotein complexes. RBPs have crucial roles in various cellular processes such as cellular function, transport, and localization. They are responsible for posttranscriptional control of RNAs, such as pre-mRNA splicing, and polyadenylation, as well as mRNA export, turnover, localization, and translation. [1]

RBPs involved in the regulation of mRNA transcription interact with the nascent pre-mRNA when genes are actively transcribed by RNA polymerase II (Pol II). [2],[3],[4] Then, the mRNA becomes 5'-capped and polyadenylated and undergoes splicing. [5] However, changes in the alternative splicing of mRNA transcribed from genes involved in cell cycle control, cell proliferation, and apoptosis have been linked to tumor formation and progression. [6]

Following synthesis, other RBPs prepare the pre-mRNA for cytoplasmic export, which requires the activity of ribonucleoprotein capable of nucleocytoplasmic shuttling. Once exported into the cytoplasm, the mature mRNA is transported to the translational machinery where, on association with ribosomes, it is decoded and used several times as a template for protein synthesis. [7] During the entire process, the mRNA is not naked, but different RBPs take turn and bind to regulatory elements, which is used to increase the expression of a gene is to stabilize its mRNA strand, which is subject to degradation by RNases. Therefore, RBPs are involved in the maintenance of mRNA stability. [8]

Altered mRNA metabolism is a feature of many cancers. Indeed, loss of function of many tumor suppressors regulating cell proliferation, survival, and differentiation results from aberrant mRNA processing, nuclear export, and/or translation. [9],[10] However, RBP seems to play a pivotal role in mRNA metabolism through modification of splicing and/or stability of some tumor or antitumor genes. Thus, we have reasons to believe that the effects of RBPs in cancer progression are essential. In fact, aberrant expression and regulation of RBPs likely results in the deregulation of splicing and/or stability of mRNA, observed in cancer. [11] This indicates that cancer-associated RBPs are normally regulated as part of the developmental pathways that are dysregulated at various stages of tumorigenesis. [12] While the regulation of these RBPs is still not well understood, some new insights are available.

Recognition of the RNA targets by RBPs is highly specific, which recognize their sequences and structures. RBPs exist as complexes of proteins and pre-mRNA, named heterogeneous ribonucleoproteins (hnRNPs). [13] In this review, we will focus on the role of hnRNPs in the cancer metastasis, as emerging evidence suggests that hnRNPs are essential factors in tumor development and metastasis.


 > The hnrnp Family Top


HnRNPs are complexes of RNA and protein present in the cell nucleus during gene transcription and subsequent posttranscriptional modification of mRNA. This family includes about 20 major polypeptides, HnRNPs A1-U, which range in size from 34 to 120 kDa. [14] HnRNPs bind RNA Pol II transcripts to form hnRNP particles, and have a wide range of roles in DNA repair, telomere biogenesis, cell signaling, and regulating the gene expression at both transcriptional and translational levels. All the hnRNP promoter regions analyzed (A1, A2, D, F, H/H', and K) contained upstream binding elements for oncogenes such as E2F/AP1, acute myeloid leukemia (AML), and c-Myc. [14] Therefore, many hnRNP genes may be regulated by oncogenes. In fact, there is emerging evidence suggesting that some hnRNPs (including hnRNP A2/B1, hnRNP M, and hnRNP K) are essential factors in tumor development and progression. [15],[16],[17],[18] However, many putative hnRNP genes that encode minor hnRNP proteins remain to be characterized. [18]

HnRNP proteins direct their influence on pre-mRNA splicing through site-specific binding with the target RNA. After binding, the business end of hnRNPs (RGG boxes, glycine-rich, acidic, or proline-rich domains) then promotes protein/protein interactions that ultimately mediate splicing decisions. [19] It has been confirmed that hnRNP A1, hnRNP A2, and hnRNP I (also known as polypyrimidine tract-binding protein, PTB) are involved in this process. In fact, defects in splicing might lead to multiple types of cancer. [20]

Each hnRNP protein contains at least one RNA-binding motif. One such element is called the adenylate + uridylate-rich element (ARE), commonly found in the 3' untranslated region (UTR) of mRNAs. AREs consist of repeating pentamers of the sequence AUUUAA, which mediate the degradation of cytokine and proto-oncogene mRNAs. [13] Another element is the internal ribosomal entry site (IRES), which is a specialized RNA structure responsible for recruiting the ribosome to the mRNA. [13] For example, hnRNP D (also known as AUF1) is an AREs-binding protein that regulates the mRNA stability of proto-oncogenes, growth factors, cytokines, and cell cycle regulatory genes. [21] In parallel, hnRNP A1 and hnRNP I have been found to bind to the c-Myc IRES sequence. [22]

Besides the regulation of mRNA stability and splicing of oncogenes, hnRNPs regulate proliferation and telomere, which are related to cancer progression. The hnRNP A1, [23] hnRNP A2/B1, [24] hnRNP D, [25] and hnRNP G [26] are associated with cellular processes that affect the cell cycle and proliferation. With regard to telomere, it is demonstrated that hnRNP D, hnRNP A2/B1, and hnRNP A1 bind human telomeric DNA sequences. [27] Additionally, hnRNP D and the UP1 isoform of the hnRNP A1 gene interact directly with telomerase. [28] HnRNPs have a suppression effect on DNA damage repair, as well. [29] The existing researches have suggested that the role of hnRNPs in cancer progression is important and interesting, even though the details are not exhaustive.


 > The Involvement of Hnrnps in Apoptosis Pathway Top


The resistance of programmed cell death, or apoptosis, is recognized as an important hallmark of cancer. [30] However, the fact is that cancer has increased frequency of apoptosis. More malignancy leads to more apoptosis. Thus, some researchers propose that apoptosis plays a key role in the malignant progression and metastasis of cancer. [31]

In fact, hnRNPs are affirmed to involve in the cancer-related apoptosis. Overexpression of hnRNP E2 in carcinoma cell lines leads to dramatic growth reduction and apoptosis, while knockdown of hnRNP K renders the tumor cells more susceptible to cytotoxicity and results in spontaneous tumor cell apoptosis. [32],[33] Also, hnRNP A2/B1 coordinates with Fyn and Sam68 to regulate apoptosis, thus promoting the proliferation and metastasis of pancreatic cancer. [34],[35] Moreover, enforced expression of hnRNP H partially counteracted apoptosis induced by etoposide. [35] Interestingly, induction of hnRNP E4 (also known as aCP-4) inhibited proliferation and tumorigenesis, while inhibition of its [36] expression increased cell death and apoptosis. [36] The function of hnRNP E4 is opposite to that of the other hnRNPs.

Indeed, a number of studies have documented the contribution of hnRNPs in the control of splice site selection in apoptotic genes and in the control of the complex and delicate balance between the activities of pro- and anti-apoptotic variants produced by apoptotic peptidase activating factor (APAF-1), [37] Bcl-x, [38] Fas, [39] and caspases. [40] For example, downregulating hnRNP K caused the skipping of a 129-nucleotide exon in APAF-1. [40]

B-cell lymphoma-extra (Bcl-X) is a well-known regulator of apoptosis. [41] Knockdown of hnRNP K shifts the splicing of the Bcl-x pre-mRNA from the anti-apoptotic Bcl-xl toward the pro-apoptotic Bcl-xs. HnRNP K influences the splicing pattern of the Bcl-X gene through binding to a splicing silencer element of Bcl-X gene and repressing the production of the Bcl-XS isoform, which is the pro-apoptotic isoform. Similarly, hnRNP A1, [42],[43] hnRNP A2/B1, [44] hnRNP F, and hnRNP H [45] also enhance mRNA splicing, giving rise to the pro-apoptotic regulator Bcl-XS.

Caspase is involved in the intrinsic apoptotic pathway and suggested to play a role as a tumor suppressor. [41] Caspase-9 has two splice variants, pro-apoptotic caspase-9a and anti-apoptotic caspase-9b. [46] An exonic splicing silencer (ESS) regulated caspase-9 pre-mRNA processing. [47] In the non-small-cell lung cancer cells (NSCLC cells), hnRNP U competed with hnRNP L for binding to ESS, and downregulation of hnRNP L expression induced an increase in the caspase-9a/9b ratio. [46] However, this splice-enhancing function is blocked by the also known as protein kinase B, PKB (AKT) pathway via phosphorylation of hnRNP L. [47] It is indicated that hnRNP K suppresses the activity of various caspases through controlling transcription of the caspase inhibitor X linked inhibitor of apoptosis protein (XIAP). [48] In addition, HnRNP K also directly binds to the promotor region of the caspase-8 inhibitor FLIP gene, thereby inhibiting caspase-8 by increasing FLIP expression. [49] Moreover, hnRNP I and hnRNP A1 have also been observed in the control of caspase-2 pre-mRNA splicing. [50]

Many of the hnRNPs are also observed to regulate p53, another famous apoptotic gene. [51] One of the most recently identified cofactors, hnRNP K, is a member of the p53 pathway, for it interacts with the mutant p53, and hnRNP K is required for p53-mediated transcription. [39] Knockdown of hnRNP K inhibits pancreatic cancer cell growth and colony formation. [52] Moreover, hnRNP C1/C2 binds to p53-IRES and partial silencing of hnRNP C1/C2 results in appreciable decrease in IRES function and consequent decrease in the level of the corresponding p53 isoform. [53] So far, mounting evidences show that hnRNPs participate in the cancer-associated apoptosis, and the mechanism is very clear and might be detailed in the near future.


 > The Role of hnRNPs in Epithelial-To-Mesenchymal Transition Top


Epithelial-to-mesenchymal transition (EMT) is one of the important events for the cancer cells to acquire invasive capacity. [54] EMT is related to changes in cell-cell adhesion, remodeling of extracellular matrix, and enhanced migratory activity, all properties that enable cancer cells to metastasize. [54] Transforming growth factor β (TGF-β) and E-cadherin have also been implicated in EMT. [12],[55],[56]

Posttranscriptional regulatory events have also been reported as the critical regulators of TGF-β actions, playing an indispensable role in TGF-β-induced EMT and metastasis. HnRNPs are shown to influence the TGF-β-modulated expression of EMT-specific proteins and EMT itself. If phosphorylated by TGF-β, hnRNP E1 releases disabled-2 (Dab2) and interleukin-like EMT inducer (ILEI) mRNAs by repressing their translation by binding TGF-β-activated translation (BAT) element in the 3' UTR of the two transcripts, thereby restoring the translation of target EMT transcripts. [57] HnRNP E1 may regulate a cohort of EMT and metastasis mRNA transcripts, although only Dab2 and ILEI have been identified so far. [55] In addition, silencing hnRNP K expression could significantly decrease the EMT phenotype which is induced by TGF-β in the A549 cells (a nonepithelial lung cancer cell line). [58] It indicates that other hnRNPs might be also involved in the TGF-β-induced EMT; however, further details need to be found.

It has been affirmed that H19 contributes to EMT and to the suppression of tumor metastasis. [59] Indeed, hnRNP U is essential for H19-mediated transcription repression. The binding between hnRNP U and H19 disrupts the interaction between hnRNP U and actin, which inhibits phosphorylation of the RNA Pol II C-terminal domain (CTD), consequently preventing RNA Pol II-mediated transcription. [60] Therefore, H19 inhibits RNA Pol II-mediated transcription by disrupting the hnRNP U-actin complex.

Expression of hnRNP A2/B1 also plays a role in EMT. [56] In fact, silencing hnRNP A2/B1 in A549 and H1703 cells correlated with an increase of E-cadherin expression and downregulation of the E-cadherin inhibitors Twist1 and Snai1. Thus, hnRNPs also could regulate E-cadherin during EMT. [56]

Anyway, hnRNPs are essential for EMT. Furthermore, it has been confirmed that hnRNPs promote invasive behavior in a number of cancer cell types. Moran-Jones et al. [61] reported that hnRNP A2 was required for the cells to invade matrigel or to migrate on a cell-derived matrix by promoting inclusion of exon 2 in transcripts of the gene encoding a p53 target, TP53INP2, in invasive cells. hnRNP I also exerts an effect on cell migration by binding to mRNAs encoding vinculin and α-actinin 4 and localizing to focal adhesions upon cell adhesion. [2] In addition, overexpression of hnRNP A1 promotes tumor invasion by regulating CD44v6. [62] Knockdown of hnRNP A1 in highly metastatic hepatocellular carcinoma (HCC) cells leads to a decrease in cell invasion, while upregulation of hnRNP A1 in poorly metastatic HCC cells results in an increase in invasive capacity. [62] Furthermore, it has been reported that hnRNP K could up-regulate the matrix metalloproteinase-3 and -10 (MMP-3 and MMP-10) in the cancer cells. [15] In fact, role of MMPs has been established in tumor invasion and metastasis. [63] Consequently, hnRNPs are necessary for the cancer cells to invade and migrate.


 > HnRNPS Participate in the Cancer Angiogenesis Top


Angiogenesis is required for invasive cancer growth and metastasis, [64] and factors that are known to stimulate angiogenesis include vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). [65],[66] Indeed, VEGF expression under hypoxia also requires posttranscriptional mRNA stability and mRNA transport mechanisms. [67] VEGF mRNA is mediated through AREs in the 3' UTR. [67] Cross-linking and affinity purification experiments identified hnRNP A1 and hnRNP L as the RBPs for this hypoxia stability region (HSR) element. [8] HnRNP L specifically binds to a 126-base region of the VEGF mRNA 3' UTR, and interestingly, this protein-RNA interaction occurs only in cells undergoing hypoxia. Moreover, hnRNP A1 has been shown to enhance translation of the angiogenic factor FGF-2, [68] providing another connection between the hnRNPs and angiogenesis. In addition, hnRNP K also regulates angiogenesis pathways. [15],[69] The hnRNP K could bind selectively to the VEGF promoter. The silencing of hnRNP K results in the down-regulation of basal VEGF gene, suggesting that hnRNP K act as an activator of VEGF transcription. [70],[71] Additionally, hnRNP H1/H2 could bind to thymidine phosphorylase (TP) pre-mRNA, hence implicating TP splicing. [72] In fact, the latter plays an important role in induction of angiogenesis. [73] Taken together, these results provide an insight into the mechanisms of posttranscriptional regulation of angiogenesis by hnRNPs.


 > HnRNPS are Potential Biomarkers and Therapeutictargets Top


illustrated above, hnRNP genes are involved in human malignancies and metastasis. Also, many reports have suggested that several hnRNPs are promising biomarkers of lung, head and neck, colon, breast, and pancreatic cancers. [16],[74],[75],[76],[77]

The hnRNP A2/B1 is overexpressed in several tumors such as glioblastoma, liver cancer, lung cancer, and breast cancer. [75],[78],[78],[79],[80],[81] Its expression level is correlated with poor prognosis. [80],[81] Moreover, the increased expression and cytoplasmic localization of hnRNP A2/B1 can be used as a diagnostic biomarker to assess the risk of human liver cancer. [82] Furthermore, knockdown of hnRNP A2/B1 induces apoptosis only in cancer cells, but not in normal cells. [83] Thus, it might be an ideal therapeutic target. In addition, plasma hnRNP B1 mRNA could be a non-invasive marker for detection of lung cancer. [74]

Overexpression of hnRNP I might be required for the development and maintenance of epithelial ovarian tumors and glioblastoma cells. Hence, it may be a novel therapeutic target in the treatment of ovarian cancer and glioblastoma. Besides, hnRNP E4 is one of the most common altered regions in lung cancer. It has been proposed that it may function as a lung tumor suppressor. Lack of expression of hnRNP E4 is frequent in highly proliferative lung tumors. It might also be a therapeutic target in lung cancer.

With regard to HCC, hnRNP K is important for hepatitis B virus replication and contributes to hepatitis C virus pathogenesis, both of which are important etiological factors contributing to this malignancy. [84] In addition, hnRNP A2/B1 could be as a regulator of HPV-16 late gene expression. [85],[86],[87] Thus, these two hnRNPs might be potential therapeutic targets for virus-induced HCC. Also, hnRNP K is a potential tissue biomarker for detection of early HCC. [84]

In addition, many other hnRNPs have been suggested as potential biomarkers of cancer. For example, overexpression of hnRNP K is an independent marker of poor prognosis in colorectal cancer and oral squamous cell carcinoma (OSCC) patients. HnRNP D may be considered as a new, additional marker for thyroid carcinoma. Genetic alterations and aberrant expression of hnRNP G might be useful markers for the early detection of human oral cancer. Recently, overexpression of hnRNP A1 is found to be a potential biomarker for colorectal cancer.


 > Conclusion Top


A growing body of studies on the biological activity of hnRNPs suggests that they have crucial functions involved in mRNA stability and cancer metastasis. The mRNAs targeted by hnRNPs may translate into a variety of factors associated with cancer cell proliferation, angiogenesis, invasion, and EMT. Aberrant expression of certain hnRNP members is related to malignancies and metastasis in different tumor tissues. Identification of factors leading to metastasis is highly important to design effective and novel anti-cancer therapeutics; thus, hnRNPs could serve as a biomarker or prognostic target for detection of different cancers. Furthermore, the investigation of posttranscriptional molecular regulation mechanism of hnRNPs in EMT could also be a possible therapeutic approach, which may involve direct prevention of hnRNPs' expression using microRNAs' interference and signaling pathway modulators or kinase inhibitors, neutralization hnRNP proteins with specific antibodies, suppression of hnRNPs' translation, and inhibition of hnRNPs' aberrant nuclear-cytoplasmic trafficking accompanied with the relevant current anti-cancer or anti-metastasis therapeutics.

In summary, significant insights have been gained from the clinical relationship of hnRNPs and cancer metastasis reviewed here, and targeting hnRNPs may be a specific anti-metastasis and anti-angiogenic therapy and contributes to the validation of pharmaceutical strategies.

 
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