Gene Summary

Gene:HNRNPA2B1; heterogeneous nuclear ribonucleoprotein A2/B1
Summary:This gene belongs to the A/B subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are RNA binding proteins and they complex with heterogeneous nuclear RNA (hnRNA). These proteins are associated with pre-mRNAs in the nucleus and appear to influence pre-mRNA processing and other aspects of mRNA metabolism and transport. While all of the hnRNPs are present in the nucleus, some seem to shuttle between the nucleus and the cytoplasm. The hnRNP proteins have distinct nucleic acid binding properties. The protein encoded by this gene has two repeats of quasi-RRM domains that bind to RNAs. This gene has been described to generate two alternatively spliced transcript variants which encode different isoforms. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:heterogeneous nuclear ribonucleoproteins A2/B1
Source:NCBIAccessed: 27 February, 2015


What does this gene/protein do?
Show (16)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 27 February 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Ribonucleoproteins
  • Non-Small Cell Lung Cancer
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B
  • Breast Cancer
  • Apoptosis
  • Protein-Serine-Threonine Kinases
  • DNA-Binding Proteins
  • Adenocarcinoma
  • RNA Interference
  • Neoplasm Proteins
  • Immunoprecipitation
  • Cell Line
  • Glioblastoma
  • Nuclear Proteins
  • Western Blotting
  • Heterogeneous-Nuclear Ribonucleoproteins
  • von Hippel-Lindau Disease
  • Transcription Factors
  • Immunohistochemistry
  • RNA-Binding Proteins
  • Transfection
  • Messenger RNA
  • Molecular Sequence Data
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Cytoplasm
  • mRNA Cleavage and Polyadenylation Factors
  • Cancer Gene Expression Regulation
  • Phosphorylation
  • Protein Binding
  • 3' Untranslated Regions
  • Repressor Proteins
  • Neoplastic Cell Transformation
  • Exons
  • Base Sequence
  • Up-Regulation
  • Alternative Splicing
  • Lung Cancer
  • Chromosome 7
Tag cloud generated 27 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: HNRNPA2B1 (cancer-related)

Kasim M, Benko E, Winkelmann A, et al.
Shutdown of achaete-scute homolog-1 expression by heterogeneous nuclear ribonucleoprotein (hnRNP)-A2/B1 in hypoxia.
J Biol Chem. 2014; 289(39):26973-88 [PubMed] Article available free on PMC after 26/09/2015 Related Publications
The basic helix-loop-helix transcription factor hASH1, encoded by the ASCL1 gene, plays an important role in neurogenesis and tumor development. Recent findings indicate that local oxygen tension is a critical determinant for the progression of neuroblastomas. Here we investigated the molecular mechanisms underlying the oxygen-dependent expression of hASH1 in neuroblastoma cells. Exposure of human neuroblastoma-derived Kelly cells to 1% O2 significantly decreased ASCL1 mRNA and hASH1 protein levels. Using reporter gene assays, we show that the response of hASH1 to hypoxia is mediated mainly by post-transcriptional inhibition via the ASCL1 mRNA 5'- and 3'-UTRs, whereas additional inhibition of the ASCL1 promoter was observed under prolonged hypoxia. By RNA pulldown experiments followed by MALDI/TOF-MS analysis, we identified heterogeneous nuclear ribonucleoprotein (hnRNP)-A2/B1 and hnRNP-R as interactors binding directly to the ASCL1 mRNA 5'- and 3'-UTRs and influencing its expression. We further demonstrate that hnRNP-A2/B1 is a key positive regulator of ASCL1, findings that were also confirmed by analysis of a large compilation of gene expression data. Our data suggest that a prominent down-regulation of hnRNP-A2/B1 during hypoxia is associated with the post-transcriptional suppression of hASH1 synthesis. This novel post-transcriptional mechanism for regulating hASH1 levels will have important implications in neural cell fate development and disease.

Barceló C, Etchin J, Mansour MR, et al.
Ribonucleoprotein HNRNPA2B1 interacts with and regulates oncogenic KRAS in pancreatic ductal adenocarcinoma cells.
Gastroenterology. 2014; 147(4):882-892.e8 [PubMed] Related Publications
BACKGROUND & AIMS: Development of pancreatic ductal adenocarcinoma (PDAC) involves activation of c-Ki-ras2 Kirsten rat sarcoma oncogene homolog (KRAS) signaling, but little is known about the roles of proteins that regulate the activity of oncogenic KRAS. We investigated the activities of proteins that interact with KRAS in PDAC cells.
METHODS: We used mass spectrometry to demonstrate that heterogeneous nuclear ribonucleoproteins (HNRNP) A2 and B1 (encoded by the gene HNRNPA2B1) interact with KRAS G12V. We used co-immunoprecipitation analyses to study interactions between HNRNPA2B1 and KRAS in KRAS-dependent and KRAS-independent PDAC cell lines. We knocked down HNRNPA2B1 using small hairpin RNAs and measured viability, anchorage-independent proliferation, and growth of xenograft tumors in mice. We studied KRAS phosphorylation using the Phos-tag system.
RESULTS: We found that interactions between HRNPA2B1 and KRAS correlated with KRAS-dependency of some human PDAC cell lines. Knock down of HNRNPA2B1 significantly reduced viability, anchorage-independent proliferation, and formation of xenograft tumors by KRAS-dependent PDAC cells. HNRNPA2B1 knock down also increased apoptosis of KRAS-dependent PDAC cells, inactivated c-akt murine thymoma oncogene homolog 1 signaling via mammalian target of rapamycin, and reduced interaction between KRAS and phosphatidylinositide 3-kinase. Interaction between HNRNPA2B1 and KRAS required KRAS phosphorylation at serine 181.
CONCLUSIONS: In KRAS-dependent PDAC cell lines, HNRNPA2B1 interacts with and regulates the activity of KRAS G12V and G12D. HNRNPA2B1 is required for KRAS activation of c-akt murine thymoma oncogene homolog 1-mammalian target of rapamycin signaling, interaction with phosphatidylinositide 3-kinase, and PDAC cell survival and tumor formation in mice. HNRNPA2B1 might be a target for treatment of pancreatic cancer.

Zuccotti P, Colombrita C, Moncini S, et al.
hnRNPA2/B1 and nELAV proteins bind to a specific U-rich element in CDK5R1 3'-UTR and oppositely regulate its expression.
Biochim Biophys Acta. 2014; 1839(6):506-16 [PubMed] Related Publications
Cyclin-dependent kinase 5 regulatory subunit 1 (CDK5R1) encodes p35, a specific activator of cyclin-dependent kinase 5 (CDK5). CDK5 and p35 have a fundamental role in neuronal migration and differentiation during CNS development. Both the CDK5R1 3'-UTR's remarkable size and its conservation during evolution strongly indicate an important role in post-transcriptional regulation. We previously validated different regulatory elements in the 3'-UTR of CDK5R1, which affect transcript stability, p35 levels and cellular migration through the binding with nELAV proteins and miR-103/7 miRNAs. Interestingly, a 138 bp-long region, named C2.1, was identified as the most mRNA destabilizing portion within CDK5R1 3'-UTR. This feature was maintained by a shorter region of 73 bp, characterized by two poly-U stretches. UV-CL experiments showed that this region interacts with protein factors. UV-CLIP assays and pull-down experiments followed by mass spectrometry analysis demonstrated that nELAV and hnRNPA2/B1 proteins bind to the same U-rich element. These RNA-binding proteins (RBPs) were shown to oppositely control CDK5R1 mRNA stability and p35 protein content at post-trascriptional level. While nELAV proteins have a positive regulatory effect, hnRNPA2/B1 has a negative action that is responsible for the mRNA destabilizing activity both of the C2.1 region and of the full-length 3'-UTR. In co-expression experiments of hnRNPA2/B1 and nELAV RBPs we observed an overall decrease of p35 content. We also demonstrated that hnRNPA2/B1 can downregulate nELAV protein content but not vice versa. This study, by providing new insights on the combined action of different regulatory factors, contributes to clarify the complex post-transcriptional control of CDK5R1 gene expression.

Han J, Tang FM, Pu D, et al.
Mechanisms underlying regulation of cell cycle and apoptosis by hnRNP B1 in human lung adenocarcinoma A549 cells.
Tumori. 2014 Jan-Feb; 100(1):102-11 [PubMed] Related Publications
AIMS AND BACKGROUND: Overexpression of heterogeneous nuclear ribonucleoprotein B1 (hnRNP B1), a nuclear RNA binding protein, has been reported to occur in early-stage lung cancer and in premalignant lesions. DNA-dependent protein kinase (DNA-PK) is known to be involved in the repair of double-strand DNA breaks. Reduced capacity to repair DNA has been associated with the risk of lung cancer.
METHODS AND STUDY DESIGN: We investigated a link between hnRNP B1 and DNA-PK and their effects on proliferation, cell cycle, and apoptosis in the human lung adenocarcinoma cell line A549.
RESULTS: We found that hnRNP B1 and DNA-PK interact with each other in a complex fashion. Reducing hnRNP B1 expression in A549 cells with the use of RNAi led to upregulation of p53 activity through upregulation of DNA-PK activity but without inducing p53 expression. Further, suppression of hnRNP B1 in A549 cells slowed cell proliferation, promoted apoptosis, and induced cell cycle arrest at the G1 stage. The presence of NU7026 reduced the arrest of cells at the G1 stage and reduced the apoptosis rate while promoting cell growth.
CONCLUSION: Taken together, our results demonstrate that by regulating DNA-PK activity, hnRNP B1 can affect p53-mediated cell cycle progression and apoptosis, resulting in greater cell survival and subsequent proliferation.

Zhou ZJ, Dai Z, Zhou SL, et al.
HNRNPAB induces epithelial-mesenchymal transition and promotes metastasis of hepatocellular carcinoma by transcriptionally activating SNAIL.
Cancer Res. 2014; 74(10):2750-62 [PubMed] Related Publications
Expression of heterogeneous nuclear ribonucleoprotein AB (HNRNPAB) has been reported to be dysregulated in tumors, but its specific contributions to tumor formation and progression are not fully understood. Here, we demonstrate that HNRNPAB is overexpressed in highly metastatic cells and tumor tissues from patients with hepatocellular carcinoma (HCC) with recurrence. We found that HNRNPAB overexpression promoted epithelial-mesenchymal transition (EMT) in a manner associated with HCC metastasis in vitro and in vivo. RNA interference-mediated silencing of the EMT factor SNAIL attenuated HNRNPAB-enhanced cell invasion in vitro and lung metastasis in vivo. Mechanistically, HNRNPAB acted to transactivate SNAIL1 transcription, which in turn inhibited transcription of the pivotal SNAIL target gene E-cadherin. Overexpression of HNRNPAB in HCC samples correlated with higher SNAIL levels, shorter overall survival, and higher tumor recurrence. HNRNPAB overexpression, alone or in combination with SNAIL, was found to be a significant independent risk factor for recurrence and survival after curative resection. In conclusion, our findings define HNRNPAB as an activator of EMT and metastasis in HCC that predicts poor clinical outcomes.

Fujiya M, Konishi H, Mohamed Kamel MK, et al.
microRNA-18a induces apoptosis in colon cancer cells via the autophagolysosomal degradation of oncogenic heterogeneous nuclear ribonucleoprotein A1.
Oncogene. 2014; 33(40):4847-56 [PubMed] Related Publications
It is well known that microRNAs (miRs) are abnormally expressed in various cancers and target the messenger RNAs (mRNAs) of cancer-associated genes. While (miRs) are abnormally expressed in various cancers, whether miRs directly target oncogenic proteins is unknown. The present study investigated the inhibitory effects of miR-18a on colon cancer progression, which was considered to be mediated through its direct binding and degradation of heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1). An MTT assay and xenograft model demonstrated that the transfection of miR-18a induced apoptosis in SW620 cells. A binding assay revealed direct binding between miR-18a and hnRNP A1 in the cytoplasm of SW620 cells, which inhibited the oncogenic functions of hnRNP A1. A competitor RNA, which included the complementary sequence of the region of the miR-18a-hnRNP A1 binding site, repressed the effects of miR-18a on the induction of cancer cell apoptosis. In vitro single and in vivo double isotope assays demonstrated that miR-18a induced the degradation of hnRNP A1. An immunocytochemical study of hnRNP A1 and LC3-II and the inhibition of autophagy by 3-methyladenine and ATG7, p62 and BAG3 siRNA showed that miR-18a and hnRNP A1 formed a complex that was degraded through the autophagolysosomal pathway. This is the first report showing a novel function of a miR in the autophagolysosomal degradation of an oncogenic protein resulting from the creation of a complex consisting of the miR and a RNA-binding protein, which suppressed cancer progression.

Guha M, Avadhani NG
Mitochondrial retrograde signaling at the crossroads of tumor bioenergetics, genetics and epigenetics.
Mitochondrion. 2013; 13(6):577-91 [PubMed] Article available free on PMC after 26/09/2015 Related Publications
Mitochondria play a central role not only in energy production but also in the integration of metabolic pathways as well as signals for apoptosis and autophagy. It is becoming increasingly apparent that mitochondria in mammalian cells play critical roles in the initiation and propagation of various signaling cascades. In particular, mitochondrial metabolic and respiratory states and status on mitochondrial genetic instability are communicated to the nucleus as an adaptive response through retrograde signaling. Each mammalian cell contains multiple copies of the mitochondrial genome (mtDNA). A reduction in mtDNA copy number has been reported in various human pathological conditions such as diabetes, obesity, neurodegenerative disorders, aging and cancer. Reduction in mtDNA copy number disrupts mitochondrial membrane potential (Δψm) resulting in dysfunctional mitochondria. Dysfunctional mitochondria trigger retrograde signaling and communicate their changing metabolic and functional state to the nucleus as an adaptive response resulting in an altered nuclear gene expression profile and altered cell physiology and morphology. In this review, we provide an overview of the various modes of mitochondrial retrograde signaling focusing particularly on the Ca(2+)/Calcineurin mediated retrograde signaling. We discuss the contribution of the key factors of the pathway such as Calcineurin, IGF1 receptor, Akt kinase and HnRNPA2 in the propagation of signaling and their role in modulating genetic and epigenetic changes favoring cellular reprogramming towards tumorigenesis.

Pacurari M, Addison JB, Bondalapati N, et al.
The microRNA-200 family targets multiple non-small cell lung cancer prognostic markers in H1299 cells and BEAS-2B cells.
Int J Oncol. 2013; 43(2):548-60 [PubMed] Article available free on PMC after 26/09/2015 Related Publications
Lung cancer remains the leading cause of cancer-related mortality for both men and women. Tumor recurrence and metastasis is the major cause of lung cancer treatment failure and death. The microRNA‑200 (miR-200) family is a powerful regulator of the epithelial-mesenchymal transition (EMT) process, which is essential in tumor metastasis. Nevertheless, miR-200 family target genes that promote metastasis in non-small cell lung cancer (NSCLC) remain largely unknown. Here, we sought to investigate whether the microRNA-200 family regulates our previously identified NSCLC prognostic marker genes associated with metastasis, as potential molecular targets. Novel miRNA targets were predicted using bioinformatics tools based on correlation analyses of miRNA and mRNA expression in 57 squamous cell lung cancer tumor samples. The predicted target genes were validated with quantitative RT-PCR assays and western blot analysis following re-expression of miR-200a, -200b and -200c in the metastatic NSCLC H1299 cell line. The results show that restoring miR-200a or miR-200c in H1299 cells induces downregulation of DLC1, ATRX and HFE. Reinforced miR-200b expression results in downregulation of DLC1, HNRNPA3 and HFE. Additionally, miR-200 family downregulates HNRNPR3, HFE and ATRX in BEAS-2B immortalized lung epithelial cells in quantitative RT-PCR and western blot assays. The miR-200 family and these potential targets are functionally involved in canonical pathways of immune response, molecular mechanisms of cancer, metastasis signaling, cell-cell communication, proliferation and DNA repair in Ingenuity pathway analysis (IPA). These results indicate that re-expression of miR-200 downregulates our previously identified NSCLC prognostic biomarkers in metastatic NSCLC cells. These results provide new insights into miR-200 regulation in lung cancer metastasis and consequent clinical outcome, and may provide a potential basis for innovative therapeutic approaches for the treatment of this deadly disease.

Babic I, Anderson ES, Tanaka K, et al.
EGFR mutation-induced alternative splicing of Max contributes to growth of glycolytic tumors in brain cancer.
Cell Metab. 2013; 17(6):1000-8 [PubMed] Article available free on PMC after 26/09/2015 Related Publications
Alternative splicing contributes to diverse aspects of cancer pathogenesis including altered cellular metabolism, but the specificity of the process or its consequences are not well understood. We characterized genome-wide alternative splicing induced by the activating EGFRvIII mutation in glioblastoma (GBM). EGFRvIII upregulates the heterogeneous nuclear ribonucleoprotein (hnRNP) A1 splicing factor, promoting glycolytic gene expression and conferring significantly shorter survival in patients. HnRNPA1 promotes splicing of a transcript encoding the Myc-interacting partner Max, generating Delta Max, an enhancer of Myc-dependent transformation. Delta Max, but not full-length Max, rescues Myc-dependent glycolytic gene expression upon induced EGFRvIII loss, and correlates with hnRNPA1 expression and downstream Myc-dependent gene transcription in patients. Finally, Delta Max is shown to promote glioma cell proliferation in vitro and augment EGFRvIII expressing GBM growth in vivo. These results demonstrate an important role for alternative splicing in GBM and identify Delta Max as a mediator of Myc-dependent tumor cell metabolism.

Guo R, Li Y, Ning J, et al.
HnRNP A1/A2 and SF2/ASF regulate alternative splicing of interferon regulatory factor-3 and affect immunomodulatory functions in human non-small cell lung cancer cells.
PLoS One. 2013; 8(4):e62729 [PubMed] Article available free on PMC after 26/09/2015 Related Publications
Heterogeneous nuclear ribonucleoparticule A1/A2 (hnRNP A1/A2) and splicing factor 2/alternative splicing factor (SF2/ASF) are pivotal for precursor messenger RNA (pre-mRNA) splicing. Interferon regulatory factor-3 (IRF-3) plays critical roles in host defense against viral and microbial infection. Truncated IRF-3 proteins resulting from alternative splicing have been identified and characterized as functional antagonists to full-length IRF-3. In this study, we examined the molecular mechanism for splicing regulation of IRF-3 pre-mRNA and first reported the regulatory effect of hnRNP A1/A2 and SF2/ASF on IRF-3 splicing and activation. RNA interference-mediated depletion of hnRNP A1/A2 or SF2/ASF in human non-small cell lung cancer (NSCLC) cells increased exclusion of exons 2 and 3 of IRF-3 gene and reduced expression levels of IRF-3 protein and IRF-3 downstream effector molecules interferon-beta and CXCL10/IP-10. In addition, direct binding of hnRNP A1 and SF2/ASF to specific binding motifs in IRF-3 intron 1 was confirmed by RNA electrophoretic mobility shift assay. Subsequent minigene splicing assay showed that IRF-3 minigenes with mutated hnRNPA 1/A2 or SF2/ASF binding motifs increased exclusion of exons 2 and 3. Moreover, knockdown of hnRNP A1/A2 or SF2/ASF in NSCLC cells reinforced phytohemagglutinin-induced tumor necrosis factor-alpha release by peripheral blood mononuclear cells (PBMC) but suppressed that of interleukin-10 in NSCLC/PBMC co-cultures. Taken together, our results suggest that specific knockdown for hnRNP A1/A2 or SF2/ASF increase exclusion of exons 2 and 3 of IRF-3 pre-mRNA and influence immunomodulatory functions of human NSCLC cells.

Chettouh H, Fartoux L, Aoudjehane L, et al.
Mitogenic insulin receptor-A is overexpressed in human hepatocellular carcinoma due to EGFR-mediated dysregulation of RNA splicing factors.
Cancer Res. 2013; 73(13):3974-86 [PubMed] Related Publications
Insulin receptor (IR) exists as two isoforms resulting from the alternative splicing of IR pre-mRNA. IR-B promotes the metabolic effects of insulin, whereas IR-A rather signals proliferative effects. IR-B is predominantly expressed in the adult liver. Here, we show that the alternative splicing of IR pre-mRNA is dysregulated in a panel of 85 human hepatocellular carcinoma (HCC) while being normal in adjacent nontumor liver tissue. An IR-B to IR-A switch is frequently observed in HCC tumors regardless of tumor etiology. Using pharmacologic and siRNA approaches, we show that the autocrine or paracrine activation of the EGF receptor (EGFR)/mitogen-activated protein/extracellular signal-regulated kinase pathway increases the IR-A:IR-B ratio in HCC cell lines, but not in normal hepatocytes, by upregulating the expression of the splicing factors CUGBP1, hnRNPH, hnRNPA1, hnRNPA2B1, and SF2/ASF. In HCC tumors, there is a significant correlation between the expression of IR-A and that of splicing factors. Dysregulation of IR pre-mRNA splicing was confirmed in a chemically induced model of HCC in rat but not in regenerating livers after partial hepatectomy. This study identifies a mechanism responsible for the generation of mitogenic IR-A and provides a novel interplay between IR and EGFR pathways in HCC. Increased expression of IR-A during neoplastic transformation of hepatocytes could mediate some of the adverse effects of hyperinsulinemia on HCC.

Gu WJ, Liu HL
Induction of pancreatic cancer cell apoptosis, invasion, migration, and enhancement of chemotherapy sensitivity of gemcitabine, 5-FU, and oxaliplatin by hnRNP A2/B1 siRNA.
Anticancer Drugs. 2013; 24(6):566-76 [PubMed] Related Publications
We investigated the effects of inhibiting heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNP A2/B1) expression on apoptosis, invasion, migration, and the chemotherapy sensitivity of pancreatic cancer cells to gemcitabine, 5-FU, and oxaliplatin chemotherapy using small interfering RNA (siRNA). Chemically synthesized siRNA hnRNP A2/B1 was transfected into the human pancreatic cancer cell lines SW1990 and BxPC-3. The IC(50) of gemcitabine, 5-FU, and oxaliplatin was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Cell apoptosis and cycle were detected using flow cytometry. The expressions of apoptosis-related genes, p53, Bax, Bcl-2, TRAIL, Survivin, multidrug resistance 1 (MDR1), E-cadherin, and matrix metalloproteinases-2 (MMP-2) were detected using real-time PCR and western blot. Plate colony formation assay, wound scratch assay, invasion, and migration were also examined. Gemcitabine, 5-FU, and oxaliplatin inhibit the proliferation of SW1990 and BxPC-3 cells in a concentration-dependent manner. Inhibition of hnRNP A2/B1 expression significantly reduced the IC(50) of gemcitabine, 5-FU, and oxaliplatin (P<0.01). hnRNP A2/B1 siRNA combined with gemcitabine, 5-FU and oxaliplatin significantly increased (P<0.01) apoptosis of pancreatic cancer cell lines SW1990 and BxPC-3, increased the expression level of Bax mRNA, decreased Bcl-2 mRNA and MDR1 mRNA expression (P<0.01), and induced no change in p53, TRAIL, and Survivin mRNA expression in SW1990. In the western blot analysis, the expression level of Bax protein increased (P<0.01); the expression of both P-glycoprotein (Pg-p) protein and Bcl-2 protein decreased (P<0.01). Silencing hnRNP A2/B1 decreased invasion and migration in the cell line SW1990. Silencing hnRNP A2/B1 in SW1990 also correlated with an increase in E-cadherin expression and a decrease in MMP-2 expression at the same time. Inhibition of hnRNP A2/B1 expression can induce apoptosis in pancreatic cancer cells and improve chemosensitivity to gemcitabine, 5-FU, and oxaliplatin. hnRNP A2/B1 may play a role in invasion and migration in the pancreatic cancer cell line SW1990 through the regulation of E-cadherin and expression of MMP-2.

Li S, Wang W, Ding H, et al.
Aptamer BC15 against heterogeneous nuclear ribonucleoprotein A1 has potential value in diagnosis and therapy of hepatocarcinoma.
Nucleic Acid Ther. 2012; 22(6):391-8 [PubMed] Related Publications
The heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) was reported to be participated in tumor development. The association between hnRNP A1 and liver cancer and the functional role of hnRNP A1 in liver cancer have never been reported. Herein, hnRNP A1-specific single-stranded DNA aptamer, BC15, was used to (a) evaluate hnRNP A1 expression in liver cancer, and (b) treat hepatocarcinoma by acting as an inhibitor of hnRNP A1. Results showed that there is high hnRNP A1 expression in liver cancer including serum α-fetoprotein-negative liver cancer tissues compared with either para-cancer or benign controls. Down regulation of hnRNP A1 expression by RNA interference inhibits the proliferation and migration of cancerous HepG2 cells, while overexpression of hnRNP A1 in normal HL-7702 cells increased the proliferation and migration of the cells. Importantly, BC15 showed a stronger inhibiting effect on the proliferation of cultured hepatoma cells than hnRNP A1 small interfering RNA, strongly suggesting that BC15 could also be a potential drug candidate for an hnRNP A1 inhibitor besides its prospect utility in in situ histological examination.

Sun Y, Zhao X, Zhou Y, Hu Y
miR-124, miR-137 and miR-340 regulate colorectal cancer growth via inhibition of the Warburg effect.
Oncol Rep. 2012; 28(4):1346-52 [PubMed] Related Publications
Colorectal cancer represents one of the most challenging diseases. Increasing evidence indicates that aberrant expression of microRNAs (miRNAs) is related to pathogenesis of colorectal cancer. Cancer cells reprogram metabolic pathways to sustain higher proliferation rates. Whether mechanisms underlying the role of miRNA in colorectal cancer are involved in metabolic reprogramming and the mechanisms through which miRNAs alter cancer metabolism are as yet unknown. Herein, we show that miR-124, miR-137 and miR-340 are associated with poor prognosis of colorectal cancer. Expression of these miRNAs inhibits the growth of colorectal cancer cells. PKM (pyruvate kinase isozyme) alternative splicing proteins (PTB1/hnRNAPA1/hnRNAPA2), which control the inclusion of exon 9 (PKM1) or exon 10 (PKM2), are targeted by miR-124, miR-137 and miR-340. Consequently, miR-124, miR-137 and miR-340 switch PKM gene expression from PKM2 to PKM1. High ratios of PKM1/PKM2 inhibit the glycolysis rate, but elevate the glucose flux into oxidative phosphorylation. These results demonstrate that miRNAs (miR-124, miR-137 and miR-340) impair colorectal cancer growth by counteracting the Warburg effect due to regulating alternative splicing of the PKM gene.

Zhou ZJ, Dai Z, Zhou SL, et al.
Overexpression of HnRNP A1 promotes tumor invasion through regulating CD44v6 and indicates poor prognosis for hepatocellular carcinoma.
Int J Cancer. 2013; 132(5):1080-9 [PubMed] Related Publications
Heterogeneous ribonucleoprotein (hnRNP) A1 is a member of the A/B subfamily of ubiquitously expressed hnRNPs, which have a wide variety of functions in gene expression and signal transduction. To investigate the biological function and clinical significance of hnRNP A1 in hepatocellular carcinoma (HCC), we measured hnRNP A1 expression in four HCC cell lines and two independent cohorts of HCC patients. We found that hnRNP A1 was overexpressed in the highly metastatic HCC cell lines and in tumor tissues of patients with recurrent HCC. Knockdown of hnRNP A1 in highly metastatic HCC cells caused a significant decrease in cell invasion, while upregulation of hnRNP A1 in poorly metastatic HCC cells led to a significant increase in their invasive capacity. We found that this effect may occur through the regulation of CD44v6 expression by hnRNP A1 in HCC cells. Both quantitative reverse transcription-polymerase chain reaction (qRT-RCR) and immunohistochemistry revealed that hnRNP A1 was upregulated in HCC tissues and coincided with overexpression of CD44v6. HCC patients with high hnRNP A1 tended to have higher levels of CD44v6, shorter overall survival (OS) and higher rates of tumor recurrence. Multivariate analyses revealed that hnRNP A1 alone or in combination with CD44v6 were independent prognostic indicators for OS and time to recurrence and have potential as therapeutic targets. In conclusion, overexpression of hnRNP A1 promotes HCC invasion by regulating the level of CD44v6 and indicates a poor prognosis for HCC patients after curative resection.

Sebban S, Golan-Gerstl R, Karni R, et al.
Alternatively spliced lysyl oxidase-like 4 isoforms have a pro-metastatic role in cancer.
Clin Exp Metastasis. 2013; 30(1):103-17 [PubMed] Related Publications
We previously found LOXL4 to be alternatively spliced in an anatomic site-specific manner in tumors involving the serosal cavities. LOXL4 splice variants were predominantly or exclusively expressed in effusion specimens from ovarian and breast carcinoma patients, and were absent in primary carcinomas. In the present study, LOXL4 full-length or splice variants were overexpressed in ES-2 and MDA-MB-231 cells and their invasive and metastatic potential and microRNA expression profile were evaluated. ES-2 cells were further injected into SCID mice ovaries and the extent of tumor progression and metastases formation were compared. We show that both splice variants have a positive effect on the metastatic potential of cells in vitro and on tumor progression in vivo. In contrast, full-length LOXL4 is not pro-metastatic, and may even be considered as a tumor suppressor. In addition, we show that LOXL4 is a possible splicing target of the oncogenic splicing factors SRSF1 and hnRNP A1. In conclusion, our results point to a significant role for LOXL4 alternative splicing in tumor progression.

Gu W, Liu W, Shen X, et al.
Emergence of heterogeneous nuclear ribonucleoprotein A2/B1 vs loss of E-cadherin: their reciprocal immunoexpression profiles in human pancreatic cancer.
Ann Diagn Pathol. 2013; 17(1):14-7 [PubMed] Related Publications
Pancreatic cancer is one of the most lethal human cancers worldwide. It is important to develop new screening methods or biomarkers related to pancreatic carcinogenesis. In our previous work, we identified heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1 as one of the up-regulated proteins in rat pancreatic cancer by using proteomic analysis. In the current study, we extended our research to investigate the immunoexpression of hnRNP A2/B1 protein in paired tumor/nontumor tissues from 42 patients with primary pancreatic ductal adenocarcinoma and its correlation to E-cadherin expression and clinicopathologic features. The results showed that the frequency of hnRNP A2/B1 expression is 71.4% (30/42), and loss of E-cadherin is 61.9% (26/42) in pancreatic cancer tissue. Emergence of hnRNP A2/B1 (P = .027) and loss of E-cadherin (P = .012) expression were significantly associated with poor differentiation of pancreatic cancer. In addition, E-cadherin loss expression was associated with lymph node metastasis (P = .042). Most importantly, there was an inverse correlation between the emergence of hnRNP A2/B1 and loss of E-cadherin expression in pancreatic cancer (P = .01). Collectively, we demonstrate altered expression profile of hnRNP A2/B1 protein in human pancreatic cancer and its reciprocal correlation to E-cadherin expression. These data indicate that hnRNP A2/B1 overexpression is novel and requires further investigation for its potential application in pancreatic carcinogenesis.

Goodarzi H, Najafabadi HS, Oikonomou P, et al.
Systematic discovery of structural elements governing stability of mammalian messenger RNAs.
Nature. 2012; 485(7397):264-8 [PubMed] Article available free on PMC after 26/09/2015 Related Publications
Decoding post-transcriptional regulatory programs in RNA is a critical step towards the larger goal of developing predictive dynamical models of cellular behaviour. Despite recent efforts, the vast landscape of RNA regulatory elements remains largely uncharacterized. A long-standing obstacle is the contribution of local RNA secondary structure to the definition of interaction partners in a variety of regulatory contexts, including--but not limited to--transcript stability, alternative splicing and localization. There are many documented instances where the presence of a structural regulatory element dictates alternative splicing patterns (for example, human cardiac troponin T) or affects other aspects of RNA biology. Thus, a full characterization of post-transcriptional regulatory programs requires capturing information provided by both local secondary structures and the underlying sequence. Here we present a computational framework based on context-free grammars and mutual information that systematically explores the immense space of small structural elements and reveals motifs that are significantly informative of genome-wide measurements of RNA behaviour. By applying this framework to genome-wide human mRNA stability data, we reveal eight highly significant elements with substantial structural information, for the strongest of which we show a major role in global mRNA regulation. Through biochemistry, mass spectrometry and in vivo binding studies, we identified human HNRPA2B1 (heterogeneous nuclear ribonucleoprotein A2/B1, also known as HNRNPA2B1) as the key regulator that binds this element and stabilizes a large number of its target genes. We created a global post-transcriptional regulatory map based on the identity of the discovered linear and structural cis-regulatory elements, their regulatory interactions and their target pathways. This approach could also be used to reveal the structural elements that modulate other aspects of RNA behaviour.

Chen ZY, Cai L, Zhu J, et al.
Fyn requires HnRNPA2B1 and Sam68 to synergistically regulate apoptosis in pancreatic cancer.
Carcinogenesis. 2011; 32(10):1419-26 [PubMed] Related Publications
PURPOSE: The Src family kinase Fyn, heterogenous nuclear ribonucleoprotein (HnRNP) A2B1 and Sam68 are thought to be associated with the metastasis of tumors, but their roles in the regulation of apoptosis remain unclear. This study investigated the role of Fyn and its potential relationship with HnRNPA2B1 and Sam68 in the regulation of apoptosis in pancreatic cancer. Experimental design. We examined both the activity of Fyn and the expression of HnRNPA2B1 in human pancreatic cancer tissues and systematically investigated the apoptotic mechanisms induced by Fyn activity using multiple experimental approaches.
RESULTS: We found that Fyn activity was increased in metastatic pancreatic cancer tissues. In the pancreatic cancer BxPc3 cell line, the inhibition of Fyn activity by kinase-dead Fyn downregulated HnRNPA2B1 expression. Further analysis showed that HnRNPA2B1 expression was associated with pancreatic cancer progression. In BxPc3 cells, HnRNPA2B1 bound to Bcl-x messenger RNA (mRNA), which affected splicing and therefore, the formation of Bcl-x(s). Downregulation of HnRNPA2B1 by RNA interference (RNAi) resulted in the increased formation of the pro-apoptotic Bcl-x(s) and promoted apoptosis of BxPc3 cells. In addition, deactivation of Fyn in BxPc3 cells reduced Sam68 phosphorylation. This resulted in increased binding between Sam68 and Bcl-x mRNA, promoting the formation of the anti-apoptotic Bcl-x(L). The knockdown of Sam68 by RNAi also increased the formation of Bcl-x(L). Finally, HnRNPA2B1 overexpression or Sam68 knockdown could rescue pancreatic cancer cells from apoptosis.
CONCLUSION: Our results suggest a mechanism by which Fyn requires HnRNPA2B1 and Sam68 to coordinate and regulate apoptosis, thus promoting the proliferation and metastasis of pancreatic cancer.

Golan-Gerstl R, Cohen M, Shilo A, et al.
Splicing factor hnRNP A2/B1 regulates tumor suppressor gene splicing and is an oncogenic driver in glioblastoma.
Cancer Res. 2011; 71(13):4464-72 [PubMed] Related Publications
The process of alternative splicing is widely misregulated in cancer, but the contribution of splicing regulators to cancer development is largely unknown. In this study, we found that the splicing factor hnRNP A2/B1 is overexpressed in glioblastomas and is correlated with poor prognosis. Conversely, patients who harbor deletions of the HNRNPA2B1 gene show better prognosis than average. Knockdown of hnRNP A2/B1 in glioblastoma cells inhibited tumor formation in mice. In contrast, overexpression of hnRNP A2/B1 in immortal cells led to malignant transformation, suggesting that HNRNPA2B1 is a putative proto-oncogene. We then identified several tumor suppressors and oncogenes that are regulated by HNRNPA2B1, among them are c-FLIP, BIN1, and WWOX, and the proto-oncogene RON. Knockdown of RON inhibited hnRNP A2/B1 mediated transformation, which implied that RON is one of the mediators of HNRNPA2B1 oncogenic activity. Together, our results indicate that HNRNPA2B1 is a novel oncogene in glioblastoma and a potential new target for glioblastoma therapy.

Nyhan MJ, El Mashad SM, O'Donovan TR, et al.
VHL genetic alteration in CCRCC does not determine de-regulation of HIF, CAIX, hnRNP A2/B1 and osteopontin.
Cell Oncol (Dordr). 2011; 34(3):225-34 [PubMed] Related Publications
BACKGROUND: Von Hippel-Lindau (VHL) tumour suppressor gene inactivation is associated with clear cell renal cell carcinoma (CCRCC) development. The VHL protein (pVHL) has been proposed to regulate the expression of several proteins including Hypoxia Inducible Factor-α (HIF-α), carbonic anhydrase (CA)IX, heterogeneous nuclear ribonucleoprotein (hnRNP)A2/B1 and osteopontin. pVHL has been characterized in vitro, however, clinical studies are limited. We evaluated the impact of VHL genetic alterations on the expression of several pVHL protein targets in paired normal and tumor tissue.
METHODS: The VHL gene was sequenced in 23 CCRCC patients and VHL transcript levels were evaluated by Real-Time RT-PCR. Expression of pVHL's protein targets were determined by Western blotting in 17 paired patient samples.
RESULTS: VHL genetic alterations were identified in 43.5% (10/23) of CCRCCs. HIF-1α, HIF-2α and CAIX were up-regulated in 88.2% (15/17), 100% (17/17) and 88.2% (15/17) of tumors respectively and their expression is independent of VHL status. hnRNP A2/B1 and osteopontin expression was variable in CCRCCs and had no association with VHL genetic status.
CONCLUSION: As expression of these proposed pVHL targets can be achieved independently of VHL mutation (and possibly by hypoxia alone), this data suggests that other pVHL targets may be more crucial in renal carcinogenesis.

Fang X, Yoon JG, Li L, et al.
Landscape of the SOX2 protein-protein interactome.
Proteomics. 2011; 11(5):921-34 [PubMed] Related Publications
SOX2 is a key gene implicated in maintaining the stemness of embryonic and adult stem cells that appears to re-activate in several human cancers including glioblastoma multiforme. Using immunoprecipitation (IP)/MS/MS, we identified 144 proteins that are putative SOX2 interacting proteins. Of note, SOX2 was found to interact with several heterogeneous nuclear ribonucleoprotein family proteins, including HNRNPA2B1, HNRNPA3, HNRNPC, HNRNPK, HNRNPL, HNRNPM, HNRNPR, HNRNPU, as well as other ribonucleoproteins, DNA repair proteins and helicases. Gene ontology (GO) analysis revealed that the SOX2 interactome was enriched for GO terms GO:0030529 ribonucleoprotein complex and GO:0004386 helicase activity. These findings indicate that SOX2 associates with the heterogeneous nuclear ribonucleoprotein complex, suggesting a possible role for SOX2 in post-transcriptional regulation in addition to its function as a transcription factor.

Jing GJ, Xu DH, Shi SL, et al.
Aberrant expression and localization of hnRNP-A2/B1 is a common event in human gastric adenocarcinoma.
J Gastroenterol Hepatol. 2011; 26(1):108-15 [PubMed] Related Publications
BACKGROUND AND AIM: Nuclear-matrix proteins can be proteomic markers for cancer lesions. The present study aimed to determine the roles of heterogeneous nuclear ribonucleoproteins--A2 and B1 (hnRNP-A2/B1) in human gastric carcinogenesis.
METHODS: Human gastric cancer and non-cancerous tissues were collected for immunohistochemical analysis. Proteomics technique, Western blot, laser confocal microscope, and real-time quantitative reverse transcription-polymerase chain reaction were performed to determine the aberrant expression of nuclear-matrix proteins.
RESULTS: hnRNP-A2/B1 existed in the nuclear matrix of gastric cancer cells, and its expression was enhanced in human gastric cancer and decreased by hexamethylene bisacetamide. The colocalization of hnRNP-A2/B1 with c-myc, c-fos, p53, and Rb was translocated from the nucleolus to the cytoplasm during the differentiation of tumor cells.
CONCLUSIONS: hnRNP-A2/B1 affected tumor cell differentiation through interaction with oncogenes and tumor-suppressor genes, and it was overexpressed in human gastric cancer. We postulate that hnRNP-A2/B1 could serve as a biomarker for the diagnosis of human gastric cancer.

Nyhan MJ, El Mashad SM, O'Donovan TR, et al.
VHL genetic alteration in CCRCC does not determine de-regulation of HIF, CAIX, hnRNP A2/B1 and osteopontin.
Anal Cell Pathol (Amst). 2010; 33(3):121-32 [PubMed] Related Publications
BACKGROUND: von Hippel-Lindau (VHL) tumour suppressor gene inactivation is associated with clear cell renal cell carcinoma (CCRCC) development. The VHL protein (pVHL) has been proposed to regulate the expression of several proteins including Hypoxia Inducible Factor-α (HIF-α), carbonic anhydrase (CA)IX, heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1 and osteopontin. pVHL has been characterized in vitro, however, clinical studies are limited. We evaluated the impact of VHL genetic alterations on the expression of several pVHL protein targets in paired normal and tumor tissue.
METHODS: The VHL gene was sequenced in 23 CCRCC patients and VHL transcript levels were evaluated by real-time RT-PCR. Expression of pVHL's protein targets were determined by Western blotting in 17 paired patient samples.
RESULTS: VHL genetic alterations were identified in 43.5% (10/23) of CCRCCs. HIF-1α, HIF-2α and CAIX were up-regulated in 88.2% (15/17), 100% (17/17) and 88.2% (15/17) of tumors respectively and their expression is independent of VHL status. hnRNP A2/B1 and osteopontin expression was variable in CCRCCs and had no association with VHL genetic status.
CONCLUSION: As expression of these proposed pVHL targets can be achieved independently of VHL mutation (and possibly by hypoxia alone), these data suggests that other pVHL targets may be more crucial in renal carcinogenesis.

Tauler J, Zudaire E, Liu H, et al.
hnRNP A2/B1 modulates epithelial-mesenchymal transition in lung cancer cell lines.
Cancer Res. 2010; 70(18):7137-47 [PubMed] Related Publications
Heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNP A2/B1) has been reported to be overexpressed in lung cancer and in other cancers such as breast, pancreas, and liver. However, a mechanism linking hnRNP A2/B1 overexpression and progression to cancer has not yet been definitively established. To elucidate this mechanism, we have silenced hnRNPA2/B1 mRNA in non-small-cell lung cancer cell lines A549, H1703, and H358. These cell lines present different levels of expression of epithelial-to-mesenchymal transition (EMT) markers such as E-cadherin, fibronectin, and vimentin. Microarray expression analysis was performed to evaluate the effect of silencing hnRNP A2/B1 in A549 cells. We identified a list of target genes, affected by silencing of hnRNP A2/B1, that are involved in regulation of migration, proliferation, survival, and apoptosis. Silencing hnRNP A2/B1 induced formation of cell clusters and increased proliferation. In the anchorage-independent assay, silencing hnRNP A2/B1 increased colony formation by 794% in A549 and 174% in H1703 compared with a 25% increase in proliferation, in both cell lines, in a two-dimensional proliferation assay. Silencing hnRNP A2/B1 decreased migration in intermediate cell line A549 and mesenchymal cell line H1703; however, no changes in proliferation were observed in epithelial cell line H358. 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. These data suggest that expression of hnRNP A2/B1 may play a role in EMT, in nonepithelial lung cancer cell lines A549 and H1703, through the regulation of E-cadherin expression.

Miyagi Y, Sasaki T, Fujinami K, et al.
ETS family-associated gene fusions in Japanese prostate cancer: analysis of 194 radical prostatectomy samples.
Mod Pathol. 2010; 23(11):1492-8 [PubMed] Related Publications
The incidence and clinical significance of the TMPRSS2:ERG gene fusion in prostate cancer has been investigated with contradictory results. It is now common knowledge that significant variability in gene alterations exists according to ethnic background in various kinds of cancer. In this study, we evaluated gene fusions involving the ETS gene family in Japanese prostate cancer. Total RNA from 194 formalin-fixed and paraffin-embedded prostate cancer samples obtained by radical prostatectomy was subjected to reverse-transcriptase polymerase chain reaction to detect the common TMPRSS2:ERG T1-E4 and T1-E5 fusion transcripts and five other non-TMPRSS2:ERG fusion transcripts. We identified 54 TMPRSS2:ERG-positive cases (54/194, 28%) and two HNRPA2B1:ETV1-positive cases (2/194, 1%). The SLC45A3-ELK4 transcript, a fusion transcript without structural gene rearrangement, was detectable in five cases (5/194, 3%). The frequencies of both TMPRSS2:ERG- and non-TMPRSS2:ERG-positive cases were lower than those reported for European, North American or Brazilian patients. Internodular heterogeneity of TMPRSS2:ERG was observed in 5 out of 11 multifocal cases (45%); a frequency similar to that found in European and North American cases. We found a positive correlation between the TMPRSS2:ERG fusion and a Gleason score of ≤7 and patient age, but found no relationship with pT stage or plasma prostate-specific antigen concentration. To exclude the possibility that Japanese prostate cancer displays novel TMPRSS2:ERG transcript variants or has unique 5' fusion partners for the ETS genes, we performed 5' RACE using fresh-frozen prostate cancer samples. We identified only the normal 5' cDNA ends for ERG, ETV1 and ETV5 in fusion-negative cases. Because we identified a relatively low frequency of TMPRSS2:ERG and other fusions, further evaluation is required before this promising molecular marker should be introduced into the management of Japanese prostate cancer patients.

Han SP, Friend LR, Carson JH, et al.
Differential subcellular distributions and trafficking functions of hnRNP A2/B1 spliceoforms.
Traffic. 2010; 11(7):886-98 [PubMed] Article available free on PMC after 26/09/2015 Related Publications
Trafficking of mRNA molecules from the nucleus to distal processes in neural cells is mediated by heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1 trans-acting factors. Although hnRNP A2/B1 is alternatively spliced to generate four isoforms, most functional studies have not distinguished between these isoforms. Here, we show, using isoform-specific antibodies and isoform-specific green fluorescent protein (GFP)-fusion expression constructs, that A2b is the predominant cytoplasmic isoform in neural cells, suggesting that it may play a key role in mRNA trafficking. The differential subcellular distribution patterns of the individual isoforms are determined by the presence or absence of alternative exons that also affect their dynamic behavior in different cellular compartments, as measured by fluorescence correlation spectroscopy. Expression of A2b is also differentially regulated with age, species and cellular development. Furthermore, coinjection of isoform-specific antibodies and labeled RNA into live oligodendrocytes shows that the assembly of RNA granules is impaired by blockade of A2b function. These findings suggest that neural cells modulate mRNA trafficking by regulating alternative splicing of hnRNP A2/B1 and controlling expression levels of A2b, which may be the predominant mediator of cytoplasmic-trafficking functions. These findings highlight the importance of considering isoform-specific functions for alternatively spliced proteins.

Rosenberger S, De-Castro Arce J, Langbein L, et al.
Alternative splicing of human papillomavirus type-16 E6/E6* early mRNA is coupled to EGF signaling via Erk1/2 activation.
Proc Natl Acad Sci U S A. 2010; 107(15):7006-11 [PubMed] Article available free on PMC after 26/09/2015 Related Publications
Certain types of human papillomaviruses (HPVs) are etiologically linked to cervical cancer. Their transforming capacity is encoded by a polycistronic premRNA, where alternative splicing leads to the translation of functional distinct proteins such as E6, E6*, and E7. Here we show that splicing of HPV16 E6/E7 ORF cassette is regulated by the epidermal growth factor (EGF) pathway. The presence of EGF was coupled to preferential E6 expression, whereas depletion of EGF, or treatment with EGF receptor (EGFR) neutralizing antibodies or the EGFR inhibitor tyrphostin AG1478, resulted in E6 exon exclusion in favor of E6*. As a consequence, increased p53 levels and enhanced translation of E7 with a subsequent reduction of the retinoblastoma protein pRb could be discerned. E6 exon exclusion upon EGF depletion was independent from promoter usage, mRNA stability, or selective mRNA transport. Time-course experiments and incubation with cycloheximide demonstrated that E6 alternative splicing is a direct and reversible effect of EGF signal transduction, not depending on de novo protein synthesis. Within this process, Erk1/2-kinase activation was the critical event for E6 exon inclusion, mediated by the upstream MAP kinase MEK1/2. Moreover, siRNA knockdown experiments revealed an involvement of splicing factors hnRNPA1 and hnRNPA2 in E6 exon exclusion, whereas the splicing factors Brm and Sam68 were found to promote E6 exon inclusion. Because there is a natural gradient of EGF and EGF receptor expression in the stratified epithelium, it is reasonable to assume that EGF modulates E6/E7 splicing during the viral life cycle and transformation.

Torosyan Y, Dobi A, Glasman M, et al.
Role of multi-hnRNP nuclear complex in regulation of tumor suppressor ANXA7 in prostate cancer cells.
Oncogene. 2010; 29(17):2457-66 [PubMed] Related Publications
Annexin-A7 (ANXA7) tumor suppressor role has been shown in various tumors, and ANXA7 expression has been particularly lost in androgen-resistant prostate cancers. In this study, we studied ANXA7 regulation in normal prostate versus androgen-sensitive and -resistant prostate cancer cells. Deletion mapping analysis showed lowest ANXA7-promoter activities in androgen-sensitive LNCaP prostate cancer cells. Genomatix analysis of ANXA7 promoter identified a cluster of steroid nuclear hormone receptor elements, including V$GREF (V$GRE.02/ARE.02). Gelshift analysis clearly indicated distinct nuclear protein occupancy at this ANXA7-promoter site (-1086/-890) in prostate cancer (LNCaP, DU145, and PC3) versus normal prostate (PrEC) cells. In matrix-assisted laser desorption time-of-flight mass spectrometry-based search for ANXA7 nuclear regulators, we identified several heterogeneous nuclear ribonucleoproteins (hnRNPs) (A1, A2/B1 and K) attached to the steroid-associated ANXA7-promoter site in the androgen-resistant PC3 prostate cancer cells with high ANXA7 gene copy number, but not in PrEC. The hnPNP role in ANXA7 regulation (that was validated by hnRNPA2/B1 antibody interference) resulted in multiple ANXA7 cDNA and protein products in PC3, but not in PrEC. Ingenuity pathways analysis showed plausible molecular paths between ANXA7 and the hnRNP-associated network in prostate cancer progression. Thus, a multi-hnRNP complex can be responsible for aberrant ANXA7 transcription and splicing, thereby affecting ANXA7 expression pattern and tumor suppressor function in prostate cancer.

Suzuki A, Iizuka A, Komiyama M, et al.
Identification of melanoma antigens using a Serological Proteome Approach (SERPA).
Cancer Genomics Proteomics. 2010 Jan-Feb; 7(1):17-23 [PubMed] Related Publications
BACKGROUND: Melanoma is an intractable cancer with a poor prognosis and increasing prevalence worldwide. Specific biomarkers for early diagnosis have yet to be found.
MATERIALS AND METHODS: Serum samples from melanoma patients and healthy volunteers were utilized for identifying melanoma marker proteins using a serological proteome approach. Specifically, G361 cell protein spots separated by 2-dimensional gel electrophoresis and transferred to a membrane were incubated with patient sera, and positive spots that reacted with more than 5 serum samples were identified using time of flight mass spectrometry.
RESULTS: Only patient sera showed many spots reacted in G361 gels. A total of 13 positive spots were detected and 5 proteins were identified: eukaryotic elongation factor2 (EEF2), enolase1 (ENO1), aldolase A (ALDOA), glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and heterogeneous nuclear ribonucleoproteins (HNRNP) A2B1. The mRNAs of four proteins (EEF2, ENO1, ALDOA and HNRNPA2B1) were highly expressed in G361 cells compared with melanocytes. EEF2, ENO1 and ALDOA mRNAs were also frequently expressed in other melanoma cell lines.
CONCLUSION: The autoantibody-based proteomic approach was effective for investigating melanoma biomarkers. This study might contribute to the development of a diagnostic device for the early detection of cancer.

Disclaimer: This site is for educational purposes only; it can not be used in diagnosis or treatment.

Cite this page: Cotterill SJ. HNRNPA2B1 gene, Cancer Genetics Web: Accessed:

Creative Commons License
This page in Cancer Genetics Web by Simon Cotterill is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Note: content of abstracts copyright of respective publishers - seek permission where appropriate.

 [Home]    Page last revised: 27 February, 2015     Cancer Genetics Web, Established 1999