The Nuclear Pore Complex and mRNA Export in Cancer

Borden, Katherine L. B.

doi:10.3390/cancers13010042

Cited by 35 publications

(36 citation statements)

References 176 publications

(356 reference statements)

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“…Our finding that nuclear JAK3 expression was unaffected by PP2A blockage, which triggered enhanced export of STAT3 as previously reported [35] and confirmed here, suggests that nuclear export of JAK3 in malignant T cells is not regulated in the same manner as STAT3 in relation to PP2A despite the shared regulation by CRM1. CRM1 specific inhibitors are being used in clinical trials as a target for number of cancer therapies including non-Hodgkin lymphomas ( [63,64] and reviewed in [65,66]). Of interest, a CRM1 inhibitor showed anticancer activity in a JAK3 mutant mouse model for T-ALL [67,68] suggesting the highly interesting possibility that shifting the dynamics of nuclear import/export and the balance between nuclear and cytoplasmic JAK3 might also be a novel potential target for therapy in CTCL.…”

Section: Discussionmentioning

confidence: 99%

JAK3 Is Expressed in the Nucleus of Malignant T Cells in Cutaneous T Cell Lymphoma (CTCL)

Vadivel

Gluud

Torres-Rusillo

et al. 2021

Cancers

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Perturbation in JAK-STAT signaling has been reported in the pathogenesis of cutaneous T cell lymphoma (CTCL). JAK3 is predominantly associated with the intra-cytoplasmic part of IL-2Rγc located in the plasma membrane of hematopoietic cells. Here we demonstrate that JAK3 is also ectopically expressed in the nucleus of malignant T cells. We detected nuclear JAK3 in various CTCL cell lines and primary malignant T cells from patients with Sézary syndrome, a leukemic variant of CTCL. Nuclear localization of JAK3 was independent of its kinase activity whereas STAT3 had a modest effect on nuclear JAK3 expression. Moreover, JAK3 nuclear localization was only weakly affected by blockage of nuclear export. An inhibitor of the nuclear export protein CRM1, Leptomycin B, induced an increased expression of SOCS3 in the nucleus, but only a weak increase in nuclear JAK3. Importantly, immunoprecipitation experiments indicated that JAK3 interacts with the nuclear protein POLR2A, the catalytic subunit of RNA Polymerase II. Kinase assays showed tyrosine phosphorylation of recombinant human Histone H3 by JAK3 in vitro—an effect which was blocked by the JAK inhibitor (Tofacitinib citrate). In conclusion, we provide the first evidence of nuclear localization of JAK3 in malignant T cells. Our findings suggest that JAK3 may have a cytokine-receptor independent function in the nucleus of malignant T cells, and thus a novel non-canonical role in CTCL.

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Section: Discussionmentioning

confidence: 99%

JAK3 Is Expressed in the Nucleus of Malignant T Cells in Cutaneous T Cell Lymphoma (CTCL)

Vadivel

Gluud

Torres-Rusillo

et al. 2021

Cancers

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“… 27 Export of mRNAs from the nucleus to the cytoplasm through NPC is a key regulatory step in protein expression. 28 It serves as a surveillance mechanism to sort out aberrant mRNAs, and controls translation and consequently the response to extracellular signals by permitting altered flow of specific mRNAs into the cytoplasm. 28 RNA export factors and NPC components regulate the export of selected mRNAs involved in nearly all aspects of malignancy, such as survival, proliferation, metastases, and invasion.…”

Section: Discussionmentioning

confidence: 99%

“…28 It serves as a surveillance mechanism to sort out aberrant mRNAs, and controls translation and consequently the response to extracellular signals by permitting altered flow of specific mRNAs into the cytoplasm. 28 RNA export factors and NPC components regulate the export of selected mRNAs involved in nearly all aspects of malignancy, such as survival, proliferation, metastases, and invasion. 28,29 Aberrant mRNA export associated with altered nucleoporin expression or function has been linked to cancers.…”

mentioning

confidence: 99%

“…28 RNA export factors and NPC components regulate the export of selected mRNAs involved in nearly all aspects of malignancy, such as survival, proliferation, metastases, and invasion. 28,29 Aberrant mRNA export associated with altered nucleoporin expression or function has been linked to cancers. 27,28 Nucleoporin 62 (NUP62), a protein complex that belongs to the class of nucleoporins, was highly expressed in squamous cell carcinomas, including head, neck and cervix, and was a key regulator of cell proliferation and differentiation via controlling the nuclear transport of p63.…”

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confidence: 99%

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Nuclear Pore Glycoprotein 62 Genetic Variant rs9523 is Associated with Clinical Outcomes of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Lung Adenocarcinoma Patients

Park

Hong²,

Lee

et al. 2021

PGPM

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Introduction Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have represented the prototype of targeted therapy in NSCLC. Patients with EGFR-mutant lung adenocarcinoma extract an extraordinary clinical benefit from EGFR-TKIs. However, the extent and duration of these responses are heterogeneous, suggesting the existence of genetic modifiers affecting an individual’s response to TKIs. We investigated whether genetic variants in miRNA binding sites are associated with the clinical outcome of EGFR-TKIs in lung adenocarcinoma patients. Methods One hundred SNPs at miRNA binding sites in cancer-related genes were selected for the analysis using the crosslinking, ligation and sequencing of hybrids (CLASH) and CancerGenes database. qRT-PCR and luciferase assays were conducted to evaluate the functional relevance of the SNPs. Results NUP62 rs9523A>G were significantly associated with worse response to EGFR-TKIs, overall survival (OS), and progression-free survival (PFS). The other three SNPs ( DVL2 rs2074216G>A, ARF1 rs11541557G>T, and UHRF1 rs2261988C>A) were significantly associated with worse OS and PFS. The rs9523A>G was significantly associated with decreased NUP62 expression in tumor tissues. In addition, a significantly decreased luciferase activity was noted in NUP62 rs9523 G allele compared to A allele. Conclusion Genetic variants in miRNA binding sites, especially NUP62 rs9523A>G, may be useful in predicting the clinical outcomes of EGFR-mutant lung adenocarcinoma patients treated with EGFR-TKIs.

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“…The export of mRNA from the nucleus to the cytoplasm is an important regulatory phase in protein expression. Abnormal RNA export has been observed in primary human cancer specimens, and these cargo RNAs code for proteins that are involved in almost every aspect of cancer (31). RBM12 is most likely involved in these processes, but more research is needed to determine the exact mechanisms of its involvement.…”

Section: Rbm12 Was Also Shown To Have a High Diagnostic Valuementioning

confidence: 99%

Increased RBM12 expression predicts poor prognosis in hepatocellular carcinoma based on bioinformatics

Gao¹,

Shen²,

Chen³

et al. 2021

J Gastrointest Oncol

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Background: Liver cancer is one of the major causes of cancer death worldwide, incurring high mortality and a significant financial burden on the healthcare system. Abnormal RNA-binding proteins (RBPs) have been found to be associated with carcinogenesis in liver cancer. Among these, RNA-binding motif protein 12 (RBM12) is located in the exon junction complex (EJC). The goal of this study was to determine what role RBM12 plays in hepatocellular carcinoma (HCC) from a biological perspective. Methods:The Tumor IMmune Estimation Resource (TIMER) and the Human Protein Atlas database were used to examine the expression level of RBM12, with the UALCAN and Gene Expression Profiling Interactive Analysis (GEPIA) databases used to investigate the relationship between RBM12 and other noteworthy clinical features. RBM12 expression in cells and tissue samples was detected using quantitative real-time polymerase chain reaction (qRT-PCR) and western blot analysis. The functional network of RBM12 in HCC was studied using LinkedOmics and gene set enrichment analysis (GSEA), while the effects of hypomethylation on the expression of RBM12 in HCC was investigated using methylation databases. Finally, we used TIMER and CIBERSORT to investigate the relationship between immune cell infiltration and RBM12 in HCC.Results: RBM12 is highly elevated in HCC tissues and cells, and it can be used to predict the prognosis of patients with HCC. Analysis with LinkedOmics and GSEA revealed RBM12 to be closely linked with tumor progression. Furthermore, hypomethylation was linked to an increase in RBM12 expression in HCC, while RBM12 was associated with immune cell infiltration.Conclusions: This study shows that an elevated level of RBM12 in HCC indicates a poor patient prognosis. Furthermore, according to LinkedOmics and GSEA analyses, RBM12 was implicated in the most important hallmark pathways. Our findings suggest that RBM12 overexpression is caused by hypomethylation and that RBM12 plays a key role in liver cancer tumor immunity.

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The Nuclear Pore Complex and mRNA Export in Cancer

Cited by 35 publications

References 176 publications

JAK3 Is Expressed in the Nucleus of Malignant T Cells in Cutaneous T Cell Lymphoma (CTCL)

JAK3 Is Expressed in the Nucleus of Malignant T Cells in Cutaneous T Cell Lymphoma (CTCL)

Nuclear Pore Glycoprotein 62 Genetic Variant rs9523 is Associated with Clinical Outcomes of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Lung Adenocarcinoma Patients

Increased RBM12 expression predicts poor prognosis in hepatocellular carcinoma based on bioinformatics

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