Nucleoporin-93 reveals a common feature of aggressive breast cancers: robust nucleocytoplasmic transport of transcription factors

Nataraj, Nishanth Belugali; Noronha, Ashish; Lee, Joo Sang; Ghosh, Soma; Raju, Harsha Raj Mohan; Sekar, Arunachalam; Zuckerman, Bert M.; Lindzen, Moshit; Tarcitano, Emilio; Srivastava, Swati; Selitrennik, Michael; Livneh, Ido; Drago-García, Diana; Rueda, Oscar M.; Caldas, Carlos; Lev, Sima; Geiger, Tamar; Ciechanover, Aaron; Ulitsky, Igor; Seger, Rony; Ruppin, Eytan

doi:10.1016/j.celrep.2022.110418

Cited by 17 publications

(16 citation statements)

References 62 publications

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“…To understand the functions and associations of these TMB-associated DEGs, GO analyses were performed. The result showed that DEGs are mainly enriched in nucleocytoplasmic and nuclear transport, and previous studies have confirmed that nucleocytoplasmic and nuclear transport are closely associated with the development of tumorigenesis [ 24 , 25 ]. Further studies have confirmed that nucleocytoplasmic and nuclear transport are closely related to HCC metastasis [ 26 ].…”

Section: Discussionmentioning

confidence: 68%

Integrated Analysis of Tumor Mutation Burden and Immune Infiltrates in Hepatocellular Carcinoma

Zhao

Huang

2022

Diagnostics

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Tumor mutation burdens (TMBs) act as an indicator of immunotherapeutic responsiveness in various tumors. However, the relationship between TMBs and immune cell infiltrates in hepatocellular carcinoma (HCC) is still obscure. The present study aimed to explore the potential diagnostic markers of TMBs for HCC and analyze the role of immune cell infiltration in this pathology. We used OA datasets from The Cancer Genome Atlas database. First, the “maftools” package was used to screen the highest mutation frequency in all samples. R software was used to identify differentially expressed genes (DEGs) according to mutation frequency and perform functional correlation analysis. Then, the gene ontology (GO) enrichment analysis was performed with “clusterProfiler”, “enrichplot”, and “ggplot2” packages. Finally, the correlations between diagnostic markers and infiltrating immune cells were analyzed, and CIBERSORT was used to evaluate the infiltration of immune cells in HCC tissues. As a result, we identified a total of 359 DEGs in this study. These DEGs may affect HCC prognosis by regulating fatty acid metabolism, hypoxia, and the P53 pathway. The top 15 genes were selected as the hub genes through PPI network analysis. SRSF1, SNRPA1, and SRSF3 showed strong similarities in biological effects, NCBP2 was demonstrated as a diagnostic marker of HCC, and high NCBP2 expression was significantly correlated with poor over survival (OS) in HCC. In addition, NCBP2 expression was correlated with the infiltration of B cells (r = 0.364, p = 3.30 × 10−12), CD8+ T cells (r = 0.295, p = 2.71 × 10−8), CD4+ T cells, (r = 0.484, p = 1.37 × 10−21), macrophages (r = 0.551, p = 1.97 × 10−28), neutrophils (r = 0.457, p = 3.26 × 10−19), and dendritic cells (r = 0.453, p = 1.97 × 10−18). Immune cell infiltration analysis revealed that the degree of central memory T-cell (Tcm) infiltration may be correlated with the HCC process. In conclusion, NCBP2 can be used as diagnostic markers of HCC, and immune cell infiltration plays an important role in the occurrence and progression of HCC.

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Section: Discussionmentioning

confidence: 68%

Integrated Analysis of Tumor Mutation Burden and Immune Infiltrates in Hepatocellular Carcinoma

Zhao

Huang

2022

Diagnostics

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“…Previous studies revealed that phosphorylated ERK1/2 was associated with nucleoporins. Nataraj et al demonstrated that nucleoporin 93 (Nup93) transported phosphorylated ERK1/2 from the cytoplasm to the nucleus by interacting with Improtin7 [ 26 ]. In our previous study, we performed Co-IP/MS (co-immunoprecipitation coupled to mass spectrometry) of total mouse testicular proteins to identify SUN5 interacting proteins and found that Nup93 was identified as a candidate interaction partner of SUN5.…”

Section: Resultsmentioning

confidence: 99%

“…The nuclear pore complex (NPC) is the sole bidirectional gateway regulating RNAs, proteins, and other macromolecules during nucleocytoplasmic transport [ 41 ]. Nataraj et al revealed that nucleoporin93 (Nup93) transported pERK1/2 from the cytoplasm to the nucleus by interacting with improtin7 [ 26 ]. In this study, we demonstrated that SUN5 accelerated the nuclear translocation of pERK1/2 by interacting with Nup93.…”

Section: Discussionmentioning

confidence: 99%

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Nuclear Membrane Protein SUN5 Is Highly Expressed and Promotes Proliferation and Migration in Colorectal Cancer by Regulating the ERK Pathway

Song

Liu

et al. 2022

Cancers

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SUN5 was first identified as a nuclear envelope protein involved in spermatocyte division. We found that SUN5 was highly expressed in some cancers, but its function and mechanism in cancer development remain unclear. In the present study, we demonstrated that SUN5 was highly expressed in colorectal cancer (CRC) tissues and cells, as indicated by bioinformatics analysis, and SUN5 promoted cell proliferation and migration in vitro. Moreover, the overexpression of SUN5 upregulated phosphorylated ERK1/2 (pERK1/2), whereas the knockdown of SUN5 yielded the opposite results. PD0325901 decreased the level of pERK1/2 to inhibit cell proliferation and migration, which was partially reversed by SUN5 overexpression, indicating that drug resistance exists in patients with high SUN5 expression. The Xenograft transplantation experiment showed that SUN5 accelerated tumor formation in vivo. Furthermore, we found that SUN5 regulated the ERK pathway via Nesprin2 mediation and promoted the nuclear translocation of pERK1/2 by interacting with Nup93. Thus, these findings indicated that highly expressed SUN5 promoted CRC proliferation and migration by regulating the ERK pathway, which may contribute to the clinical diagnosis and new treatment strategies for CRC.

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“…Loss of NUP93 resulted in defective podocyte migration, impaired podocyte proliferation, and increased sensitivity to oxidative stress [71]. The pathogenesis of nephrotic syndrome is thought to involve aberrant TGF-ß/SMAD signalling [71] and the importance for NUP93 in TGF-ß/SMAD was recently confirmed in the context of breast cancer characterised by NUP93 over-expression [84,85]. Elevated expression of NUP93 further activated the Rho GTPases Cdc42 and Rac1 [84].…”

Section: Nephrotic Syndromesmentioning

confidence: 99%

From the sideline: Tissue‐specific nucleoporin function in health and disease, an update

Jühlen,

Fahrenkrog

2023

FEBS Letters

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The subcellular compartmentalisation of eukaryotic cells requires selective exchange between the cytoplasm and the nucleus. Intact nucleocytoplasmic transport is vital for normal cell function and mutations in the executing machinery have been causally linked to human disease. Central players in nucleocytoplasmic exchange are nuclear pore complexes (NPCs), which are built from ~30 distinct proteins collectively termed nucleoporins. Aberrant nucleoporin expression was detected in human cancers and autoimmune diseases since quite some time, while it was through the increasing use of next generation sequencing that mutations in nucleoporin genes associated with mainly rare hereditary diseases were revealed. The number of newly identified mutations is steadily increasing, as is the number of diseases. Mutational hotspots have emerged: mutations in the scaffold nucleoporins seemingly affect primarily inner organs, such as heart, kidney, and ovaries, whereas genetic alterations in peripheral, cytoplasmic nucleoporins affect primarily the central nervous system and development. In this review, we summarise latest insights on altered nucleoporin function in the context of human hereditary disorders, with a focus on those where mechanistic insights are beginning to emerge.

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Nucleoporin-93 reveals a common feature of aggressive breast cancers: robust nucleocytoplasmic transport of transcription factors

Cited by 17 publications

References 62 publications

Integrated Analysis of Tumor Mutation Burden and Immune Infiltrates in Hepatocellular Carcinoma

Integrated Analysis of Tumor Mutation Burden and Immune Infiltrates in Hepatocellular Carcinoma

Nuclear Membrane Protein SUN5 Is Highly Expressed and Promotes Proliferation and Migration in Colorectal Cancer by Regulating the ERK Pathway

From the sideline: Tissue‐specific nucleoporin function in health and disease, an update

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