Ran GTPase promotes cancer progression via Met receptor-mediated downstream signaling

Yuen, Hiu Fung; Chan, Kristy Kwan‐Shuen; Platt-Higgins, Angela; Dakir, El Habib; Matchett, Kyle B.; Haggag, Yusuf A.; Jithesh, Puthen V.; Habib, Tanwir; Faheem, Ahmed; Dean, Fennell A.; Morgan, Richard; Rudland, Philip S.; El‐Tanani, Mohamed

doi:10.18632/oncotarget.12420

Cited by 32 publications

(50 citation statements)

References 40 publications

(59 reference statements)

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“…RAN is a small GTPase of the RAS superfamily and is involved in several biological processes, such as nucleocytoplasmic transport, nuclear envelope formation, and mitotic spindle assembly . Moreover, overexpression of RAN has already been reported in myriad of cancers, which is also correlated with poor prognosis, increased aggressiveness, and metastasis, inhibition of which can lead to suppression of cancer . Therefore, to precisely address the oncogenic role of RAN in tumorigenesis of fibrosarcoma, which we found to be upregulated in fibrosarcoma as well.…”

Section: Resultsmentioning

confidence: 85%

“…[33][34][35] Moreover, overexpression of RAN has already been reported in myriad of cancers, which is also correlated with poor prognosis, increased aggressiveness, and metastasis, [36][37][38] inhibition of which can lead to suppression of cancer. 39 Therefore, to precisely address the oncogenic role of RAN in tumorigenesis of fibrosarcoma, which we found to be upregulated in fibrosarcoma as well. We cotransfected RAN along with miR-197-3p mimic in fibrosarcoma cells and observed that restoration of miR-197-3p abrogated the effect of RAN on cell proliferation and migration.…”

Section: Discussionmentioning

confidence: 94%

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Restoration of microRNA‐197 expression suppresses oncogenicity in fibrosarcoma through negative regulation of RAN

2020

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MicroRNAs (miRNAs) act as crucial regulators of biological pathways/processes by reinforcing transcriptional programs and moderating transcripts. Emerging evidences have shown the involvement of dysregulated miRNAs in pathophysiology of human diseases including several cancer types. Recently, miR‐197‐3p has been reported to play different roles in different cancers; however, its role in fibrosarcoma, a highly aggressive and malignant soft tissue sarcoma originated from the mesenchymal tissues, has not yet been studied. Therefore, this study aims to investigate the possible regulatory roles of miR‐197‐3p in the oncogenicity of fibrosarcoma. For this, we initially performed qRT‐PCR of miR‐197‐3p, which we found to be downregulated in HT1080 human fibrosarcoma cells compared with IMR90‐tert normal fibroblast cells. Subsequently, we performed gain‐of‐function study by employing several methods such as MTT assay, clonogenic assay, wound healing, flow cytometry cell cycle analysis, and acridine orange staining after transfecting HT1080 cells with miR‐197‐3p mimic. From these assays, we observed that miR‐197‐3p significantly inhibits viability, colony forming, and migration ability as well as triggers G2/M phase cell cycle arrest and autophagy in fibrosarcoma cells. To understand the mechanism through which miRNA performs these functions, we predicted its targets using TargetScan and performed pathway enrichment analysis after screening them by their expression in fibrosarcoma. Among the enriched targets, we found RAN (ras‐related nuclear protein) to be a crucial target through which miR‐197‐3p represses tumorigenesis by binding to its 3´ UTR, validated by luciferase reporter assay. The tumor suppressive role of the miRNA was further confirmed by transfecting its mimic in RAN‐overexpressed cells which showed significant attenuation in tumorigenic effect of RAN in fibrosarcoma as seen in different assays. Taken together, our study unveiled that miR‐197‐3p acts as an oncosuppressor in fibrosarcoma through G2/M phase arrest and induction of autophagy, and raises the possibility to act as a novel therapeutic intervention for the malignancy.

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Section: Resultsmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 94%

Restoration of microRNA‐197 expression suppresses oncogenicity in fibrosarcoma through negative regulation of RAN

2020

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“…Gene ontology and KEGG pathways for these 24 genes were then performed using the web‐based online pathway tool NIH‐DAVID (Table) . Among KEGG pathways for the 24 genes, the RNA transport pathway was attractive as a therapeutic target because it included XPO1 and RAN , which are well characterized therapeutic targets for human cancers, including lung cancer . Our screening studies identified eIF2 β as an additional gene of the RNA transport pathway.…”

Section: Resultsmentioning

confidence: 99%

“…19,20 Among KEGG pathways for the 24 genes, the RNA transport pathway was attractive as a therapeutic target because it included XPO1 and RAN, which are well characterized therapeutic targets for human cancers, including lung cancer. [8][9][10][11] Our screening studies identified eIF2b as an additional gene of the RNA transport pathway. This gene encodes the b-subunit of EIF2, which is a heterotrimeric G protein comprising a-, band c-subunits, and functions as a translation initiator factor.…”

Section: Discussionmentioning

confidence: 97%

“…In particular, eIF2b (also known as EIF2S2) is a subunit of heterotrimeric G protein EIF2, which comprises the 3 subunits eIF2a, eIF2b and eIF2c. 6,7 In gene ontology analyses that included the well-studied therapeutic targets for human cancer RAN member RAS oncogene family and exportin 1 (XPO1), [8][9][10][11] we showed that eIF2b is an RNA transport molecule and demonstrated its potential as a therapeutic target.…”

Section: Introductionmentioning

confidence: 93%

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eIF2β, a subunit of translation‐initiation factor EIF2, is a potential therapeutic target for non‐small cell lung cancer

et al. 2018

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To identify novel therapeutic targets for non‐small cell lung cancer (NSCLC), we conducted an integrative study in the following 3 stages: (i) identification of potential target gene(s) through shRNA functional screens in 2 independent NSCLC cell lines; (ii) validation of the clinical relevance of identified gene(s) using public databases; and (iii) investigation of therapeutic potential of targeting the identified gene(s) in vitro. A semi‐genome‐wide shRNA screen was performed in NCI‐H358 cells, and was integrated with data from our previous screen in NCI‐H460 cells. Among genes identified in shRNA screens, 24 were present in both NCI‐H358 and NCI‐H460 cells and were considered potential targets. Among the genes, we focused on eIF2β, which is a subunit of heterotrimeric G protein EIF2 and functions as a transcription initiation factor. The eIF2β protein is highly expressed in lung cancer cell lines compared with normal bronchial epithelial cells, and gene copy number analyses revealed that eIF2β is amplified in a subset of NSCLC cell lines. Gene expression analysis using The Cancer Genome Atlas (TCGA) dataset revealed that eIF2β expression is significantly upregulated in lung cancer tissues compared with corresponding normal lung tissues. Furthermore, high eIF2β expression was correlated with poor survival in patients with lung adenocarcinoma, as shown in other cohorts using publicly available online tools. RNAi‐mediated depletion of eIF2β suppresses growth of lung cancer cells independently of p53 mutation status, in part through G1 cell cycle arrest. Our data suggest that eIF2β is a therapeutic target for lung cancer.

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Anti-Invasive and Anti-Proliferative Effects of shRNA-Loaded Poly(Lactide-Co-Glycolide) Nanoparticles Following RAN Silencing in MDA-MB231 Breast Cancer Cells

et al. 2018

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BackgroundOverexpression of the RAN GTP (RAN) gene has been shown to be linked to metastatic activity of MDA-MB231 human breast cancer cells by increasing Ras/MEK/ERK and PI3K/Akt/mTORC1 signalling. The aim of this study was to investigate the potential of polymeric nanoparticles to deliver two novel shRNA sequences, targeted against the RAN gene, to MDA-MB231 cells grown in culture and to assess their effects in a range of biological assays.MethodsBiodegradable PLGA nanoparticles, loaded with shRNA-1 and shRNA-4, were fabricated using a double emulsion solvent evaporation technique and characterised for size, zeta potential and polydispersity index before testing on the MDA-MB231 cell line in a range of assays including cell viability, migration, invasion and gene knock down.ResultsshRNA-loaded nanoparticles were successfully fabricated and delivered to MDA-MB231 cells in culture, where they effectively released their payload, causing a decrease in both cell invasion and cell migration by knocking down RAN gene expression.ConclusionResults indicate the anti-RAN shRNA-loaded nanoparticles deliver and release biological payload to MDA-MB231 cells in culture. This works paves the way for further investigations into the possible use of anti-RAN shRNA-loaded NP formulations for the treatment of breast cancer in vivo.

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Ran GTPase promotes cancer progression via Met receptor-mediated downstream signaling

Cited by 32 publications

References 40 publications

Restoration of microRNA‐197 expression suppresses oncogenicity in fibrosarcoma through negative regulation of RAN

Restoration of microRNA‐197 expression suppresses oncogenicity in fibrosarcoma through negative regulation of RAN

eIF2β, a subunit of translation‐initiation factor EIF2, is a potential therapeutic target for non‐small cell lung cancer

Anti-Invasive and Anti-Proliferative Effects of shRNA-Loaded Poly(Lactide-Co-Glycolide) Nanoparticles Following RAN Silencing in MDA-MB231 Breast Cancer Cells

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