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Nuclear Transport Factor 2 (NTF2) suppresses WM983B metastatic melanoma by modifying cell migration, metastasis, and gene expression.

ABSTRACT: While changes in nuclear structure and organization are frequently observed in cancer cells, relatively little is known about how nuclear architecture impacts cancer progression and pathology. To begin to address this question, we studied Nuclear Transport Factor 2 (NTF2) because its levels decrease during melanoma progression. We show that increasing NTF2 expression in WM983B metastatic melanoma cells reduces cell proliferation and motility while increasing apoptosis. We also demonstrate that increasing NTF2 expression in these cells significantly inhibits metastasis and prolongs survival of mice. NTF2 levels affect the expression and nuclear positioning of a number of genes associated with cell proliferation and migration, and increasing NTF2 expression leads to changes in nuclear size, nuclear lamin A levels, and chromatin organization. Thus, ectopic expression of NTF2 in WM983B metastatic melanoma abrogates phenotypes associated with advanced stage cancer both in vitro and in vivo, concomitantly altering nuclear and chromatin structure and generating a gene expression profile with characteristics of primary melanoma. We propose that NTF2 is a melanoma tumor suppressor and could be a novel therapeutic target to improve health outcomes of melanoma patients.

SUBMITTER: Vukovic LD

PROVIDER: S-EPMC8654834 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Nuclear Transport Factor 2 (NTF2) suppresses WM983B metastatic melanoma by modifying cell migration, metastasis, and gene expression.

Vuković Lidija D LD Chen Pan P Mishra Sampada S White Karen H KH Gigley Jason P JP Levy Daniel L DL

Scientific reports 20211208 1

While changes in nuclear structure and organization are frequently observed in cancer cells, relatively little is known about how nuclear architecture impacts cancer progression and pathology. To begin to address this question, we studied Nuclear Transport Factor 2 (NTF2) because its levels decrease during melanoma progression. We show that increasing NTF2 expression in WM983B metastatic melanoma cells reduces cell proliferation and motility while increasing apoptosis. We also demonstrate that i ...[more]

PMID: 34880267

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Project description:BACKGROUND: Macrophage migration inhibitory factor (MIF) is a widely expressed cytokine involved in a variety of cellular processes including cell cycle regulation and the control of proliferation. Overexpression of MIF has been reported in a number of cancer types and it has previously been shown that MIF is upregulated in melanocytic tumours with the highest expression levels occurring in malignant melanoma. However, the clinical significance of high MIF expression in melanoma has not been reported. METHODS: MIF expression was depleted in human melanoma cell lines using siRNA-mediated gene knockdown and effects monitored using in vitro assays of proliferation, cell cycle, apoptosis, clonogenicity and Akt signalling. In silico analyses of expression microarray data were used to correlate MIF expression levels in melanoma tumours with overall patient survival using a univariate Cox regression model. RESULTS: Knockdown of MIF significantly decreased proliferation, increased apoptosis and decreased anchorage-independent growth. Effects were associated with reduced numbers of cells entering S phase concomitant with decreased cyclin D1 and CDK4 expression, increased p27 expression and decreased Akt phosphorylation. Analysis of clinical outcome data showed that MIF expression levels in primary melanoma were not associated with outcome (HR = 1.091, p = 0.892) whereas higher levels of MIF in metastatic lesions were significantly associated with faster disease progression (HR = 2.946, p = 0.003 and HR = 4.600, p = 0.004, respectively in two independent studies). CONCLUSIONS: Our in vitro analyses show that MIF functions upstream of the PI3K/Akt pathway in human melanoma cell lines. Moreover, depletion of MIF inhibited melanoma proliferation, viability and clonogenic capacity. Clinically, high MIF levels in metastatic melanoma were found to be associated with faster disease recurrence. These findings support the clinical significance of MIF signalling in melanoma and provide a strong rationale for both targeting and monitoring MIF expression in clinical melanoma.

Project description:BackgroundDespite advancements in targeted therapy and immunotherapy, cutaneous melanoma continues to have a high mortality rate and poor prognosis, with therapies having limited efficacy in advanced melanoma. Therefore, it is crucial to develop novel therapeutics with proven clinical potential. In this study, we evaluated the efficacy of arcyriaflavin A (ArcA), a potent inhibitor of the cyclin D1/CDK4 complex, in suppressing aggressive phenotypes of metastatic melanoma.MethodsThe effects of ArcA on viability and cell cycle were evaluated across four melanoma cell lines: WM239A and its metastatic derivatives: 113-6/4L, 131/4-5B1, and 131/4-5B2. Additionally, we performed wound healing and transwell invasion assays, followed by western blot. We further established xenograft mouse models by subcutaneously injecting them with the four melanoma cell lines and measured tumor size and weight biweekly. Immunohistochemistry analysis was performed to compare protein expression.ResultsArcA demonstrated dose-dependent cytotoxicity, selectively targeting melanoma cells without affecting normal cells, and induced G1 cell cycle arrest. Moreover, ArcA significantly inhibited cell migration and invasion in metastatic melanoma cell lines, accompanied by reduced expression levels of p-GSK-3β (Ser9), MMP-9, and MMP-13, suggesting that its anti-metastatic effects may be partially mediated through GSK-3β, MMP-9, and MMP-13. These findings were further validated using mouse xenograft models; ArcA-treated mice exhibited significantly smaller tumor volumes and lighter tumor weights compared to vehicle-treated mice. Immunohistochemistry further confirmed decreased expression of p-GSK-3β, MMP-9, and MMP-13 in tumor tissues from ArcA-treated mice.ConclusionsCollectively, our findings indicate that ArcA possesses substantial anti-tumor potential, including cytotoxic effects and inhibition of migration and invasion in metastatic melanoma. These results suggest that ArcA could enhance therapeutic efficacy in the treatment of metastatic melanoma.

Dataset Information

Nuclear Transport Factor 2 (NTF2) suppresses WM983B metastatic melanoma by modifying cell migration, metastasis, and gene expression.

Publications

Nuclear Transport Factor 2 (NTF2) suppresses WM983B metastatic melanoma by modifying cell migration, metastasis, and gene expression.

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