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.
Highlights
Cancer cells exhibit many characteristics that distinguish them from normal cells, including higher proliferation rates, immortalization, suppressed apoptosis, and metastasis[1]
With 20 ng/ml doxycycline added to the growth media, on average 7.8-fold higher Nuclear Transport Factor 2 (NTF2) protein expression was observed compared to the parental cell line (Fig. 1A), well within the physiological range of NTF2 protein expression variation reported in numerous cultured cell lines[27]
Stably transfected cells not treated with doxycycline expressed ~ fourfold higher and more variable NTF2 protein levels compared to the parental cell line, an indication of promoter leakiness that has been reported by o thers[28]
Summary
Cancer cells exhibit many characteristics that distinguish them from normal cells, including higher proliferation rates, immortalization, suppressed apoptosis, and metastasis[1]. Based on data from 4 patient-derived cell lines and 24 biopsies, we found that as nuclear size increases during melanoma progression, the levels of Nuclear Transport Factor 2 (NTF2) d ecrease[12]. This led us to hypothesize that reductions in NTF2 expression might promote melanoma progression to more advanced stages of disease, motivating our current study to test if ectopic NTF2 expression in metastatic melanoma could abrogate certain cancer cell phenotypes. These results highlight NTF2 as a potential novel therapeutic target to treat metastatic melanoma
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