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Rsf?1 regulates malignant melanoma cell viability and chemoresistance via NF??B/Bcl?2 signaling.

ABSTRACT: Remodeling and spacing factor 1 (Rsf?1) has been reported as overexpressed in numerous cancers; however, its expression, biological functions and mechanisms in malignant melanoma remain unknown. In the present study, the expression of Rsf?1 was investigated in 50 cases of malignant melanoma samples using immunohistochemistry. The results revealed that Rsf?1 expression was elevated in 38% of specimens. MTT, colony formation, Transwell and flow cytometry assays were performed to investigate the functions of Rsf?1. Knockdown of Rsf?1 in the MV3 and A375 melanoma cell lines decreased the viability, invasion and cell cycle transition of cells. Conversely, overexpression of Rsf?1 in M14 cells with low endogenous Rsf?1 expression induced opposing effects. Further analysis revealed that Rsf?1 knockdown decreased matrix metalloproteinase?2, cyclin E and phosphorylated?I?B expression. Additionally, Rsf?1 depletion reduced cisplatin resistance and significantly increased the cisplatin?associated apoptotic rate, whereas Rsf?1 overexpression exhibited opposing effects. Rsf?1 also maintained the mitochondrial membrane potential following cisplatin treatment. Analysis of apoptosis?associated proteins revealed that Rsf?1 positively regulated B?cell lymphoma 2 (Bcl?2), cellular inhibitor of apoptosis 1 (cIAP1) and cIAP2, and downregulated Bcl?2?associated X protein expression. Nuclear factor ??light?chain?enhancer of activated B?cells (NF??B) inhibition reversed the effects of Rsf?1 on Bcl?2. In conclusion, Rsf?1 was overexpressed in malignant melanoma and may contribute to the malignant behaviors of melanoma cells, possibly via the regulation of NF??B signaling. Therefore, Rsf?1 may be a potential therapeutic target in the treatment of malignant melanoma.

SUBMITTER: He J

PROVIDER: S-EPMC6755232 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Rsf‑1 regulates malignant melanoma cell viability and chemoresistance via NF‑κB/Bcl‑2 signaling.

He Jiani J Fu Lin L Li Qingchang Q

Molecular medicine reports 20190823 4

Remodeling and spacing factor 1 (Rsf‑1) has been reported as overexpressed in numerous cancers; however, its expression, biological functions and mechanisms in malignant melanoma remain unknown. In the present study, the expression of Rsf‑1 was investigated in 50 cases of malignant melanoma samples using immunohistochemistry. The results revealed that Rsf‑1 expression was elevated in 38% of specimens. MTT, colony formation, Transwell and flow cytometry assays were performed to investigate the fu ...[more]

PMID: 31485613

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Project description:Melanoma is the most lethal cutaneous cancer with a high metastatic rate worldwide, causing ~55,500 deaths annually. Although the selective B-Raf oncogene serine/threonine-kinase (BRAF) inhibitors, dabrafenib and vemurafenib, have been approved for the treatment of BRAF-mutant metastatic melanoma, the 5-year survival rate remains unfavorable due to acquired therapy resistance. Therefore, it is of great importance to develop alternative therapeutic drugs and uncover their mechanisms for the treatment of melanoma. 7-dehydrocholesterol (7-DHC) has been demonstrated to inhibit melanoma, but the mechanism is unclear. Therefore, the present study aimed to elucidate the mechanisms of the inhibitory effect of 7-DHC in melanoma cells via analyzing the proliferation, migration, apoptosis, cell cycle and transcriptional sequencing of melanoma cells treated with 7-DHC, as well as constructing a gene signature according to public data of patients with melanoma. In the present study, 7-DHC, the precursor of vitamin D3, was able to induce apoptosis and inhibit cell proliferation and invasion of melanoma cells in a dose-dependent manner. RNA sequencing of melanoma cells treated with different concentrations of 7-DHC revealed that, compared with untreated melanoma cells, 65 genes were downregulated, and genes involved in the regulation of NF-ĸB import into the nucleus and NF-ĸB signaling were significantly repressed. Consistently, the Akt kinase family was one of most common somatic mutation hotspots in patients with melanoma according to The Cancer Genome Atlas enrichment analysis. Furthermore, 7-DHC decreased the phosphorylation of Akt1-Ser473 rather than that of MEK1, and the decreased phosphorylation of Akt1 subsequently inhibited the translocation of free RELA proto-oncogene NF-κB subunit to the nucleus. Finally, by intersecting downregulated genes by 7-DHC treatment and upregulated genes in patients with melanoma, a 7-DHC gene signature was identified, which was negatively associated with the prognosis. Overall, the present results demonstrated that 7-DHC suppressed melanoma cell proliferation and invasion via the Akt1/NF-ĸB signaling pathway, and 7-DHC key target genes were negatively associated with the prognosis. These findings highlight the potential application of 7-DHC for the treatment of melanoma in the future.

Dataset Information

Rsf?1 regulates malignant melanoma cell viability and chemoresistance via NF??B/Bcl?2 signaling.

Publications

Rsf‑1 regulates malignant melanoma cell viability and chemoresistance via NF‑κB/Bcl‑2 signaling.

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