7-dehydrocholesterol suppresses melanoma cell proliferation and invasion via Akt1/NF-κB signaling.
7-dehydrocholesterol suppresses melanoma cell proliferation and invasion via Akt1/NF-κB signaling.
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7-脱氢胆固醇通过AKT1/NF-κB信号传导抑制黑色素瘤细胞的增殖和侵袭。
DOI：
10.3892/ol.2020.12261
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发表时间：
2020-12
期刊：
影响因子：
2.9
通讯作者：
Yuan Y
中科院分区：
文献类型：
--
作者：
Liu J;Zhong F;Cao L;Zhu R;Qu J;Yang L;Chen T;Hu Y;Wang Y;Yao M;Xiao W;Li C;Li B;Yuan Y
黑色素瘤是最致命的皮肤癌，在世界范围内具有高转移率，每年造成约55，500人死亡。尽管选择性B-Raf癌基因丝氨酸/苏氨酸激酶（BRAF）抑制剂达拉非尼和维罗非尼已被批准用于治疗BRAF突变型转移性黑色素瘤，但由于获得性治疗耐药性，5年生存率仍然不利。因此，开发新的治疗药物并揭示其作用机制对黑色素瘤的治疗具有重要意义。7-脱氢胆固醇（7-DHC）已被证明可以抑制黑色素瘤，但其机制尚不清楚。因此，本研究旨在通过分析7-DHC对黑色素瘤细胞增殖、迁移、凋亡、细胞周期和转录序列的影响，并根据公开的黑色素瘤患者数据构建基因标签，阐明7-DHC对黑色素瘤细胞的抑制作用机制。在本研究中，7-DHC，维生素D3的前体，能够诱导细胞凋亡，抑制细胞增殖和黑色素瘤细胞的侵袭，以剂量依赖性的方式。用不同浓度的7-DHC处理的黑色素瘤细胞的RNA测序显示，与未处理的黑色素瘤细胞相比，有65个基因下调，参与调节NF-κ B输入细胞核和NF-κ B信号传导的基因被显著抑制。因此，Akt激酶家族是黑色素瘤患者中最常见的体细胞突变热点之一。此外，7-DHC降低了Akt 1-Ser 473的磷酸化水平，而不是MEK 1的磷酸化水平，Akt 1磷酸化水平的降低抑制了游离RELA原癌基因NF-κB亚基的核转位。最后，通过交叉7-DHC治疗下调的基因和黑色素瘤患者上调的基因，鉴定了与预后负相关的7-DHC基因标签。总之，本研究结果表明，7-DHC通过Akt 1/NF-κ B信号通路抑制黑色素瘤细胞增殖和侵袭，7-DHC关键靶基因与预后呈负相关。这些发现突出了7-DHC在未来治疗黑色素瘤的潜在应用。
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.
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影响因子：
50.5
作者：
Michielin, O.;van Akkooi, A. C. J.;Keilholz, U.
通讯作者：
Keilholz, U.
影响因子：
8.4
作者：
Crocetti, Emanuele;Mallone, Sandra;Eisemann, Nora
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4.5
作者：
Moutzouri, Elisavet;Elisaf, Moses;Liberopoulos, Evangelos N.
通讯作者：
Liberopoulos, Evangelos N.
影响因子：
0.9
作者：
Bentz, MH;Magnette, J
通讯作者：
Magnette, J
影响因子：
120.7
作者：
Mokdad, AH;Bowman, BA;Koplan, JP
通讯作者：
Koplan, JP