Malignant melanoma remains the most lethal form of skin cancer, exhibiting poor prognosis after forming distant metastasis. Owing to their potential tumor-suppressive properties by regulating oncogenes and tumor suppressor genes, microRNAs are important player in melanoma development and progression. We defined the loss of miR-101-3p expression in melanoma cells compared with melanocytes and melanoblast-related cells as an early event in tumor development and aimed to understand the tumor suppressive role of miR-101-3p and its regulation of important cellular processes. Reexpression of miR-101-3p resulted in inhibition of proliferation, increase in DNA damage, and induction of apoptosis. We further determined the nuclear structure protein Lamin B1, which influences nuclear processes and heterochromatin structure, ATRX, CASP3, and PARP as an important direct target of miR-101-3p. RNA sequencing and differential gene expression analysis after miR-101-3p reexpression supported our findings and the importance of loss of mir-101-3p for melanoma progression. The validated functional effects are related to genomic instability, as recent studies suggest miRNAs plays a key role in mediating this cellular process. Therefore, we concluded that miR-101-3p reexpression increases the genomic instability, leading to irreversible DNA damage, which leads to apoptosis induction. Our findings suggest that the loss of miR-101-3p in melanoma serves as an early event in melanoma progression by influencing the genomic integrity to maintain the increased bioenergetic demand.

中文翻译：

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黑色素瘤中 miR-101-3p 的缺失可稳定基因组完整性，从而预防细胞死亡

恶性黑色素瘤仍然是最致命的皮肤癌，在形成远处转移后表现出较差的预后。由于它们通过调节癌基因和抑癌基因而具有潜在的肿瘤抑制特性，microRNA 在黑色素瘤的发生和进展中发挥着重要作用。我们将黑色素瘤细胞中 miR-101-3p 表达的丧失（与黑色素细胞和成黑素细胞相关细胞相比）定义为肿瘤发展的早期事件，旨在了解 miR-101-3p 的肿瘤抑制作用及其对重要细胞过程的调节。miR-101-3p 的重新表达导致增殖抑制、DNA 损伤增加和细胞凋亡诱导。我们进一步确定影响核过程和异染色质结构的核结构蛋白 Lamin B1、ATRX、CASP3 和 PARP 作为 miR-101-3p 的重要直接靶标。miR-101-3p 重新表达后的 RNA 测序和差异基因表达分析支持了我们的发现以及 mir-101-3p 丢失对黑色素瘤进展的重要性。经验证的功能效应与基因组不稳定性有关，因为最近的研究表明 miRNA 在介导这一细胞过程中发挥着关键作用。因此，我们得出结论，miR-101-3p重新表达增加了基因组不稳定性，导致不可逆的DNA损伤，从而诱导细胞凋亡。我们的研究结果表明，黑色素瘤中 miR-101-3p 的缺失是黑色素瘤进展的早期事件，通过影响基因组完整性来维持增加的生物能需求。