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首页> 外文期刊>PLoS Genetics >Autophagy gene haploinsufficiency drives chromosome instability, increases migration, and promotes early ovarian tumors
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Autophagy gene haploinsufficiency drives chromosome instability, increases migration, and promotes early ovarian tumors

机译：自噬基因HAPLOUSUBINUCINGS驱动染色体不稳定性，增加迁移，并促进早期的卵巢肿瘤

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Autophagy, particularly with BECN1 , has paradoxically been highlighted as tumor promoting in Ras-driven cancers, but potentially tumor suppressing in breast and ovarian cancers. However, studying the specific role of BECN1 at the genetic level is complicated due to its genomic proximity to BRCA1 on both human (chromosome 17) and murine (chromosome 11) genomes. In human breast and ovarian cancers, the monoallelic deletion of these genes is often co-occurring. To investigate the potential tumor suppressor roles of two of the most commonly deleted autophagy genes in ovarian cancer, BECN1 and MAP1LC3B were knocked-down in atypical ( BECN1 +/+ and MAP1LC3B +/+) ovarian cancer cells. Ultra-performance liquid chromatography mass-spectrometry metabolomics revealed reduced levels of acetyl-CoA which corresponded with elevated levels of glycerophospholipids and sphingolipids. Migration rates of ovarian cancer cells were increased upon autophagy gene knockdown. Genomic instability was increased, resulting in copy-number alteration patterns which mimicked high grade serous ovarian cancer. We further investigated the causal role of Becn1 haploinsufficiency for oncogenesis in a MISIIR SV40 large T antigen driven spontaneous ovarian cancer mouse model. Tumors were evident earlier among the Becn1 +/- mice, and this correlated with an increase in copy-number alterations per chromosome in the Becn1 +/- tumors. The results support monoallelic loss of BECN1 as permissive for tumor initiation and potentiating for genomic instability in ovarian cancer.
机译：自噬，特别是与BECN1的矛盾被突出被突出显示为在RAS驱动的癌症中促进肿瘤，但潜在的肿瘤抑制在乳腺癌和卵巢癌中。然而，由于其在人（染色体17）和鼠（染色体11）基因组上的基因组接近于BRCA1，研究BECN1在遗传水平处的具体作用是复杂的。在人乳腺和卵巢癌中，这些基因的单相连缺失通常是共同的。为了探讨卵巢癌中两种最常见的自噬基因的潜在肿瘤抑制作用，BECN1和MAP1LC3B在非典型（BECN1 + / +和MAP1LC3B + / +）卵巢癌细胞中被击倒。超级性液相色谱法质谱型代谢物显露，乙酰-CoA的水平降低，其对应于升高水平的甘油磷脂和鞘磷脂。自噬基因敲低时增加卵巢癌细胞的迁移率。基因组不稳定性增加，导致拷贝数改变模式，模仿高级浆液癌癌症。我们进一步研究了MISIIR SV40大T抗原驱动的自发性卵巢癌小鼠模型中BECN1 HAPHOUSUFCUINCUS的因果作用。 BECN1 +/-小鼠的肿瘤早期是显而易见的，这与BECN1 +/-肿瘤中每种染色体的拷贝数改变的增加相关。结果支持单独损失BECN1作为肿瘤起始和增强卵巢癌基因组不稳定性的允许。

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