Autophagy gene haploinsufficiency drives chromosome instability, increases migration, and promotes early ovarian tumors.,PLOS Genetics

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Autophagy gene haploinsufficiency drives chromosome instability, increases migration, and promotes early ovarian tumors.
PLOS Genetics ( IF 4.0 ) Pub Date : 2020-01-10 , DOI: 10.1371/journal.pgen.1008558
Joe R Delaney _{1,

2,

3,

4,

5} , Chandni B Patel _{1,

2} , Jaidev Bapat _{1,

2,

5} , Christian M Jones ₄ , Maria Ramos-Zapatero _{1,

2,

5} , Katherine K Ortell ₄ , Ralph Tanios ₄ , Mina Haghighiabyaneh _{1,

2} , Joshua Axelrod _{1,

2} , John W DeStefano ₄ , Isabelle Tancioni _{1,

2} , David D Schlaepfer _{1,

2} , Olivier Harismendy _{1,

6} , Albert R La Spada _{3,

5} , Dwayne G Stupack _{1,

2}

Affiliation

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.

中文翻译：

自噬基因单倍体不足会导致染色体不稳定、增加迁移并促进早期卵巢肿瘤。

自噬，尤其是 BECN1，自相矛盾地被强调为 Ras 驱动的癌症中的肿瘤促进作用，但在乳腺癌和卵巢癌中可能具有肿瘤抑制作用。然而，由于 BECN1 在人类（17 号染色体）和小鼠（11 号染色体）基因组上都与 BRCA1 接近，因此在基因水平上研究 BECN1 的具体作用很复杂。在人类乳腺癌和卵巢癌中，这些基因的单等位基因缺失通常同时发生。为了研究卵巢癌中两种最常见缺失的自噬基因的潜在抑癌作用，在非典型卵巢癌细胞（BECN1+/+ 和 MAP1LC3B+/+）中敲除 BECN1 和 MAP1LC3B。超高效液相色谱质谱代谢组学显示乙酰辅酶A水平降低，这与甘油磷脂和鞘脂水平升高相对应。自噬基因敲除后卵巢癌细胞的迁移率增加。基因组不稳定性增加，导致拷贝数改变模式模仿高级别浆液性卵巢癌。我们进一步研究了 Becn1 单倍体不足在 MISIIR SV40 大 T 抗原驱动的自发性卵巢癌小鼠模型中肿瘤发生的因果作用。 Becn1+/- 小鼠中的肿瘤较早出现，这与 Becn1+/- 肿瘤中每条染色体拷贝数改变的增加相关。结果支持 BECN1 的单等位基因缺失可以促进肿瘤的发生并增强卵巢癌基因组的不稳定性。

更新日期：2020-02-18

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