ALDH1A2 Is a Candidate Tumor Suppressor Gene in Ovarian Cancer
ALDH1A2 Is a Candidate Tumor Suppressor Gene in Ovarian Cancer
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DOI：
10.3390/cancers11101553
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发表时间：
2019-10-01
期刊：
影响因子：
5.2
通讯作者：
Kim, Jae-Hoon
中科院分区：
文献类型：
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作者：
Choi, Jung-A;Kwon, Hyunja;Kim, Jae-Hoon
乙醛脱氢酶1家族成员A2（ALDH 1A 2）是参与细胞视黄酸合成的限速酶。然而，其在卵巢癌中的功能作用仍然难以捉摸。在这里，我们发现，ALDH 1A 2是卵巢癌细胞中ALDH家族成员中最显着下调的基因，根据互补DNA微阵列数据。ALDH 1A 2低表达与卵巢癌患者预后不良、无病生存期和总生存期较短相关。值得注意的是，ALDH 1A 2的超甲基化在卵巢癌细胞系中显著高于永生化的人卵巢表面上皮细胞系。在用DNA甲基化抑制剂5-氮杂-2 '-脱氧胞苷处理后，ALDH 1A 2表达在各种卵巢癌细胞系中恢复。此外，沉默DNA甲基转移酶1（DNMT 1）或3B（DNMT 3B）恢复ALDH 1A 2在卵巢癌细胞系中的表达。功能研究表明，强制ALDH 1A 2表达显着损害卵巢癌细胞的增殖和它们的侵袭活性。据我们所知，这是第一项研究表明ALDH 1A 2表达受DNMT的表观遗传调控，随后它可能在卵巢癌中作为肿瘤抑制因子，进一步表明增强ALDH 1A 2相关信号可能为卵巢癌的治疗干预提供新的机会。
Aldehyde dehydrogenase 1 family member A2 (ALDH1A2) is a rate-limiting enzyme involved in cellular retinoic acid synthesis. However, its functional role in ovarian cancer remains elusive. Here, we found that ALDH1A2 was the most prominently downregulated gene among ALDH family members in ovarian cancer cells, according to complementary DNA microarray data. Low ALDH1A2 expression was associated with unfavorable prognosis and shorter disease-free and overall survival for ovarian cancer patients. Notably, hypermethylation of ALDH1A2 was significantly higher in ovarian cancer cell lines when compared to that in immortalized human ovarian surface epithelial cell lines. ALDH1A2 expression was restored in various ovarian cancer cell lines after treatment with the DNA methylation inhibitor 5-aza-2'-deoxycytidine. Furthermore, silencing DNA methyltransferase 1 (DNMT1) or 3B (DNMT3B) restored ALDH1A2 expression in ovarian cancer cell lines. Functional studies revealed that forced ALDH1A2 expression significantly impaired the proliferation of ovarian cancer cells and their invasive activity. To the best of our knowledge, this is the first study to show that ALDH1A2 expression is regulated by the epigenetic regulation of DNMTs, and subsequently that it might act as a tumor suppressor in ovarian cancer, further suggesting that enhancing ALDH1A2-linked signaling might provide new opportunities for therapeutic intervention in ovarian cancer.