Paradoxical impact of two folate receptors, FRα and RFC, in ovarian cancer: effect on cell proliferation, invasion and clinical outcome.
Paradoxical impact of two folate receptors, FRα and RFC, in ovarian cancer: effect on cell proliferation, invasion and clinical outcome.
复制标题
DOI：
10.1371/journal.pone.0047201
复制
发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Cheung AN
中科院分区：
文献类型：
--
作者：
Siu MK;Kong DS;Chan HY;Wong ES;Ip PP;Jiang L;Ngan HY;Le XF;Cheung AN
尽管叶酸是一种必需的维生素，但它与促进肿瘤生长有关，这一点已被关于癌中叶酸受体α（FRα）过表达的报道所证实。另一种叶酸转运蛋白，还原叶酸载体（RFC）的作用在很大程度上是未知的。本研究探讨叶酸、FRα和RFC在卵巢癌中的作用。我们证明FRα mRNA和蛋白质过表达以及RFC表达减少分别与FRα基因扩增和RFC启动子高甲基化相关。FRα过表达与肿瘤进展相关，而RFC表达则导致良好的临床结局。在卵巢癌细胞系中也观察到这种相互表达模式。叶酸在体外可促进癌细胞的增殖、迁移和侵袭，并下调E-钙粘蛋白的表达。这种效应在FRα稳定敲除或RFC异位过表达后被阻断。这一迄今未报道的现象表明，RFC可以作为FRα的平衡伴侣，并在FRα高表达的卵巢癌患者中发挥保护作用，其延长的总体和无病生存期证明了这一点。总之，我们报告了FRα（推定致癌）和RFC（推定肿瘤抑制）在人类恶性肿瘤中的矛盾影响。FRα和RFC可能分别作为治疗靶点和预后指标。我们建议谨慎和额外的研究叶酸补充剂在癌症患者。
Despite being an essential vitamin, folate has been implicated to enhance tumor growth, as evidenced by reports on overexpression of folate receptor alpha (FRα) in carcinomas. The role of another folate transporter, reduced folate carrier (RFC), is largely unknown. This study investigated the roles of folate, FRα and RFC in ovarian cancers. We demonstrated FRα mRNA and protein overexpression and reduced RFC expression in association with FRα gene amplification and RFC promoter hypermethylation, respectively. FRα overexpression was associated with tumor progression while RFC expression incurred a favorable clinical outcome. Such reciprocal expression pattern was also observed in ovarian cancer cell lines. Folate was shown to promote cancer cell proliferation, migration and invasion in vitro, and down-regulate E-cadherin expression. This effect was blocked after either stable knockdown of FRα or ectopic overexpression of RFC. This hitherto unreported phenomenon suggests that, RFC can serve as a balancing partner of FRα and confer a protective effect in patients with high FRα-expressing ovarian carcinomas, as evidenced by their prolonged overall and disease-free survivals. In conclusion, we report on the paradoxical impact of FRα (putative oncogenic) and RFC (putative tumor suppressive) in human malignancies. FRα and RFC may potentially be explored as therapeutic target or prognostic marker respectively. We recommend caution and additional research on folate supplements in cancer patients.
登录
查看更多内容
影响因子：
4.7
作者：
Kalli, Kimberly R.;Oberg, Ann L.;Hartmann, Lynn C.
通讯作者：
Hartmann, Lynn C.
影响因子：
5.1
作者：
Figini, M;Ferri, R;Canevari, S
通讯作者：
Canevari, S
影响因子：
6.2
作者：
Goodman, MT;Howe, HL;Chen, VW
通讯作者：
Chen, VW
DOI：
10.1073/pnas.94.7.3290
发表时间：
1997-04-01
影响因子：
11.1
作者：
Blount, BC;Mack, MM;Ames, BN
通讯作者：
Ames, BN
影响因子：
6.7
作者：
Duthie, SJ
通讯作者：
Duthie, SJ