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首页 » BIOON报道 » JBC & Oncogene:DNA修复蛋白KLF8或成为乳腺癌和卵巢癌治疗的新靶点

JBC & Oncogene:DNA修复蛋白KLF8或成为乳腺癌和卵巢癌治疗的新靶点

来源:生物谷 2013-01-29 23:15

2013年1月29日 讯 /生物谷BIOON/ --正如我们的机体可以对抗生素产生耐药性一样,某些杀灭癌细胞的方法也会使得产生耐药性的癌细胞,近日来自中佛罗里达大学的研究者在包括乳腺癌、卵巢癌等许多类型癌症中发现了一种名为KLF8的蛋白质,其可以保护肿瘤细胞免于药物杀灭,甚至可以帮助肿瘤细胞再生,相关研究刊登于国际杂志Journal of Biological ChemistryOncogene上。

研究者Jihe Zhao说,所有的细胞存在DNA修复机制,这就是为什么我们可以在面临无数次的DNA损伤威胁的情况下安然无恙。但是蛋白质KLF8在某些癌症中是高度表达的,比如说乳腺癌和卵巢癌中。如果我们可以抑制该蛋白质的表达,那么我就可以使用疗法来治疗癌症,但是我们仍然需要深入地研究才能确定。

目前在美国有250万至270万人患乳腺癌,而且其中有10%-20%的患者病情都会复发,每年有22,200位女性被诊断出卵巢癌。

基于DNA损伤的化疗依赖于癌细胞DNA损伤修复的失败来发挥作用,细胞中DNA修复功能的异常高水平表现不仅会增加细胞对于疗法的耐药性,而且会出现更多的恶性癌细胞。

这项研究中,研究者的团队检测了用于治疗乳腺癌的特殊癌症抵御药物来确定蛋白质KLF8所扮演的重要作用。研究者Zhao表示,的确,我们的研究结果揭示了,KLF8促进的耐药细胞的DNA修复和多柔比星诱导的细胞死亡直接相关。当然,依然需要深入研究来确定是否KLF8在遗传毒性因子(如DNA烷化剂等)促使的DNA损伤修复中是否扮演着类似重要的角色。

当然该研究也揭示了KLF8可以通过其异常的DNA修复功能以及促使恶性肿瘤发展的功能,在破坏基因组的完整性上也扮演着重要的角色。(生物谷Bioon.com)

A Novel Role of Krüppel-like Factor 8 in DNA Repair in Breast Cancer Cells*

Heng Lu‡, Liu Hu‡, Tianshu Li‡, Satadru Lahiri‡, Chao Shen‡, Melissa S. Wason‡, Debarati Mukherjee‡, Hui Xie§, Lin Yu‡ and Jihe Zhao‡

Krüppel-like factor 8 (KLF8) regulates critical gene transcription and cellular events associated with cancer. However, the role of KLF8 in cancer remains largely unknown. Here, we report a surprisingly novel role for KLF8 in DNA repair in breast cancer cells. Comet, clonogenic, and WST-1 assays showed that KLF8 expression is required for protecting human breast cancer cells from doxorubicin-induced DNA damage and cell death. Western blotting indicated that overexpression of ectopic KLF8 attenuated the levels of the DNA damage marker γH2A.X in doxorubicin-treated PARP-1+/+ but not PARP-1−/− mouse embryonic fibroblasts, whereas the PARP-1-binding-defective KLF8 mutant failed to do so. Interestingly, in response to the DNA damage, KLF8 was phosphorylated by the DNA-dependent protein kinase catalytic subunit and, subsequently, SUMOylated by SUMO E3 ligases protein inhibitors of activated STAT (PIASs), which depends upon the interaction of KLF8 with DNA-dependent protein kinase catalytic subunit, PIASs, and PARP-1 as well as their enzymatic activities. Lastly, we show evidence that KLF8 was recruited to the DNA damage site. These results suggest a novel role and mechanism for KLF8 in the regulation of DNA repair and therapeutic resistance in breast cancer cells.

Transformation of human ovarian surface epithelial cells by Krüppel-like factor 8

H Lu, X Wang, A M Urvalek, T Li, H Xie, L Yu and J Zhao

We have previously demonstrated that Krüppel-like factor 8 (KLF8) participates in oncogenic transformation of mouse fibroblasts and is highly overexpressed in human ovarian cancer. In this work, we first correlated KLF8 overexpression with the aggressiveness of ovarian patient tumors and then tested if KLF8 could transform human ovarian epithelial cells. Using the immortalized non-tumorigenic human ovarian surface epithelial cell line T80 and retroviral infection, we generated cell lines that constitutively overexpress KLF8 alone or its combination with the known ovarian oncogenes c-Myc, Stat3c and/or Akt and examined the cell lines for anchorage-independent growth and tumorigenesis. The soft agar clonogenic assay showed that T80/KLF8 cells formed significantly more colonies than the mock cells. Interestingly, the cells expressing both KLF8 and c-Myc formed the largest amounts of colonies, greater than the sum of colonies formed by the cells expressing KLF8 and c-Myc alone. These results suggested that KLF8 might be a weak oncogene that works cooperatively with c-Myc to transform ovarian cells. Surprisingly, overexpression of KLF8 alone was sufficient to induce tumorigenesis in nude mice resulting in short lifespan irrespective of whether the T80/KLF8 cells were injected subcutaneously, intraperitoneally or orthotopically into the ovarian bursa. Histopathological studies confirmed that the T80/KLF8 tumors were characteristic of human serous ovarian carcinomas. Comparative expression profiling and functional studies identified the cell cycle regulators cyclin D1 and USP44 as primary KLF8 targets and effectors for the T80 transformation. Overall, we identified KLF8 overexpression as an important factor in human ovarian carcinoma pathogenesis.

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