就像機(jī)體會(huì)對(duì)抗生素產(chǎn)生抵抗一樣,，腫瘤細(xì)胞也會(huì)對(duì)特定的抗癌藥物產(chǎn)生抵抗,。中佛羅里達(dá)大學(xué)UCF的研究人員發(fā)現(xiàn),，在乳腺癌和卵巢癌等數(shù)種癌癥中出現(xiàn)的KLF8蛋白，是癌細(xì)胞抗性和癌癥復(fù)發(fā)的關(guān)鍵,。KLF8是一種DNA修復(fù)蛋白,，研究顯示它既能幫助腫瘤細(xì)胞抵抗抗癌藥物，也能夠幫助腫瘤細(xì)胞再生,。
“所有細(xì)胞都有DNA修復(fù)機(jī)制,，”領(lǐng)導(dǎo)這項(xiàng)研究的UCF醫(yī)學(xué)院副教授趙季和（音譯：Jihe Zhao）解釋道，短短幾個(gè)月間他已經(jīng)連續(xù)在Journal of Biological Chemistry和Oncogene等雜志上發(fā)表了數(shù)篇有關(guān)KLF8蛋白的文章。“這也是我們?cè)诓粩嗟腄NA損傷威脅下得以存活的原因,。KLF8在乳腺癌和卵巢癌等多種癌癥中均存在過表達(dá)現(xiàn)象,。如果我們能夠在癌癥治療中阻止這一基因的啟動(dòng)，就有望阻止腫瘤復(fù)發(fā),。當(dāng)然這還需要進(jìn)一步深入研究,，不過前景是非常樂觀的。”
據(jù)美國(guó)癌癥協(xié)會(huì)統(tǒng)計(jì),，全美有兩百五十萬至兩百七十萬女性患有乳腺癌,，其中10-20%的患者會(huì)經(jīng)歷癌癥復(fù)發(fā)。現(xiàn)有的治療方式取決于癌癥發(fā)展的階段,，包括手術(shù)切除和一系列抗癌的化療藥物,。每年約有22,200名女性也被診斷出卵巢癌。
以破壞DNA為目的的化療方法,，依賴于癌細(xì)胞修復(fù)失敗,，并由此促使癌細(xì)胞死亡。不過細(xì)胞中DNA修復(fù)功能的水平過高,，不但可能增加癌細(xì)胞對(duì)這類化療的抗性,，也可能會(huì)因DNA修復(fù)不當(dāng)使基因組/染色體不穩(wěn)定從而增加惡性細(xì)胞。
趙副教授的團(tuán)隊(duì)利用一種治療乳腺癌的抗癌藥物,，來確定KLF8蛋白的作用,。“確實(shí)，研究顯示促進(jìn)DNA修復(fù)的KLF8與癌細(xì)胞對(duì)阿霉素產(chǎn)生抗性有著明顯的關(guān)聯(lián),，” 趙副教授說,。“在其他類型基因毒性劑（DNA烷化劑和電離輻射等）引起的DNA損傷修復(fù)過程中,，KLF8蛋白是否也起到同樣的作用,，這一點(diǎn)還需要進(jìn)一步研究來驗(yàn)證。
此外,，研究還指出KLF8蛋白除了增強(qiáng)癌細(xì)胞的抗藥性以外,，還可能因DNA異常修復(fù)干擾基因組的完整性，并最終引發(fā)癌癥的侵襲進(jìn)程,。(生物谷Bioon.com)
doi:10.1038/onc.2012.545
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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.
doi: 10.1074/jbc.M112.418053
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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.
