卵巢癌復(fù)發(fā)率高一直困擾醫(yī)學(xué)界。美國得克薩斯大學(xué)研究人員新近發(fā)現(xiàn)了休眠的卵巢癌細(xì)胞在人體內(nèi)的存活機制。這項研究有望幫助人們找到治療卵巢癌的新途徑,。
據(jù)最新一期美國《臨床檢查雜志》月刊報道,，一些卵巢癌患者切除腫瘤兩三年之后,，體內(nèi)再次出現(xiàn)腫瘤,，其主要原因是體內(nèi)休眠的卵巢癌細(xì)胞在作祟。這些卵巢癌細(xì)胞休眠時不進(jìn)行細(xì)胞分裂,，不易被發(fā)現(xiàn),，然而一旦重新生長，腫瘤就會再次出現(xiàn),。
研究人員介紹說,，一種名為ARHI的基因是卵巢癌細(xì)胞自體吞噬機制能否啟動的關(guān)鍵，決定著細(xì)胞是否會依靠自噬機制“自我滅亡”,。在以該基因為重點的研究中,，他們發(fā)現(xiàn)在移植了卵巢癌細(xì)胞的實驗鼠體內(nèi)有幾種蛋白質(zhì)存活因子導(dǎo)致ARHI基因表達(dá)異常，從而使細(xì)胞自噬機制無法正常啟動,。在通過阻止上述蛋白質(zhì)存活因子發(fā)揮作用使ARHI基因表達(dá)恢復(fù)到正常水平后,，細(xì)胞自噬機制又能完全啟動，最終使卵巢癌細(xì)胞在數(shù)天內(nèi)死亡,。
研究人員表示,，自噬機制無法正常啟動導(dǎo)致卵巢癌細(xì)胞得以休眠并等待合適時機重新分裂,。如果能阻止上述蛋白質(zhì)存活因子發(fā)揮作用，自噬機制就會消滅休眠的卵巢癌細(xì)胞,，從而治愈卵巢癌,。（生物谷Bioon.com）
生物谷推薦原始出處：
J. Clin. Invest. 118(12): 3917-3929 (2008). doi:10.1172/JCI35512.
The tumor suppressor gene ARHI regulates autophagy and tumor dormancy in human ovarian cancer cells
Zhen Lu1, Robert Z. Luo1, Yiling Lu2, Xuhui Zhang1, Qinghua Yu2, Shilpi Khare1, Seiji Kondo3, Yasuko Kondo3, Yinhua Yu1, Gordon B. Mills2, Warren S.-L. Liao1,4 and Robert C. Bast, Jr.1
1Department of Experimental Therapeutics,
2Department of Molecular Therapeutics,
3Department of Neurosurgery, and
4Department of Biochemistry and Molecular Biology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
The role of autophagy in oncogenesis remains ambiguous, and mechanisms that induce autophagy and regulate its outcome in human cancers are poorly understood. The maternally imprinted Ras-related tumor suppressor gene aplasia Ras homolog member I (ARHI; also known as DIRAS3) is downregulated in more than 60% of ovarian cancers, and here we show that re-expression of ARHI in multiple human ovarian cancer cell lines induces autophagy by blocking PI3K signaling and inhibiting mammalian target of rapamycin (mTOR), upregulating ATG4, and colocalizing with cleaved microtubule-associated protein light chain 3 (LC3) in autophagosomes. Furthermore, ARHI is required for spontaneous and rapamycin-induced autophagy in normal and malignant cells. Although ARHI re-expression led to autophagic cell death when SKOv3 ovarian cancer cells were grown in culture, it enabled the cells to remain dormant when they were grown in mice as xenografts. When ARHI levels were reduced in dormant cells, xenografts grew rapidly. However, inhibition of ARHI-induced autophagy with chloroquine dramatically reduced regrowth of xenografted tumors upon reduction of ARHI levels, suggesting that autophagy contributed to the survival of dormant cells. Further analysis revealed that autophagic cell death was reduced when cultured human ovarian cancer cells in which ARHI had been re-expressed were treated with growth factors (IGF-1, M-CSF), angiogenic factors (VEGF, IL-8), and matrix proteins found in xenografts. Thus, ARHI can induce autophagic cell death, but can also promote tumor dormancy in the presence of factors that promote survival in the cancer microenvironment.
