來自英國(guó)倫敦大學(xué)瑪麗女王學(xué)院的研究人員發(fā)現(xiàn)兩個(gè)表明干細(xì)胞如何能夠發(fā)展成癌癥的基因之間存在關(guān)聯(lián)。這項(xiàng)研究成果近日在線發(fā)表 PLoS ONE期刊上,。
在這項(xiàng)研究中,，研究人員發(fā)現(xiàn)一種新的能夠促進(jìn)干細(xì)胞形成腫瘤的機(jī)制。
論文通訊作者,、倫敦大學(xué)瑪麗女王學(xué)院研究員Ahmad Waseem博士說,，“這是一項(xiàng)非常令人意外的發(fā)現(xiàn)。我們著手研究干細(xì)胞基因K15(編碼角蛋白15),，人們?cè)J(rèn)為該基因是正常干細(xì)胞的一個(gè)生物標(biāo)記分子,。”
Waseem博士說，“通過我們的研究,，我們發(fā)現(xiàn)K15與臭名昭著的癌基因FOXM1存在關(guān)聯(lián),。我們發(fā)現(xiàn)FOXM1能夠靶向K15從而誘導(dǎo)癌癥形成。”
當(dāng)干細(xì)胞存在問題時(shí),，癌癥就產(chǎn)生,。在整個(gè)人體中，干細(xì)胞能夠執(zhí)行內(nèi)部修復(fù),。因而,，干細(xì)胞功能丟失導(dǎo)致它們自己不受控制地分裂而最終發(fā)展成腫瘤。
研究小組利用極其敏感的細(xì)胞和分子方法而建立起這種關(guān)聯(lián),。
這項(xiàng)研究為人們?cè)谖磥龛b定出新的抗癌藥物鋪平道路,，而且這些藥物經(jīng)修飾后可能還能夠靶向癌干細(xì)胞。
論文共同作者Iain Hutchison教授說,，“我們對(duì)這項(xiàng)研究發(fā)現(xiàn)感到非常興奮,，因?yàn)樗赡軐?dǎo)致我們開發(fā)出更加有效的抗癌藥物來靶向癌干細(xì)胞，從而阻止癌癥復(fù)發(fā),。”
doi:10.1371/journal.pone.0038599
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Two Mechanisms Regulate Keratin K15 Expression In Keratinocytes: Role of PKC/AP-1 and FOXM1 Mediated Signalling
Amrita Bose1, Muy-Teck Teh1, Iain L. Hutchison1, Hong Wan1, Irene M. Leigh2, Ahmad Waseem
Background Keratin 15 (K15) is a type I keratin that is used as a marker of stem cells. Its expression is restricted to the basal layer of stratified epithelia, and the bulge in hair follicles. However, in certain clinical situations including oral lichen planus, K15 is induced in suprabasal layers, which is inconsistent with the role of a stem cell marker. This study provides insights into the mechanisms of K15 expression in the basal and differentiating keratinocytes.
Methodology/Principal Findings Human keratinocytes were differentiated by three different methods; suspension in methylcellulose, high cell density and treatment with phorbol ester. The expression of mRNA was determined by quantitative PCR and protein by western blotting and immunostaining. Keratinocytes in suspension suppressed β1-integrin expression, induced differentiation-specific markers and K15, whereas FOXM1 (a cell cycle regulated protein) and K14 were downregulated. Rescuing β1-integrin by either fibronectin or the arginine-glycine-aspartate peptide suppressed K15 but induced K14 and FOXM1 expression. Specific inhibition of PKCδ, by siRNA, and AP-1 transcription factor, by TAM67 (dominant negative c-Jun), suppressed K15 expression, suggesting that PKC/AP-1 pathway plays a role in the differentiation-specific expression of K15. The basal cell-specific K15 expression may involve FOXM1 because ectopic expression of the latter is known to induce K15. Using chromatin immunoprecipitation, we have identified a single FOXM1 binding motif in the K15 promoter.
Conclusions/Significance The data suggests that K15 is induced during terminal differentiation mediated by the down regulation of β1-integrin. However, this cannot be the mechanism of basal/stem cell-specific K15 expression in stratified epithelia, because basal keratinocytes do not undergo terminal differentiation. We propose that there are two mechanisms regulating K15 expression in stratified epithelia; differentiation-specific involving PKC/AP-1 pathway, and basal-specific mediated by FOXM1, and therefore the use of K15 expression as a marker of stem cells must be viewed with caution.
