近日,，國際權(quán)威學(xué)術(shù)期刊美國《國家科學(xué)院院刊》（PNAS）上發(fā)表了廈門大學(xué)生命科學(xué)學(xué)院的研究人員的研究論文,，揭示了FOXO調(diào)控神經(jīng)母細(xì)胞瘤分化的分子機(jī)制,。
神經(jīng)母細(xì)胞瘤（NB）是兒童常見的惡性腫瘤,，年發(fā)病率大約為1/10萬,，僅低于白血病和中樞神經(jīng)腫瘤,。在神經(jīng)母細(xì)胞瘤的發(fā)病過程中一個(gè)關(guān)鍵的早期事件就是成神經(jīng)細(xì)胞不同階段的分化停滯。利用TPA和PDGF-BB促使成神經(jīng)瘤細(xì)胞終末分化可作為有效治療神經(jīng)細(xì)胞瘤的策略,。然而直到現(xiàn)在研究人員對(duì)于這一過程中的信號(hào)通路還不是很清楚,。
領(lǐng)導(dǎo)這一研究的是廈門大學(xué)生命科學(xué)學(xué)院教授、博士生導(dǎo)師尤涵,。生命科學(xué)學(xué)院博士研究生梅楊,，張蕾和第一醫(yī)院王占祥為本文的共同第一作者。此項(xiàng)研究獲得了科技部和國家自然科學(xué)基金委資助課題,。
近年來,，F(xiàn)OXO家族分子因在神經(jīng)系統(tǒng)發(fā)育中的作用受到關(guān)注。已有研究表明：FOXO參與了神經(jīng)干細(xì)胞(neural stem cell,，NSCs)的穩(wěn)態(tài)維持和分化,；FOXO對(duì)神經(jīng)元極化有至關(guān)重要的作用。PDGFRA屬于受體酪氨酸激酶（Receptor Tyrosine Kinase,，RTK）家族成員,，研究表明其配體PDGF具有神經(jīng)營養(yǎng)因子效應(yīng)，可促進(jìn)神經(jīng)母細(xì)胞瘤細(xì)胞在應(yīng)激條件下發(fā)生分化,。
研究人員發(fā)現(xiàn)FOXO在生理?xiàng)l件和應(yīng)激條件下（如血清饑餓）調(diào)控了PDGFRA的轉(zhuǎn)錄表達(dá)。在TPA誘導(dǎo)神經(jīng)母細(xì)胞瘤細(xì)胞分化的研究體系中,，他們進(jìn)一步發(fā)現(xiàn)FOXO-PDGFRA通路對(duì)神經(jīng)母細(xì)胞瘤細(xì)胞分化起決定性作用,，并且闡明PDGFRA是FOXO調(diào)控神經(jīng)母細(xì)胞瘤細(xì)胞分化的關(guān)鍵下游靶分子,。
誘導(dǎo)神經(jīng)母細(xì)胞瘤細(xì)胞分化是臨床治療神經(jīng)母細(xì)胞瘤患者的手段之一，然而由于調(diào)控神經(jīng)母細(xì)胞瘤分化的分子機(jī)理不甚明確,，使得該治療手段療效甚微。
新研究結(jié)果揭示了TPA誘導(dǎo)NB分化的關(guān)鍵分子機(jī)制,，為設(shè)計(jì)有效靶向藥物逆轉(zhuǎn)NB的分化提供了重要的理論依據(jù)。（生物谷Bioon.com）
doi:10.1073/pnas.1119535109
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Regulation of neuroblastoma differentiation by forkhead transcription factors FOXO1/3/4 through the receptor tyrosine kinase PDGFRA
Mei, Yang; Wang, Zhanxiang; Zhang, Lei; Zhang, Yiru; Li, Xiaoyu; Liu, Huihui; Ye, Jing; You, Han
Neuroblastoma is a common childhood malignant tumor originated from the neural crest-derived sympathetic nervous system. A crucial early event in neuroblastoma pathogenesis is arrested differentiation of neuroblasts at various stages. Treatment of neuroblastoma with TPA and PDGF-BB leads to terminal differentiation of neuroblastoma cells. However, the signaling pathways that are involved in this process remain largely unknown. Here, we report that inhibition of endogenous FOXO proteins attenuated TPA/PDGF-BB mediated differentiation of neuroblastoma cells. Activated FOXO transcription factors acted on PDGFRA promoter to direct its basal mRNA expression as well as its induction upon serum deprivation. Depletion of endogenous PDGFRA in neuroblastoma cells significantly diminished neurite formation and extension under TPA/PDGF-BB treatment. Furthermore, ectopic expression of PDGFRA abolished the blockage of neuroblastoma differentiation by FOXOs inhibition. These findings define the FOXO–PDGFRA axis as crucial mechanistic components that govern TPA-induced neuroblastoma differentiation.
