胰腺導(dǎo)管腺癌(PDAC)及其亞型是最常見(jiàn)的胰腺腫瘤,，占胰腺腫瘤的85％～90％,。統(tǒng)計(jì)結(jié)果表明,，在所有的癌癥中,，PDAC幾乎是存活率最低的，發(fā)病率和死亡率幾乎相等,。研究發(fā)現(xiàn),，PDAC對(duì)細(xì)胞應(yīng)激有顯著抗性。
在胰腺,，核蛋白1(Nupr1)介導(dǎo)了細(xì)胞的應(yīng)激反應(yīng),，并在胰腺癌中表現(xiàn)出上調(diào)的表達(dá)水平。近日,，來(lái)自法國(guó)的研究人員Juan Lucio Iovanna等人發(fā)現(xiàn),，Nupr1對(duì)胰腺癌的發(fā)生有著至關(guān)重要的作用。它能夠促進(jìn)胰腺癌的發(fā)展,，并通過(guò)抑制凋亡來(lái)保護(hù)細(xì)胞免受壓力影響,。相關(guān)論文發(fā)表在5月8日的The Journal of Clinical Investigation。
在能夠持續(xù)表達(dá)原癌基因KrasG12D的老鼠胰腺癌模型里,，他們發(fā)現(xiàn),，缺失Nupr1的細(xì)胞不會(huì)發(fā)生胰腺上皮內(nèi)瘤變(PanINs)。此外,，在培養(yǎng)的胰腺細(xì)胞,，營(yíng)養(yǎng)缺乏激活了Nupr1的表達(dá)，反而利于細(xì)胞繼續(xù)存活,。
研究發(fā)現(xiàn),，通過(guò)一個(gè)依賴(lài)IER3和轉(zhuǎn)錄因子RelB的信號(hào)通路，Nupr1抑制了細(xì)胞凋亡,，保護(hù)細(xì)胞免受壓力而存活,。在表達(dá)有KrasG12D的老鼠胰腺，NUPR1,、RELB及IER3蛋白能夠聯(lián)合表達(dá),。而且，在胰腺細(xì)胞特異性缺失Relb后,，PanIN的發(fā)展出現(xiàn)延遲,。
結(jié)果表明，PanIN形成依賴(lài)于Nupr1及Relb的表達(dá),，這也可能與IER3有關(guān),。在PDAC患者中發(fā)現(xiàn)，NUPR1,、RELB及IER3的表達(dá)與PDAC的不良預(yù)后高度相關(guān),。
總的來(lái)說(shuō)，這些結(jié)果表明,，NUPR1,、RELB及IER3與胰腺致癌性轉(zhuǎn)化息息相關(guān),。（生物谷Deepblue編譯）
doi: 10.1172/JCI60144
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Nuclear protein 1 promotes pancreatic cancer development and protects cells from stress by inhibiting apoptosis
Tewfik Hamidi, Hana Algül, Carla Eliana Cano, Maria José Sandi, Maria Inés Molejon, Marc Riemann, Ezequiel Luis Calvo, Gwen Lomberk, Jean-Charles Dagorn, Falk Weih, Raul Urrutia, Roland Michael Schmid and Juan Lucio Iovanna.
Pancreatic ductal adenocarcinoma (PDAC) has the lowest survival rate of all cancers and shows remarkable resistance to cell stress. Nuclear protein 1 (Nupr1), which mediates stress response in the pancreas, is frequently upregulated in pancreatic cancer.Here, we report that Nupr1 plays an essential role in pancreatic tumorigenesis. In a mouse model of pancreatic cancer with constitutively expressed oncogenic KrasG12D, we found that loss of Nupr1 protected from the development of pancreatic intraepithelial neoplasias (PanINs).Further, in cultured pancreatic cells, nutrient deprivation activated Nupr1 expression, which we found to be required for cell survival. We found that Nupr1 protected cells from stress-induced death by inhibiting apoptosis through a pathway dependent on transcription factor RelB and immediate early response 3 (IER3).NUPR1, RELB, and IER3 proteins were coexpressed in mouse PanINs from KrasG12D-expressing pancreas. Moreover, pancreas-specific deletion of Relb in a KrasG12D background resulted in delayed in PanIN development associated with a lack of IER3 expression.Thus, efficient PanIN formation was dependent on the expression of Nupr1 and Relb, with likely involvement of IER3. Finally, in patients with PDAC, expression of NUPR1, RELB, and IER3 was significantly correlated with a poor prognosis.Cumulatively, these results reveal a NUPR1/RELB/IER3 stress-related pathway that is required for oncogenic KrasG12D-dependent transformation of the pancreas.
