免疫組化結(jié)果顯示PHD3在正常結(jié)腸組織中的表達(dá)水平高于結(jié)腸癌中的
近日，消化系統(tǒng)研究領(lǐng)域的權(quán)威雜志《胃腸病學(xué)》（Gastroenterology）在線發(fā)表了中國(guó)科學(xué)院上海生命科學(xué)研究院營(yíng)養(yǎng)科學(xué)研究所方靖研究組的一項(xiàng)最新研究結(jié)果：脯氨酸羥基化酶3（Prolyl Hydroxylase-3,，PHD3）在結(jié)直腸癌中低表達(dá)并與腫瘤的惡性程度密切相關(guān),，PHD3通過(guò)IKKβ/NF-κB通路發(fā)揮作用。
PHD家族包括PHD1,，PHD2和PHD3三個(gè)成員,，最初作為低氧誘導(dǎo)因子HIF的脯氨酸羥基化酶被發(fā)現(xiàn)。在氧氣存在條件下,，PHD羥基化HIF?分子中特定的脯氨酸從而引起HIF?的降解,。由于PHD的酶活性嚴(yán)格受氧氣濃度的調(diào)節(jié)，因而被認(rèn)為是機(jī)體的氧氣感受器,。結(jié)直腸癌是人類(lèi)常見(jiàn)的消化道腫瘤,，全球每年新增病例數(shù)達(dá)94萬(wàn)，每年有近50萬(wàn)人死于結(jié)直腸癌,，居癌癥死因第3位,。在我國(guó)，結(jié)直腸癌居惡性腫瘤發(fā)病率第4位,，且呈明顯上升趨勢(shì),。結(jié)直腸癌發(fā)病與生活方式的改變及膳食結(jié)構(gòu)不合理密切相關(guān)。
營(yíng)養(yǎng)所方靖研究員指導(dǎo)的博士研究生薛婧等通過(guò)分析結(jié)直腸癌臨床樣本,，發(fā)現(xiàn)腫瘤中PHD3的表達(dá)水平明顯低于正常結(jié)直腸組織中的,，且PHD3的表達(dá)水平與腫瘤的分級(jí)和轉(zhuǎn)移呈負(fù)相關(guān),。細(xì)胞和動(dòng)物實(shí)驗(yàn)顯示抑制PHD3表達(dá)可以顯著加速腫瘤細(xì)胞的生長(zhǎng)和腫瘤的生成。進(jìn)一步的研究提示,，PHD3可能通過(guò)抑制IKKβ/NF-κB信號(hào)通路發(fā)揮作用,，并且這一作用不依賴(lài)于其羥基化酶的活性。研究結(jié)果揭示了PHD3的新功能,，有助于認(rèn)識(shí)結(jié)直腸癌的生長(zhǎng)機(jī)制以及尋找治療新靶標(biāo),。
該研究工作受到了國(guó)家自然科學(xué)基金委、科技部,、中科院以及上海生科院的資助,。（生物谷Bioon.com）
生物谷推薦原始出處：
Gastroenterology doi:10.1053/j.gastro.2009.09.049
Prolyl Hydroxylase-3 Is Downregulated in Colorectal Cancer Cells and Inhibits IKKβ, Independent of Hydroxylase Activity
Jing Xue1, Xuebing Li1, Shi Jiao1, Ye Wei2, Guohao Wu2, Jing Fang1
Background & aims:
Prolyl hydroxylase (PHD) hydroxylates HIFα, leading to HIFα degradation. The PHD family comprises PHD1, PHD2, and PHD3. The enzymatic activity of PHDs is O2-dependent, so PHDs are believed to be oxygen sensors as well as tumor suppressors. However, the expression pattern of PHDs in colorectal cancer and the correlation between their expression level and tumorigenesis is unclear.
Methods:
We determined the expression of PHDs in 60 human primary colorectal carcinoma tissues, paired with normal colorectal tissues. PHD3 expression levels was knocked down using small interfering (si)RNAs; cells were analyzed by immunoblotting, immunoprecipitation, and histochemical analyses. In vivo tumor growth was analyzed in nu/nu mice.
Results:
Expression of PHD3 is decreased in colorectal cancer tissues. Decreased expression of PHD3 is associated with higher tumor grade and metastasis. PHD3 inhibits phosphorylation of IKKβ and activation of NF-κB, independent of its hydroxylase activity. PHD3 associates with IKKβ but does not target it for destruction; instead, PHD3 blocks the interaction between IKKβ and Hsp90 that is required for phosphorylation of IKKβ. Knockdown of PHD3 increased resistance of colorectal cancer cells to the effects of tumor necrosis factor-α and tumorigenesis.
Conclusion:
PHD3 appears to be a tumor suppressor in colorectal cancer cells that inhibits IKKβ/NF-κB signaling, independent of its hydroxylase activity. Activation of NF-κB has been observed in colon cancer. Determination of PHD3 status could aid targeted therapy selection for patients with colorectal tumors that have increased NF-κB activity.
1 Key Laboratory of Nutrition and Metabolisms, Institute of Nutritional Sciences, SIBS, Chinese Academy of Sciences, Shanghai 200031
2 Department of Surgery, Zhongshan Hospital, Fudan University School of Medicine, Shanghai 200031, China
