免疫组化结果显示PHD3在正常结肠组织中的表达水平高于结肠癌中的
近日，消化系统研究领域的权威杂志《胃肠病学》（Gastroenterology）在线发表了中国科学院上海生命科学研究院营养科学研究所方靖研究组的一项最新研究结果：脯氨酸羟基化酶3（Prolyl Hydroxylase-3，PHD3）在结直肠癌中低表达并与肿瘤的恶性程度密切相关，PHD3通过IKKβ/NF-κB通路发挥作用。
PHD家族包括PHD1，PHD2和PHD3三个成员，最初作为低氧诱导因子HIF的脯氨酸羟基化酶被发现。在氧气存在条件下，PHD羟基化HIF?分子中特定的脯氨酸从而引起HIF?的降解。由于PHD的酶活性严格受氧气浓度的调节，因而被认为是机体的氧气感受器。结直肠癌是人类常见的消化道肿瘤，全球每年新增病例数达94万，每年有近50万人死于结直肠癌，居癌症死因第3位。在我国，结直肠癌居恶性肿瘤发病率第4位，且呈明显上升趋势。结直肠癌发病与生活方式的改变及膳食结构不合理密切相关。
营养所方靖研究员指导的博士研究生薛婧等通过分析结直肠癌临床样本，发现肿瘤中PHD3的表达水平明显低于正常结直肠组织中的，且PHD3的表达水平与肿瘤的分级和转移呈负相关。细胞和动物实验显示抑制PHD3表达可以显著加速肿瘤细胞的生长和肿瘤的生成。进一步的研究提示，PHD3可能通过抑制IKKβ/NF-κB信号通路发挥作用，并且这一作用不依赖于其羟基化酶的活性。研究结果揭示了PHD3的新功能，有助于认识结直肠癌的生长机制以及寻找治疗新靶标。
该研究工作受到了国家自然科学基金委、科技部、中科院以及上海生科院的资助。（生物谷Bioon.com）
生物谷推荐原始出处：
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
