Genotyping and expression analysis of IDO2 in human pancreatic cancer: a novel, active target.
Genotyping and expression analysis of IDO2 in human pancreatic cancer: a novel, active target.
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DOI：
10.1016/j.jamcollsurg.2008.12.018
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发表时间：
2009-05
影响因子：
5.2
通讯作者：
Brody, Jonathan R.
中科院分区：
文献类型：
--
作者：
Witkiewicz, Agnieszka K.;Costantino, Christina L.;Metz, Richard;Muller, Alexander J.;Prendergast, George C.;Yeo, Charles J.;Brody, Jonathan R.
我们最近发现吲哚胺2，3-双加氧酶（IDO）在原发性胰腺导管腺癌（PDA）和淋巴结转移中过表达（J Am科尔外科杂志5：849-54：2008）。IDO 2是最近发现的具有独特信号传导性质的IDO的相对物（Cancer Res.67：7082-7087：2007）。值得注意的是，IDO 2基因具有两种在人群中常见的功能多态性，其消除了其酶活性（R235 W和Y359 STOP）。IDO和IDO 2都抑制免疫系统，我们假设PDA中这些酶的表达可能有助于癌细胞逃避免疫检测。基于IDO 2可能是D-1-甲基-色氨酸（1-MT）的优先靶点的证据，1-MT是IDO的临床主要抑制剂，目前正在I期试验中进行评估，我们对36例切除的PDA中的IDO 2进行测序，并评估其与两种已知遗传多态性相关的表达。在我们的患者队列中，我们发现58%（21/36）的病例为R235 W多态性杂合型; 28%（10/36）为野生型纯合型;只有14%（5/36）为功能失活多态性纯合型。有趣的是，IDO 2在两个胰腺癌细胞系中具有纯合野生型构型，而一个细胞系（MiaPaCa 2细胞）对于R235 W多态性是纯合的。至于Y359 STOP多态性（见于细胞系Hs 766 T），我们发现27%（10/36）的病例为杂合型，62%（22/36）为野生型纯合型，只有11%（4/36）为该功能失活等位基因的纯合型。排除了复合多态性变体的可能性，我们估计75%的切除患者队列具有活性IDO 2酶，保守估计58%的患者具有至少一个功能性等位基因。在免疫组化分析中，我们发现IDO 2在每个基因多态性亚组的胰腺癌组织中同样过表达。我们还检测了暴露于IFN-γ后在遗传上不同的胰腺癌细胞系中的IDO 2蛋白表达，确定即使是功能多态性IDO 2序列也可以产生IDO 2蛋白。这些是报道IDO 2在PDA中表达的第一个数据，并表明IDO 2遗传多态性不否定IFN-γ诱导的蛋白质表达。IDO 2基因分型和我们的PDA患者组织库和细胞系的表达分析表明，IDO 2是活跃的，并在大多数PDA患者中表达。总之，这些数据强烈表明，通过IDO 2起作用的临床先导化合物D-1-MT可能单独或与其他抗肿瘤方式组合用于治疗PDA。
We recently discovered that the enzyme indoleamine 2,3-dioxygenase (IDO) is overexpressed in primary pancreatic ductal adenocarcinomas (PDA) and in lymph node metastases (J Am Coll Surg. 5:849-54: 2008). IDO2 is a recently discovered relative of IDO that has unique signaling properties (Cancer Res. 67:7082-7087: 2007). Notably, the IDO2 gene has two functional polymorphisms commonly found in human populations that abolish its enzymatic activity (R235W and Y359STOP). Both IDO and IDO2 repress the immune system and we hypothesize that expression of these enzymes in PDA may help cancer cells evade immune detection. Based on evidence that the IDO2 may be a preferential target of D-1-methyl-tryptophan (1-MT), a clinical lead inhibitor of IDO currently being evaluated in Phase I trials, we sequenced IDO2 in 36 resected PDAs and evaluated its expression in relation to the two known genetic polymorphisms. In our patient cohort, we found that 58% (21/36) of the cases were heterozygous for the R235W polymorphism; 28% (10/36) were homozygous wild-type; and only 14% (5/36) were homozygous for the functionally inactive polymorphism. Interestingly, IDO2 had a homozygous wild-type configuration in two pancreatic cancer cell lines whereas one cell line (MiaPaCa2 cells) was homozygous for the R235W polymorphism. As for the Y359STOP polymorphism (seen in the cell line Hs766T), we found that 27% (10/36) of the cases were heterozygous, 62% (22/36) were homozygous wild-type, and only 11% (4/36) were homozygous for this functionally inactive allele. Ruling out the possibility of compound polymorphic variants, we estimated 75% of our resected patient cohort had an active IDO2 enzyme with a conservative estimate that 58% of the patients had at least one functional allele. In immunohistochemical analyses, we found that IDO2 was equally overexpressed in pancreatic cancer tissue from each genetially polymorphic subgroup. We also detected IDO2 protein expression in the genetically distinct pancreatic cancer cell lines after exposure with IFN-γ, establishing that even functionally polymorphic IDO2 sequences can generate IDO2 protein. These are the first data to report IDO2 expression in PDA and indicate that IDO2 genetic polymorphisms do not negate IFN-γ-inducible protein expression. IDO2 genotyping and expression analysis of our PDA patient tissue bank and cell lines show that IDO2 is active and expressed in a majority of PDA patients. Taken together, these data strongly suggest that the clinical lead compound D-1-MT acting through IDO2 might be useful in treatment of PDA, either alone or in combination with other anti-tumor modalities.
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影响因子：
11.2
作者：
Calhoun, Eric S.;Hucl, Tomas;Kern, Scott E.
通讯作者：
Kern, Scott E.
影响因子：
11.5
作者：
Brandacher, G;Perathoner, A;Amberger, A
通讯作者：
Amberger, A
影响因子：
11.2
作者：
Hou, De-Yan;Muller, Alexander J.;Munn, David H.
通讯作者：
Munn, David H.
影响因子：
11.2
作者：
Iacobuzio-Donahue, CA;van der Heijden, MS;Kern, SE
通讯作者：
Kern, SE
DOI：
10.1073/pnas.83.17.6622
发表时间：
1986-09-01
影响因子：
11.1
作者：
YASUI, H;TAKAI, K;HAYAISHI, O
通讯作者：
HAYAISHI, O