The insulin receptor substrate 1 (IRS1) in intestinal epithelial differentiation and in colorectal cancer.
The insulin receptor substrate 1 (IRS1) in intestinal epithelial differentiation and in colorectal cancer.
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DOI：
10.1371/journal.pone.0036190
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Mariani-Costantini R
中科院分区：
文献类型：
--
作者：
Esposito DL;Aru F;Lattanzio R;Morgano A;Abbondanza M;Malekzadeh R;Bishehsari F;Valanzano R;Russo A;Piantelli M;Moschetta A;Lotti LV;Mariani-Costantini R
结直肠癌（CRC）与影响胰岛素/IGF信号的生活方式因素有关，其中胰岛素受体底物1 （IRS1）是一个关键的传感器。我们研究了IRS1在无癌结肠上皮、伴肝转移的原发性结肠癌细胞和体外极化Caco2和HT29细胞中的表达、定位和病理相关性。在家族性腺瘤性息肉患者的腺瘤和过表达c-MYC、ß-catenin、InsRß和IGF1R的crc中，IRS1 mRNA和蛋白含量相对于配对粘膜较高。对24例伴有结肠上皮和肝转移的原发性结直肠癌进行IRS1免疫染色分析，结果显示，转移灶的染色强度明显高于原发性结直肠癌（P<0.01）和结肠上皮（P<0.01）。与结肠上皮相比，原发性和转移性crc中irs1阳性细胞的数量显著增加（P = 0.013和P = 0.014）。163例原发性crc的病理相关性显示，弥漫性IRS1染色与分化表型和侵袭性标志物（高Ki67、p53和ß-catenin）的肿瘤相关。在Caco 2中，IRS1和InsR在极化后表达最多，而IGF1R在极化前细胞中表达最多。未检测到核IRS1，而随着极化，磷酸化的IRS1 （pIRS1）从外侧转移到顶质膜，仅在表面细胞中表达。在HT29中，携带组成性激活生存信号的突变，IRS1和IGF1R随着极化而减少，而pIRS1在整个过程中定位于核点。总的来说，这些数据提供了IRS1根据CRC分化进行调节的证据，并支持IRS1在CRC进展和肝转移中的作用。
Colorectal cancer (CRC) is associated with lifestyle factors that affect insulin/IGF signaling, of which the insulin receptor substrate 1 (IRS1) is a key transducer. We investigated expression, localization and pathologic correlations of IRS1 in cancer-uninvolved colonic epithelium, primary CRCs with paired liver metastases and in vitro polarizing Caco2 and HT29 cells. IRS1 mRNA and protein resulted higher, relative to paired mucosa, in adenomas of familial adenomatous polyposis patients and in CRCs that overexpressed c-MYC, ß-catenin, InsRß, and IGF1R. Analysis of IRS1 immunostaining in 24 cases of primary CRC with paired colonic epithelium and hepatic metastasis showed that staining intensity was significantly higher in metastases relative to both primary CRC (P<0.01) and colonic epithelium (P<0.01). Primary and metastatic CRCs, compared to colonic epithelium, contained significantly higher numbers of IRS1-positive cells (P = 0.013 and P = 0.014, respectively). Pathologic correlations in 163 primary CRCs revealed that diffuse IRS1 staining was associated with tumors combining differentiated phenotype and aggressive markers (high Ki67, p53, and ß-catenin). In Caco 2 IRS1 and InsR were maximally expressed after polarization, while IGF1R was highest in pre-polarized cells. No nuclear IRS1 was detected, while, with polarization, phosphorylated IRS1 (pIRS1) shifted from the lateral to the apical plasma membrane and was expressed in surface cells only. In HT29, that carry mutations constitutively activating survival signaling, IRS1 and IGF1R decreased with polarization, while pIRS1 localized in nuclear spots throughout the course. Overall, these data provide evidence that IRS1 is modulated according to CRC differentiation, and support a role of IRS1 in CRC progression and liver metastatization.
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影响因子：
56.9
作者：
Behrens, J;Jerchow, BA;Birchmeier, W
通讯作者：
Birchmeier, W
影响因子：
2.8
作者：
Chiang, J. M.;Yeh, C. Y.;Chen, J. R.
通讯作者：
Chen, J. R.
影响因子：
254.7
作者：
Giovannucci, Edward;Harlan, David M.;Yee, Douglas
通讯作者：
Yee, Douglas
影响因子：
4.7
作者：
Bach, SP;Renehan, AG;Potten, CS
通讯作者：
Potten, CS
DOI：
10.3109/10799899309063266
发表时间：
1993-01-01
期刊：
JOURNAL OF RECEPTOR RESEARCH
影响因子：
--
作者：
MACDONALD, RS;THORNTON, WH;BEAN, TL
通讯作者：
BEAN, TL