The HMGA1-COX-2 axis: a key molecular pathway and potential target in pancreatic adenocarcinoma.
The HMGA1-COX-2 axis: a key molecular pathway and potential target in pancreatic adenocarcinoma.
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DOI：
10.1016/j.pan.2012.05.005
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发表时间：
2012-07
期刊：
影响因子：
--
通讯作者：
Resar LM
中科院分区：
文献类型：
--
作者：
Hillion J;Smail SS;Di Cello F;Belton A;Shah SN;Huso T;Schuldenfrei A;Nelson DM;Cope L;Campbell N;Karikari C;Aderinto A;Maitra A;Huso DL;Resar LM
虽然胰腺癌是一种常见的、高致死性的恶性肿瘤，但使前驱病变成为浸润性癌的分子事件仍不清楚。我们以前报道过高迁移率族A1（HMGA 1）蛋白在>90%的原发性胰腺癌中过表达，而在早期前体病变中不表达或表达水平较低。在这里，我们研究HMGA 1在胰腺上皮细胞重编程为浸润性癌细胞中的作用。我们评估了HMGA 1在表达活化K-RAS的非转化胰腺上皮细胞中诱导的致癌特性。我们还探讨了人胰腺癌细胞中的HMGA 1-环氧合酶（考克斯-2）通路以及考克斯-2抑制剂在异种移植瘤发生中的治疗作用。HMGA 1与活化的K-RAS协同诱导来自正常人胰腺上皮的细胞系中的迁移、侵袭和锚定非依赖性细胞生长。HMGA 1和考克斯-2在胰腺癌细胞系中的表达呈正相关（r2=0.93; p<0.001）。在三种胰腺癌细胞系中，HMGA 1在体内AT富集区与考克斯-2启动子直接结合。此外，HMGA 1诱导胰腺上皮细胞中的考克斯-2表达，而HMGA 1的敲低导致胰腺癌细胞中考克斯-2的抑制。引人注目的是，我们还发现舒林酸（一种考克斯-1/考克斯-2抑制剂）或塞来昔布（一种更特异的考克斯-2抑制剂）阻断表达高水平HMGA 1的胰腺癌细胞的异种移植肿瘤发生。我们的研究首次确定了HMGA 1-考克斯-2通路在胰腺癌中的重要作用，并表明靶向该通路可能有效治疗甚至预防胰腺癌。
Although pancreatic cancer is a common, highly lethal malignancy, the molecular events that enable precursor lesions to become invasive carcinoma remain unclear. We previously reported that the high-mobility group A1 (HMGA1) protein is overexpressed in >90% of primary pancreatic cancers, with absent or low levels in early precursor lesions. Here, we investigate the role of HMGA1 in reprogramming pancreatic epithelium into invasive cancer cells. We assessed oncogenic properties induced by HMGA1 in non-transformed pancreatic epithelial cells expressing activated K-RAS. We also explored the HMGA1-cyclooxygenase (COX-2) pathway in human pancreatic cancer cells and the therapeutic effects of COX-2 inhibitors in xenograft tumorigenesis. HMGA1 cooperates with activated K-RAS to induce migration, invasion, and anchorage-independent cell growth in a cell line derived from normal human pancreatic epithelium. Moreover, HMGA1 and COX-2 expression are positively correlated in pancreatic cancer cell lines (r2=0.93; p<0.001). HMGA1 binds directly to the COX-2 promoter at an AT-rich region in vivo in three pancreatic cancer cell lines. In addition, HMGA1 induces COX-2 expression in pancreatic epithelial cells, while knock-down of HMGA1 results in repression of COX-2 in pancreatic cancer cells. Strikingly, we also discovered that Sulindac (a COX-1/COX-2 inhibitor) or Celecoxib (a more specific COX-2 inhibitor) block xenograft tumorigenesis from pancreatic cancer cells expressing high levels of HMGA1. Our studies identify for the first time an important role for the HMGA1-COX-2 pathway in pancreatic cancer and suggest that targeting this pathway could be effective to treat, or even prevent, pancreatic cancer.
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影响因子：
8
作者：
Dhar, A;Hu, J;Colburn, NH
通讯作者：
Colburn, NH
影响因子：
11.2
作者：
Hillion J;Dhara S;Sumter TF;Mukherjee M;Di Cello F;Belton A;Turkson J;Jaganathan S;Cheng L;Ye Z;Jove R;Aplan P;Lin YW;Wertzler K;Reeves R;Elbahlouh O;Kowalski J;Bhattacharya R;Resar LM
通讯作者：
Resar LM
DOI：
10.1158/1541-7786.mcr-08-0336
发表时间：
2009-11
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Hillion J;Wood LJ;Mukherjee M;Bhattacharya R;Di Cello F;Kowalski J;Elbahloul O;Segal J;Poirier J;Rudin CM;Dhara S;Belton A;Joseph B;Zucker S;Resar LM
通讯作者：
Resar LM
影响因子：
3.4
作者：
El-Rayes, BF;Zalupski, MM;Philip, PA
通讯作者：
Philip, PA
影响因子：
11.5
作者：
Csiki, I;Morrow, JD;Johnson, DH
通讯作者：
Johnson, DH