Hematology Division, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States.
Pancreatology. 2012 Jul-Aug;12(4):372-9. doi: 10.1016/j.pan.2012.05.005. Epub 2012 May 29.
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 (r(2) = 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.
尽管胰腺癌是一种常见的、高度致命的恶性肿瘤，但使前体病变发展为浸润性癌的分子事件仍不清楚。我们之前的研究报道，高迁移率族蛋白 A1（HMGA1）蛋白在>90%的原发性胰腺癌中过表达，而在早期前体病变中则无表达或低表达。
在这里，我们研究了 HMGA1 在将胰腺上皮细胞重编程为浸润性癌细胞中的作用。我们评估了在表达激活型 K-RAS 的非转化胰腺上皮细胞中，HMGA1 诱导的致癌特性。我们还探索了人胰腺癌细胞中的 HMGA1-环氧化酶（COX-2）途径以及 COX-2 抑制剂在异种移植肿瘤发生中的治疗效果。
HMGA1 与激活型 K-RAS 合作，在源自正常人类胰腺上皮的细胞系中诱导迁移、侵袭和锚定非依赖性细胞生长。此外，HMGA1 和 COX-2 表达在胰腺癌细胞系中呈正相关（r²=0.93；p<0.001）。HMGA1 在三种胰腺癌细胞系中体内直接结合 COX-2 启动子上的富含 AT 区。此外，HMGA1 在胰腺上皮细胞中诱导 COX-2 表达，而敲低 HMGA1 导致胰腺癌细胞中 COX-2 表达受到抑制。引人注目的是，我们还发现 Sulindac（COX-1/COX-2 抑制剂）或 Celecoxib（更特异的 COX-2 抑制剂）阻断了表达高水平 HMGA1 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 HMGA1-COX-2 途径在胰腺癌中的重要作用，并表明靶向该途径可能对治疗甚至预防胰腺癌有效。
