| First Author | Criscimanna A | Year | 2013 |
| Journal | Cancer Res | Volume | 73 |
| Issue | 15 | Pages | 4781-90 |
| PubMed ID | 23749643 | Mgi Jnum | J:199471 |
| Mgi Id | MGI:5502823 | Doi | 10.1158/0008-5472.CAN-13-0566 |
| Citation | Criscimanna A, et al. (2013) PanIN-Specific Regulation of Wnt Signaling by HIF2alpha during Early Pancreatic Tumorigenesis. Cancer Res 73(15):4781-4790 |
| abstractText | Hypoxia promotes angiogenesis, proliferation, invasion, and metastasis of pancreatic cancer. Essentially, all studies of the hypoxia pathway in pancreatic cancer research to date have focused on fully malignant tumors or cancer cell lines, but the potential role of hypoxia inducible factors (HIF) in the progression of premalignant lesions has not been critically examined. Here, we show that HIF2alpha is expressed early in pancreatic lesions both in human and in a mouse model of pancreatic cancer. HIF2alpha is a potent oncogenic stimulus, but its role in Kras-induced pancreatic neoplasia has not been discerned. We used the Ptf1aCre transgene to activate KrasG12D and delete Hif2alpha solely within the pancreas. Surprisingly, loss of Hif2alpha in this model led to markedly higher, rather than reduced, number of low-grade pancreatic intraepithelial neoplasia (mPanIN) lesions. These lesions, however, failed to progress to high-grade mPanINs, and displayed exclusive loss of beta-catenin and SMAD4. The relationship among HIF2alpha, beta-catenin, and Smad4 was further confirmed in vitro, where silencing of Hif2alpha resulted in reduced beta-catenin and Smad4 transcript levels. Thus, with oncogenic Ras expressed in the pancreas, HIF2alpha modulates Wnt-signaling during mPanIN progression by maintaining appropriate levels of both Smad4 and beta-catenin. Cancer Res; 73(15); 4781-90. (c)2013 AACR. |
