論文 - 詳細
| RRC ID | 51653 |
|---|---|
| 著者 | Hijiya N, Tsukamoto Y, Nakada C, Tung Nguyen L, Kai T, Matsuura K, Shibata K, Inomata M, Uchida T, Tokunaga A, Amada K, Shirao K, Yamada Y, Mori H, Takeuchi I, Seto M, Aoki M, Takekawa M, Moriyama M. |
| タイトル | Genomic Loss of DUSP4 Contributes to the Progression of Intraepithelial Neoplasm of Pancreas to Invasive Carcinoma. |
| ジャーナル | Cancer Res |
| Abstract |
The progression from precursor lesions of pancreatic cancer, including pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasm (IPMN), to invasive disease is characterized by stepwise accumulation of genetic alterations. However, it remains unclear whether additional alterations are required for the progression of high-grade neoplasms to invasive pancreatic carcinoma. We compared the genomic profiles of paired noninvasive and invasive carcinoma tissues collected from patients with IPMN. We demonstrate that the frequency of genomic copy-number aberrations significantly increased during the course of invasion, and the loss of 8p11.22-ter was more often associated with invasive tissues. Expression profiling in pancreatic cancer cell lines with and without 8p11.22-ter revealed that DUSP4, an MAPK phosphatase, was significantly downregulated in cells lacking 8p11.22-ter as well as in invasive carcinomas due to genomic loss. Restoration of DUSP4 expression in pancreatic cancer cells significantly suppressed invasiveness and anoikis resistance via ERK inactivation. Accordingly, we found that blockade of ERK signaling by MEK inhibition was effective in an orthotopic xenograft model and significantly extended survival. Collectively, our findings demonstrate a genetic mechanism by which pancreatic precursor lesions progress to invasive carcinomas and highlight DUSP4 as a novel invasion suppressor that can be therapeutically exploited through manipulation of ERK signaling. Cancer Res; 76(9); 2612-25. ©2016 AACR. |
| 巻・号 | 76(9) |
| ページ | 2612-25 |
| 公開日 | 2016-5-1 |
| DOI | 10.1158/0008-5472.CAN-15-1846 |
| PII | 0008-5472.CAN-15-1846 |
| PMID | 26941286 |
| MeSH | Adenocarcinoma in Situ / genetics Adenocarcinoma in Situ / pathology* Adenocarcinoma, Mucinous / genetics Adenocarcinoma, Mucinous / mortality Adenocarcinoma, Mucinous / pathology Adenocarcinoma, Papillary / genetics Adenocarcinoma, Papillary / mortality Adenocarcinoma, Papillary / pathology Animals Carcinoma, Pancreatic Ductal / genetics Carcinoma, Pancreatic Ductal / mortality Carcinoma, Pancreatic Ductal / pathology* Comparative Genomic Hybridization Disease Progression Dual-Specificity Phosphatases / genetics Dual-Specificity Phosphatases / metabolism* Heterografts Humans Kaplan-Meier Estimate Mice Microscopy, Confocal Mitogen-Activated Protein Kinase Phosphatases / genetics Mitogen-Activated Protein Kinase Phosphatases / metabolism* Neoplasm Invasiveness Oligonucleotide Array Sequence Analysis Pancreatic Neoplasms / genetics Pancreatic Neoplasms / mortality Pancreatic Neoplasms / pathology* Transcriptome |
| IF | 9.727 |
| 引用数 | 16 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 2 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | PANC-1(RCB2095) PK-1(RCB1972) KP4-1(RCB1006) PK-45H(RCB1973) PK-59(RCB1901) MIA Paca2(RCB2094) |