Loss of canonical Smad4 signaling promotes KRAS driven malignant transformation of human pancreatic duct epithelial cells and metastasis.
Loss of canonical Smad4 signaling promotes KRAS driven malignant transformation of human pancreatic duct epithelial cells and metastasis.
复制标题
DOI：
10.1371/journal.pone.0084366
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Tsao MS
中科院分区：
文献类型：
--
作者：
Leung L;Radulovich N;Zhu CQ;Wang D;To C;Ibrahimov E;Tsao MS
胰腺导管腺癌（PDAC）是北美第四大常见的癌症死亡原因。激活KRAS突变和Smad 4丢失分别发生在约90%和55%的PDAC中。虽然它们在PDAC发育的早期阶段的作用已在遗传修饰的小鼠模型中得到证实，但它们在人胰管细胞的多步恶性转化中的作用尚未得到直接证实。在这里，我们报告说，Smad 4代表KRAS介导的恶性转化的近正常的永生化人胰腺导管上皮（HPDE）细胞系模型的障碍。在表达KRAS G12 V的HPDE细胞中，通过shRNA显著下调Smad 4未能引起致瘤性转化。然而，KRAS介导的恶性转化发生在一种新的HPDE-TGF-β抗性（TβR）细胞系中，该细胞系完全缺乏Smad 4蛋白表达，并且对TGF-β的有丝分裂抑制活性具有抗性。当细胞原位植入小鼠胰腺时，这种转化导致肿瘤形成和转移表型的发展。Smad 4恢复重建了TGF-β敏感性，通过促进细胞凋亡显著增加了肿瘤潜伏期，并降低了转移潜力。这些结果直接确立了KRAS癌基因和Smad 4完全失活在正常人HPDE细胞的多阶段恶性转化和转移进展中的关键组合。
Pancreatic ductal adenocarcinoma (PDAC) is the fourth most common cause of cancer death in North America. Activating KRAS mutations and Smad4 loss occur in approximately 90% and 55% of PDAC, respectively. While their roles in the early stages of PDAC development have been confirmed in genetically modified mouse models, their roles in the multistep malignant transformation of human pancreatic duct cells have not been directly demonstrated. Here, we report that Smad4 represents a barrier in KRAS-mediated malignant transformation of the near normal immortalized human pancreatic duct epithelial (HPDE) cell line model. Marked Smad4 downregulation by shRNA in KRAS G12V expressing HPDE cells failed to cause tumorigenic transformation. However, KRAS-mediated malignant transformation occurred in a new HPDE-TGF-β resistant (TβR) cell line that completely lacks Smad4 protein expression and is resistant to the mito-inhibitory activity of TGF-β. This transformation resulted in tumor formation and development of metastatic phenotype when the cells were implanted orthotopically into the mouse pancreas. Smad4 restoration re-established TGF-β sensitivity, markedly increased tumor latency by promoting apoptosis, and decreased metastatic potential. These results directly establish the critical combination of the KRAS oncogene and complete Smad4 inactivation in the multi-stage malignant transformation and metastatic progression of normal human HPDE cells.
登录
查看更多内容
影响因子：
4.8
作者：
Ahmed, MM;Alcock, A;Freeman, JW
通讯作者：
Freeman, JW
影响因子：
3.5
作者：
Löhr, M;Müller, P;Jesnowski, R
通讯作者：
Jesnowski, R
影响因子：
3.7
作者：
Leung L;Radulovich N;Zhu CQ;Organ S;Bandarchi B;Pintilie M;To C;Panchal D;Tsao MS
通讯作者：
Tsao MS
影响因子：
64.8
作者：
Biankin, Andrew V.;Waddell, Nicola;Kassahn, Karin S.;Gingras, Marie-Claude;Muthuswamy, Lakshmi B.;Johns, Amber L.;Miller, David K.;Wilson, Peter J.;Patch, Ann-Marie;Wu, Jianmin;Chang, David K.;Cowley, Mark J.;Gardiner, Brooke B.;Song, Sarah;Harliwong, Ivon;Idrisoglu, Senel;Nourse, Craig;Nourbakhsh, Ehsan;Manning, Suzanne;Wani, Shivangi;Gongora, Milena;Pajic, Marina;Scarlett, Christopher J.;Gill, Anthony J.;Pinho, Andreia V.;Rooman, Ilse;Anderson, Matthew;Holmes, Oliver;Leonard, Conrad;Taylor, Darrin;Wood, Scott;Xu, Qinying;Nones, Katia;Fink, J. Lynn;Christ, Angelika;Bruxner, Tim;Cloonan, Nicole;Kolle, Gabriel;Newell, Felicity;Pinese, Mark;Mead, R. Scott;Humphris, Jeremy L.;Kaplan, Warren;Jones, Marc D.;Colvin, Emily K.;Nagrial, Adnan M.;Humphrey, Emily S.;Chou, Angela;Chin, Venessa T.;Chantrill, Lorraine A.;Mawson, Amanda;Samra, Jaswinder S.;Kench, James G.;Lovell, Jessica A.;Daly, Roger J.;Merrett, Neil D.;Toon, Christopher;Epari, Krishna;Nguyen, Nam Q.;Barbour, Andrew;Zeps, Nikolajs;Kakkar, Nipun;Zhao, Fengmei;Wu, Yuan Qing;Wang, Min;Muzny, Donna M.;Fisher, William E.;Brunicardi, F. Charles;Hodges, Sally E.;Reid, Jeffrey G.;Drummond, Jennifer;Chang, Kyle;Han, Yi;Lewis, Lora R.;Dinh, Huyen;Buhay, Christian J.;Beck, Timothy;Timms, Lee;Sam, Michelle;Begley, Kimberly;Brown, Andrew;Pai, Deepa;Panchal, Ami;Buchner, Nicholas;De Borja, Richard;Denroche, Robert E.;Yung, Christina K.;Serra, Stefano;Onetto, Nicole;Mukhopadhyay, Debabrata;Tsao, Ming-Sound;Shaw, Patricia A.;Petersen, Gloria M.;Gallinger, Steven;Hruban, Ralph H.;Maitra, Anirban;Iacobuzio-Donahue, Christine A.;Schulick, Richard D.;Wolfgang, Christopher L.;Morgan, Richard A.;Lawlor, Rita T.;Capelli, Paola;Corbo, Vincenzo;Scardoni, Maria;Tortora, Giampaolo;Tempero, Margaret A.;Mann, Karen M.;Jenkins, Nancy A.;Perez-Mancera, Pedro A.;Adams, David J.;Largaespada, David A.;Wessels, Lodewyk F. A.;Rust, Alistair G.;Stein, Lincoln D.;Tuveson, David A.;Copeland, Neal G.;Musgrove, Elizabeth A.;Scarpa, Aldo;Eshleman, James R.;Hudson, Thomas J.;Sutherland, Robert L.;Wheeler, David A.;Pearson, John V.;McPherson, John D.;Gibbs, Richard A.;Grimmond, Sean M.
通讯作者：
Grimmond, Sean M.
影响因子：
8
作者：
Duda, DG;Sunamura, M;Horii, A
通讯作者：
Horii, A