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Recent Research On SMAD4 In Pancreatic Cancer

Curator: David Orchard-Webb, PhD

 

Deleted in Pancreatic Cancer, locus 4 (DPC4) officially known as SMAD4 is a component of the Transforming Growth Factor Beta (TGFß) pathway with tumour suppressive properties. As its name suggests it is frequently lost in pancreatic cancer, although through a variety of mechanisms in addition to gene deletion. The loss of SMAD4 is important in the progression of pancreatic intraepithelial neoplasia (PanIN) towards pancreatic ductal adenocarcinoma (PDAC). The expression of SMAD4 can suppress metastasis, angiogenesis, and cancer stem-like cell generation. SMAD4 can promote cancer cell apoptosis through a recently described mechanism involving a lethal epithelial to mesenchymal transition (EMT). SMAD4 status has a predictive role in pancreatic cancer personalised medicine. This curation categorises recent publications of note regarding SMAD4.

 

Role of SMAD4 in neoplastic progression towards PDAC

 

Garcia-Carracedo, Dario, Chih-Chieh Yu, Nathan Akhavan, Stuart A. Fine, Frank Schönleben, Naoki Maehara, Dillon C. Karg, et al. ‘Smad4 Loss Synergizes with TGFα Overexpression in Promoting Pancreatic Metaplasia, PanIN Development, and Fibrosis’. Edited by Ilse Rooman. PLOS ONE 10, no. 3 (24 March 2015): e0120851. doi:10.1371/journal.pone.0120851.

 

Norris, A M, A Gore, A Balboni, A Young, D S Longnecker, and M Korc. ‘AGR2 Is a SMAD4-Suppressible Gene That Modulates MUC1 Levels and Promotes the Initiation and Progression of Pancreatic Intraepithelial Neoplasia’. Oncogene 32, no. 33 (15 August 2013): 3867–76. doi:10.1038/onc.2012.394.

 

Leung, Lisa, Nikolina Radulovich, Chang-Qi Zhu, Dennis Wang, Christine To, Emin Ibrahimov, and Ming-Sound Tsao. ‘Loss of Canonical Smad4 Signaling Promotes KRAS Driven Malignant Transformation of Human Pancreatic Duct Epithelial Cells and Metastasis’. Edited by Hidayatullah G Munshi. PLoS ONE 8, no. 12 (27 December 2013): e84366. doi:10.1371/journal.pone.0084366.

 

Mechanism of SMAD4 deactivation

 

Xia, Xiang, Kundong Zhang, Gang Cen, Tao Jiang, Jun Cao, Kejian Huang, Chen Huang, Qian Zhao, and Zhengjun Qiu. ‘MicroRNA-301a-3p Promotes Pancreatic Cancer Progression via Negative Regulation of SMAD4’. Oncotarget 6, no. 25 (28 August 2015): 21046–63. doi:10.18632/oncotarget.4124.

 

Murphy, Stephen J., Steven N. Hart, Geoffrey C. Halling, Sarah H. Johnson, James B. Smadbeck, Travis Drucker, Joema Felipe Lima, et al. ‘Integrated Genomic Analysis of Pancreatic Ductal Adenocarcinomas Reveals Genomic Rearrangement Events as Significant Drivers of Disease’. Cancer Research 76, no. 3 (1 February 2016): 749–61. doi:10.1158/0008-5472.CAN-15-2198.

 

Sawai, Yugo, Yuzo Kodama, Takahiro Shimizu, Yuji Ota, Takahisa Maruno, Yuji Eso, Akira Kurita, et al. ‘Activation-Induced Cytidine Deaminase Contributes to Pancreatic Tumorigenesis by Inducing Tumor-Related Gene Mutations’. Cancer Research 75, no. 16 (15 August 2015): 3292–3301. doi:10.1158/0008-5472.CAN-14-3028.

 

Demagny, Hadrien, and Edward M De Robertis. ‘Point Mutations in the Tumor Suppressor Smad4/DPC4 Enhance Its Phosphorylation by GSK3 and Reversibly Inactivate TGF-β Signaling’. Molecular & Cellular Oncology 3, no. 1 (2 January 2016): e1025181. doi:10.1080/23723556.2015.1025181.

 

Foster, David. ‘BxPC3 Pancreatic Cancer Cells Express a Truncated Smad4 Protein upon PI3K and mTOR Inhibition’. Oncology Letters, 28 January 2014. doi:10.3892/ol.2014.1833.

 

Hao, Jun, Shuyu Zhang, Yingqi Zhou, Cong Liu, Xiangui Hu, and Chenghao Shao. ‘MicroRNA 421 Suppresses DPC4/Smad4 in Pancreatic Cancer’. Biochemical and Biophysical Research Communications 406, no. 4 (25 March 2011): 552–57. doi:10.1016/j.bbrc.2011.02.086.

 

SMAD4 effects on cell motility

 

Zhang, Xueying, Junxia Cao, Yujun Pei, Jiyan Zhang, and Qingyang Wang. ‘Smad4 Inhibits Cell Migration via Suppression of JNK Activity in Human Pancreatic Carcinoma PANC‑1 Cells’. Oncology Letters, 7 April 2016. doi:10.3892/ol.2016.4427.

 

Kang, Ya ’an, Jianhua Ling, Rei Suzuki, David Roife, Xavier Chopin-Laly, Mark J. Truty, Deyali Chatterjee, et al. ‘SMAD4 Regulates Cell Motility through Transcription of N-Cadherin in Human Pancreatic Ductal Epithelium’. Edited by Neil A. Hotchin. PLoS ONE 9, no. 9 (29 September 2014): e107948. doi:10.1371/journal.pone.0107948.

 

Chen, Yu-Wen, Pi-Jung Hsiao, Ching-Chieh Weng, Kung-Kai Kuo, Tzu-Lei Kuo, Deng-Chyang Wu, Wen-Chun Hung, and Kuang-Hung Cheng. ‘SMAD4 Loss Triggers the Phenotypic Changes of Pancreatic Ductal Adenocarcinoma Cells’. BMC Cancer 14, no. 1 (2014): 1. https://bmccancer.biomedcentral.com/articles/10.1186/1471-2407-14-181.

 

SMAD4 effects on angiogenesis

 

Zhou, Zhichao, Juming Lu, Jingtao Dou, Zhaohui Lv, Xi Qin, and Jing Lin. ‘FHL1 and Smad4 Synergistically Inhibit Vascular Endothelial Growth Factor Expression’. Molecular Medicine Reports 7, no. 2 (February 2013): 649–53. doi:10.3892/mmr.2012.1202.

 

SMAD4 mediated repression of cancer stem-like cells

 

Hoshino, Yukari, Jun Nishida, Yoko Katsuno, Daizo Koinuma, Taku Aoki, Norihiro Kokudo, Kohei Miyazono, and Shogo Ehata. ‘Smad4 Decreases the Population of Pancreatic Cancer–Initiating Cells through Transcriptional Repression of ALDH1A1’. The American Journal of Pathology 185, no. 5 (2015): 1457–1470. http://www.sciencedirect.com/science/article/pii/S0002944015000802.

 

SMAD4 mediated growth inhibition/ apoptosis induction

 

David, Charles J., Yun-Han Huang, Mo Chen, Jie Su, Yilong Zou, Nabeel Bardeesy, Christine A. Iacobuzio-Donahue, and Joan Massagué. ‘TGF-β Tumor Suppression through a Lethal EMT’. Cell 164, no. 5 (February 2016): 1015–30. doi:10.1016/j.cell.2016.01.009.

 

Wang, Qi, Juanjuan Li, Wei Wu, Ruizhe Shen, He Jiang, Yuting Qian, Yanping Tang, et al. ‘Smad4-Dependent Suppressor Pituitary Homeobox 2 Promotes PPP2R2A-Mediated Inhibition of Akt Pathway in Pancreatic Cancer’. Oncotarget 7, no. 10 (8 March 2016): 11208–22. doi:10.18632/oncotarget.7158.

 

Poorly characterised targets of SMAD4

 

Fullerton, Paul T., Chad J. Creighton, and Martin M. Matzuk. ‘Insights Into SMAD4 Loss in Pancreatic Cancer From Inducible Restoration of TGF-β Signaling’. Molecular Endocrinology (Baltimore, Md.) 29, no. 10 (October 2015): 1440–53. doi:10.1210/me.2015-1102.

 

Li, Lei, Zhaoshen Li, Xiangyu Kong, Dacheng Xie, Zhiliang Jia, Weihua Jiang, Jiujie Cui, et al. ‘Down-Regulation of MicroRNA-494 via Loss of SMAD4 Increases FOXM1 and β-Catenin Signaling in Pancreatic Ductal Adenocarcinoma Cells’. Gastroenterology 147, no. 2 (August 2014): 485–497.e18. doi:10.1053/j.gastro.2014.04.048.

 

Drugs that restore SMAD4

 

Lin, Sheng-Zhang, Jin-Bo Xu, Xu Ji, Hui Chen, Hong-Tao Xu, Ping Hu, Liang Chen, et al. ‘Emodin Inhibits Angiogenesis in Pancreatic Cancer by Regulating the Transforming Growth Factor-Β/drosophila Mothers against Decapentaplegic Pathway and Angiogenesis-Associated microRNAs’. Molecular Medicine Reports 12, no. 4 (October 2015): 5865–71. doi:10.3892/mmr.2015.4158.

 

Predictive value of SMAD4 status in personalised medicine

 

Whittle, Martin C., Kamel Izeradjene, P. Geetha Rani, Libing Feng, Markus A. Carlson, Kathleen E. DelGiorno, Laura D. Wood, et al. ‘RUNX3 Controls a Metastatic Switch in Pancreatic Ductal Adenocarcinoma’. Cell 161, no. 6 (June 2015): 1345–60. doi:10.1016/j.cell.2015.04.048.

 

Boone, Brian A., Shirin Sabbaghian, Mazen Zenati, J. Wallis Marsh, A. James Moser, Amer H. Zureikat, Aatur D. Singhi, Herbert J. Zeh, and Alyssa M. Krasinskas. ‘Loss of SMAD4 Staining in Pre-Operative Cell Blocks Is Associated with Distant Metastases Following Pancreaticoduodenectomy with Venous Resection for Pancreatic Cancer’. Journal of Surgical Oncology 110, no. 2 (August 2014): 171–75. doi:10.1002/jso.23606.

 

Herman, Joseph M., Katherine Y. Fan, Aaron T. Wild, Laura D. Wood, Amanda L. Blackford, Ross C. Donehower, Manuel Hidalgo, et al. ‘Correlation of Smad4 Status With Outcomes in Patients Receiving Erlotinib Combined With Adjuvant Chemoradiation and Chemotherapy After Resection for Pancreatic Adenocarcinoma’. International Journal of Radiation Oncology*Biology*Physics 87, no. 3 (November 2013): 458–59. doi:10.1016/j.ijrobp.2013.06.2039.

 

Other Related Articles Published In This Open Access Online Journal Include The Following:

 

https://pharmaceuticalintelligence.com/2016/06/10/pancreatic-cancer-modeling-using-retrograde-viral-vector-delivery-and-in-vivo-crisprcas9-mediated-somatic-genome-editing/

https://pharmaceuticalintelligence.com/2015/04/10/wnt%CE%B2-catenin-signaling-7-10/