Depletion of Epithelial to Mesenchymal Transition (EMT) mediator RUNX2 reduced gemcitabine resistance in mutant p53 pancreatic cancer cell lines

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Runt-related transcription factor 2 (RUNX2) is upregulated in pancreatic cancer (Figure 1) [1]. In a prostate cancer cell line it was found that RUNX2 overexpression induced genes involved in epithelial to mesenchymal transition (EMT) a known mechanism of stromal generation in pancreatic cancer [2]. In normal mammary epithelial cells RUNX2 overexpression induced EMT-like changes [3]. In addition in a mouse pluripotent mesenchymal precursor cell line activation of the EMT inducing Transforming Growth Factor Beta 1 (TGF-ß1) pathway upregulated RUNX2 [4]. EMT is known to enhance drug resistance of tumour cells.

 

 

RUNX2

Figure 1: An analysis of RUNX2 expression from microarray gene-expression profiles of 45 matching pairs of pancreatic tumor and adjacent non-tumor tissues from 45 patients with pancreatic ductal adenocarcinoma (PDAC) (GEO Series GSE28735). RMA = robust multi-array average (mRNA expression).

 

The guardian of the genome p53 is deleted/truncated or missense mutated in 50-70% of pancreatic ductal adenocarcinomas (PDACs). Normally it functions as a tumour suppressor, however it can acquire gain of function mutations during pancreatic cancer progression which convert it to a metastasis promoter through mechanisms such as promoting EMT [5]. Pancreatic cancer cell lines that have either lost p53 expression or gained missense mutation are more resistant to the chemotherapeutic gemcitabine than cell lines expressing wild type (normal) p53 [6, 7].  In both cell lines with loss of p53 and missense mutation of p53 reduction of the RUNX2 transcription factor expression enhanced the effectiveness of gemcitabine treatment [6, 7].

 

It will be important to directly confirm that RUNX2 mediates aspects of EMT, which have been strongly suggested by the analysis of other cell systems, in pancreatic cancer models. Targeting EMT in pancreatic cancer can potentially improve the effectiveness of existing drugs through multiple mechanisms.

 

Refs

 

  1. Kayed, H, X Jiang, S Keleg, R Jesnowski, T Giese, M R Berger, I Esposito, M Löhr, H Friess, and J Kleeff. ‘Regulation and Functional Role of the Runt-Related Transcription Factor-2 in Pancreatic Cancer’. British Journal of Cancer 97, no. 8 (22 October 2007): 1106–15. doi:10.1038/sj.bjc.6603984.
  2. Baniwal, Sanjeev K., Omar Khalid, Yankel Gabet, Ruchir R. Shah, Daniel J. Purcell, Deepak Mav, Alice E. Kohn-Gabet, Yunfan Shi, Gerhard A. Coetzee, and Baruch Frenkel. ‘Runx2 Transcriptome of Prostate Cancer Cells: Insights into Invasiveness and Bone Metastasis’. Molecular Cancer 9, no. 1 (2010): 1. http://molecular-cancer.biomedcentral.com/articles/10.1186/1476-4598-9-258.
  3. Owens, T. W., R. L. Rogers, S. A. Best, A. Ledger, A.-M. Mooney, A. Ferguson, P. Shore, et al. ‘Runx2 Is a Novel Regulator of Mammary Epithelial Cell Fate in Development and Breast Cancer’. Cancer Research 74, no. 18 (15 September 2014): 5277–86. doi:10.1158/0008-5472.CAN-14-0053.
  4. Lee, Kyeong-Sook, Seung-Hyun Hong, and Suk-Chul Bae. ‘Both the Smad and p38 MAPK Pathways Play a Crucial Role in Runx2 Expression Following Induction by Transforming Growth Factor-Beta and Bone Morphogenetic Protein’. Oncogene 21, no. 47 (17 October 2002): 7156–63. doi:10.1038/sj.onc.1205937.
  5. https://pharmaceuticalintelligence.com/2016/05/09/the-guardian-of-the-genome-p53-in-pancreatic-cancer/
  6. Sugimoto, H, M Nakamura, H Yoda, K Hiraoka, K Shinohara, M Sang, K Fujiwara, O Shimozato, H Nagase, and T Ozaki. ‘Silencing of RUNX2 Enhances Gemcitabine Sensitivity of p53-Deficient Human Pancreatic Cancer AsPC-1 Cells through the Stimulation of TAp63-Mediated Cell Death’. Cell Death Discovery 1 (10 August 2015): 15010. doi:10.1038/cddiscovery.2015.10.
  7. Nakamura, M, H Sugimoto, T Ogata, K Hiraoka, H Yoda, M Sang, M Sang, et al. ‘Improvement of Gemcitabine Sensitivity of p53-Mutated Pancreatic Cancer MiaPaCa-2 Cells by RUNX2 Depletion-Mediated Augmentation of TAp73-Dependent Cell Death’. Oncogenesis 5, no. 6 (13 June 2016): e233. doi:10.1038/oncsis.2016.40.
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