miR-137 expression induces cellular senescence in p53+ pancreatic cancer cells

 

The microRNA 137 (miR-137) is down-regulated in pancreatic cancer cell lines and cancer tissue [1]. In PANC-1 and MIA PaCa-2 pancreatic cancer cell lines exogenous expression of miR-137 decreased cell invasion and induced sensitivity to the chemotherapeutic 5-FU. In a mouse xengraft of MIA PaCa-2 miR-137 expression significantly reduced tumour volume and weight [1]. Now a new study indicates a possible mechanism of action – the induction of senescence via p53 [2] (figure 1).

 

miR-137-mechanism
Figure 1: Model of senescence induction by miR-137. This figure is sourced from Figure 7 of ref [2]. No changes were made. Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0).

 

For the first time it has been shown that miR-137 targets KDM4A mRNA for degradation. KDM4A inhibits p53. RAS activation which is constitutive in 90% of PDAC normally leads to miR-137 upregulation and consequent release of p53 from KDM4A suppression which leads to p53 mediated cellular senescence. When miR-137 expression is restored in the pancreatic cancer cell line PANC-1 senescence is induced. This study suggests that restoring miR-137 expression may be therapeutically beneficial in early stage pancreatic cancer however p53 loss through mutation is frequent during pancreatic cancer progression which would be expected to negate benefit derived from miR-137 expression.

 

Refs

  1. Xiao, Jie, Feng Peng, Chao Yu, Min Wang, Xu Li, Zhipeng Li, Jianxin Jiang, and Chengyi Sun. ‘microRNA-137 Modulates Pancreatic Cancer Cells Tumor Growth, Invasion and Sensitivity to Chemotherapy’. Int J Clin Exp Pathol 7, no. 11 (2014): 7442–50. http://www.ijcep.com/files/ijcep0000933.pdf.
  2. Neault, Mathieu, Frédérick A. Mallette, and Stéphane Richard. ‘miR-137 Modulates a Tumor Suppressor Network-Inducing Senescence in Pancreatic Cancer Cells’. Cell Reports 14, no. 8 (March 2016): 1966–78. doi:10.1016/j.celrep.2016.01.068.
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