Targeting Epigenetic Regulation of miR-34a for Treatment of Pancreatic Cancer by Inhibition of Pancreatic Cancer Stem Cells

Nalls D, Tang SN, Rodova M, Srivastava RK, Shankar S. “PLoS 1. 2011 Aug”

BACKGROUND:
MicroRNA-34a (miR-34a) can be a transcriptional target of p53 and it is down-regulated in pancreatic cancer. This research aimed to research the functional significance of miR-34a in pancreatic cancer progression via its epigenetic restoration with chromatin modulators, demethylating agent 5-Aza-2′-deoxycytidine (5-Aza-dC) and HDAC inhibitor Vorinostat (SAHA).

METHODOLOGY/PRINCIPAL FINDINGS:
Re-expression of miR-34a in human pancreatic cancer stem cells (CSCs) and in human pancreatic cancer cell lines upon remedy with 5-Aza-dC and SAHA firmly inhibited the cell proliferation, cell cycle progression, self-renewal, epithelial to mesenchymal changeover (EMT) and invasion. In pancreatic CSCs, modulation of miR-34a induced apoptosis by activating caspase-3/7. Remedy of pancreatic CSCs with the chromatin-modulating agents resulted inside the inhibition of Bcl-2, CDK6 and SIRT1, which are the putative targets of miR-34a. MiR-34a upregulation by these agents also induced acetylated p53, p21(WAF1), p27(KIP1) and PUMA in pancreatic CSCs. Inhibition of miR-34a by antagomiR abrogates the effects of 5-Aza-dC and SAHA, suggesting that 5-Aza-dC and SAHA regulate stem cell characteristics through miR-34a. In CSCs, SAHA inhibited Notch pathway, suggesting its suppression may possibly lead to inhibition from the self-renewal capability and induction of apoptosis. Curiously, therapy of pancreatic CSCs with SAHA resulted inside the inhibition of EMT with the transcriptional up-regulation of E-Cadherin and down-regulation of N-Cadherin. Expression of EMT inducers (Zeb-1, Snail and Slug) was inhibited in CSCs on treatment with SAHA. 5-Aza-dC and SAHA also retard in vitro migration and invasion of CSCs.

CONCLUSIONS:
The existing study thus demonstrates the function of miR-34a being a critical regulator of pancreatic cancer progression with the regulating CSC characteristics. The restoration of its expression by 5-Aza-dC and SAHA in CSCs will not only supply mechanistic perception and therapeutic targets for pancreatic cancer but additionally promising reagents to boost individual response to existing chemotherapies or as a standalone cancer drug by getting rid of the CSC characteristics.

Keywords:

p53, cancer stem cells (CSCs)

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  2. Reactive Oxygen Species Induced by Bile Acid Induce Apoptosis and Shield In opposition to Necrosis in Pancreatic Acinar Cells

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