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Inhibition of PRDM14 expression in pancreatic cancer suppresses cancer stem-like properties and liver metastasis in mice.
- Source :
-
Carcinogenesis [Carcinogenesis] 2017 Jun 01; Vol. 38 (6), pp. 638-648. - Publication Year :
- 2017
-
Abstract
- Pancreatic cancer is one of the most lethal types of cancer, with aggressive properties characterized by metastasis, recurrence and drug resistance. Cancer stem cells are considered to be responsible for these properties. PRDM14, a transcriptional regulator that maintains pluripotency in embryonic stem cells, is overexpressed in some cancers. Here, we assessed PRDM14 expression and the effects of PRDM14 knockdown on cancer stem-like phenotypes in pancreatic cancer. We observed that PRDM14 protein was overexpressed in pancreatic cancer tissues compared with normal pancreatic tissues. Using lentiviral shRNA-transduced pancreatic cancer cells, we found that PRDM14 knockdown decreased sphere formation, number of side population and cell surface marker-positive cells and subcutaneous xenograft tumors and liver metastasis in mice. This was accompanied by upregulation of some microRNAs (miRNAs), including miR-125a-3p. miR-125a-3p, a tumor suppressor that is down-regulated in pancreatic cancer, has been suggested to regulate the expression of the Src-family kinase, Fyn. In PRDM14-knockdown cells, Fyn was expressed at lower levels and downstream proteins were less activated. These changes were considered to cause suppression of the above cancer phenotypes. In addition, we used small interfering RNA (siRNA)-based therapy targeting PRDM14 in a mouse model of liver metastasis induced using MIA-PaCa2 cells, and this treatment significantly decreased metastasis and in vitro migration. Taken together, these results suggest that targeting the overexpression of PRDM14 suppresses cancer stem-like phenotypes, including liver metastasis, via miRNA regulation and siRNA-based therapy targeting it shows promise as a treatment for patients with pancreatic cancer.<br /> (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Subjects :
- Animals
Carcinoma, Pancreatic Ductal metabolism
Carcinoma, Pancreatic Ductal pathology
Carcinoma, Pancreatic Ductal prevention & control
DNA-Binding Proteins
Humans
Liver Neoplasms metabolism
Liver Neoplasms secondary
Male
Mice
Mice, Inbred BALB C
Mice, Nude
MicroRNAs
Neoplasm Recurrence, Local genetics
Neoplasm Staging
Neoplastic Stem Cells metabolism
Pancreatic Neoplasms metabolism
Pancreatic Neoplasms pathology
RNA, Small Interfering
RNA-Binding Proteins
Transcription Factors genetics
Transcription Factors metabolism
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Liver Neoplasms prevention & control
Neoplastic Stem Cells pathology
Pancreatic Neoplasms prevention & control
Transcription Factors antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2180
- Volume :
- 38
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Carcinogenesis
- Publication Type :
- Academic Journal
- Accession number :
- 28498896
- Full Text :
- https://doi.org/10.1093/carcin/bgx040