Inhibition of PRDM14 expression in pancreatic cancer suppresses cancer stem-like properties and liver metastasis in mice
Autor: | Chiharu Moriya, Hiroaki Taniguchi, Nobuhiro Nishiyama, Kohzoh Imai, Kazunori Kataoka, Kanjiro Miyata |
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Rok vydání: | 2017 |
Předmět: |
Male
0301 basic medicine Oncology Cancer Research medicine.medical_specialty Small interfering RNA Mice Nude Biology Metastasis Mice 03 medical and health sciences Side population Cancer stem cell Pancreatic cancer Internal medicine microRNA Tumor Cells Cultured medicine Animals Humans RNA Small Interfering Neoplasm Staging Mice Inbred BALB C Liver Neoplasms RNA-Binding Proteins Cancer General Medicine medicine.disease Xenograft Model Antitumor Assays DNA-Binding Proteins Pancreatic Neoplasms MicroRNAs 030104 developmental biology Neoplastic Stem Cells Cancer research CA19-9 Neoplasm Recurrence Local Carcinoma Pancreatic Ductal Transcription Factors |
Zdroj: | Carcinogenesis. 38:638-648 |
ISSN: | 1460-2180 0143-3334 |
Popis: | 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. |
Databáze: | OpenAIRE |
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