Nuclear expression of Y‐box binding protein‐1 is associated with poor prognosis in patients with pancreatic cancer and its knockdown inhibits tumor growth and metastasis in mice tumor models

Abstract

The objective of this study was to examine the implication of Y-box-binding protein-1 (YB-1) for the aggressive phenotypes, prognosis and therapeutic target in pancreatic ductal adenocarcinoma (PDAC). YB-1 expression in PDAC, pancreatic intraepithelial neoplasia (PanIN) and normal pancreas specimens was evaluated by immunohistochemistry, and its correlation with clinicopathological features was assessed in patients with PDAC. The effects of YB-1 on proliferation, invasion and expressions of cell cycle-related proteins and matrix metalloproteinases (MMPs) were analyzed by WST-8, cell cycle and Matrigel invasion assays, Western blotting and quantitative RT-PCR in PDAC cells transfected with YB-1-siRNAs. To verify the significance of YB-1 for tumor progression in vivo, the growth and metastasis were monitored after intrasplenic implantation of ex vivo YB-1 siRNA-transfected PDAC cells, and YB-1-targeting antisense oligonucleotides were intravenously administered in nude mice harboring subcutaneous tumor. The intensity of YB-1 expression and positivity of nuclear YB-1 expression were higher in PDAC than PanIN and normal pancreatic tissues. Nuclear YB-1 expression was significantly associated with dedifferentiation, lymphatic/venous invasion and unfavorable prognosis. YB-1 knockdown inhibited cell proliferation via cell cycle arrest by Sphase kinase-associated protein 2 downregulation and consequent p27 accumulation, and decreased the invasion due to downregulated membranous-type 2 MMP expression in PDAC cells. Tumor growth and liver metastasis formation were significantly suppressed in nude mice after implantation of YB-1-silenced PDAC cells, and the YB-1 targeting antisense oligonucleotide significantly inhibited the growth of subcutaneous tumors. In conclusion, YB-1 may be involved in aggressive natures of PDAC and a promising therapeutic target.Pancreatic ductal adenocarcinoma (PDAC), the main histological type of pancreatic cancer, is one of the most aggressive solid tumors worldwide with an overall 5-year survival rate of 4 to 6%. 1-3 Although surgical complete resection (clinical state of no residual cancer: R0) may provide a unique curative option for PDAC, R0 surgery is only conducted in approximately 15% of patients because of the difficulty in early diagnosis. Furthermore, the 5-year survival for patients with R0 resection remains at <20% because of early and high recurrence of microresidual PDAC cells that are resistant to anticancer drugs, irradiation, or their combinations. 4-6 Therefore, it is urgently necessary to clarify the mechanism underlying the aggressiveness of PDAC and to develop novel therapeutic strategies.Y-box-binding protein-1 (YB-1), encoded by the YBX1 gene, is a member of the cold-shock domain protein superfamily and plays important roles in various biological processes, including transcriptional and translational regulation of gene expression, cell proliferation, DNA injury repair, pre-mRNA splicing, and multidrug resistance. 7,8 A series of studies using clinical specimens have shown...

Y‐box binding protein‐1 promotes tumorigenesis and progression via the epidermal growth factor receptor/AKT pathway in spinal chordoma

“…Y‐box binding protein‐1 (YBX1), encoded by the YBX1 gene, is a member of the cold‐shock protein superfamily and participates in a wide variety of cellular processes . Many studies have indicated that YBX1 expression is significantly elevated and correlates with poor outcome and recurrence in common tumor types, such as pancreatic cancer and melanoma . In addition, YBX1 regulates tumor cell proliferation, apoptosis, invasion, migration and chemoresistance through the related pathways .…”

“…7 Many studies have indicated that YBX1 expression is significantly elevated and correlates with poor outcome and recurrence in common tumor types, such as pancreatic cancer and melanoma. 8,9 In addition, YBX1 regulates tumor cell proliferation, apoptosis, invasion, migration and chemoresistance through the related pathways. 10 Multiple key molecules that interact with YBX1 have been shown to be overexpressed in chordoma and contribute to chordoma development, such as hypoxia inducible factor 1 alpha subunit (HIF-1α), a mechanistic target of rapamycin kinase (mTOR) and RB transcriptional corepressor 1 (RB).…”

Secreted protein YB-1 and its prognostic significance

“…Высокая экспрессия этого гена ассо-циирована с ухудшением показателя безрецидивной выживаемости больных РМЖ [12], а также больных с другими новообразованиями [13,14]. Кроме того, белок YB-1 является потенциальной мишенью для тар-гетной терапии [15].…”

Antisense Oligonucleotides Targeting Y-Box Binding Protein-1 Inhibit Tumor Angiogenesis by Downregulating Bcl-xL-VEGFR2/-Tie Axes

“…Y-box binding protein-1 (YB-1), originally identified as a member of the cold-shock protein superfamily,7, 8 is overexpressed not only in cancer cells,9, 10, 11, 12 but also in vascular endothelia in tumor tissues 13 . YB-1 plays an important role in proliferation, invasion, multi-drug resistance, and malignant transformation in a variety of cancers 14, 15, 16.…”