PAUF functions in the metastasis of human pancreatic cancer cells and upregulates CXCR4 expression

Abstract

Pancreatic cancer is characterized by early metastatic spread, but the process of tumor cell dissemination is largely unknown. In this study we show that the soluble protein pancreatic adenocarcinoma upregulated factor (PAUF) has an important role in the metastasis and progression of the disease. Variations in the level of PAUF, either by overexpression or knockdown, resulted in altered migration, invasion and proliferation capacity of pancreatic cancer cells. Moreover, depletion of PAUF in metastatic cells dramatically abrogated the spread of the cells to distant organs in an orthotopic xenograft mouse model. PAUF elicited the activation of the extracellular signalregulated kinase (ERK), c-Jun N-terminal kinase (JNK) and AKT intracellular signaling cascades and consequently their downstream transcription factors in an autocrine manner. Genome-wide expression analysis revealed that C-X-C chemokine receptor type 4 (CXCR4) expression was induced by PAUF overexpression but was repressed by PAUF knockdown. The PAUF-mediated increase in cancer cell motility was attenuated by the CXCR4 inhibitor, AMD3100, or by anti-CXCR4 antibody. Furthermore, immunohistochemical analysis of pancreatic tumor tissues clearly showed a significant positive correlation between PAUF and CXCR4 expression. Collectively, these findings indicate that PAUF enhances the metastatic potential of pancreatic cancer cells, at least in part, by upregulating CXCR4 expression.

Silencing of pancreatic adenocarcinoma upregulated factor by RNA interference inhibits the malignant phenotypes of human colorectal cancer cells

“…PAUF also plays important roles in cancer progression, including cell proliferation, adhesion, migration and invasion (20)(21)(22)(23). In our present study, we detected the expression levels of PAUF in 48 cases of CRC by using real-time RT-PCR.…”

PAUF promotes adhesiveness of pancreatic cancer cells by modulating focal adhesion kinase

“…Analysis of the X-ray crystal structure revealed that PAUF is a mammalian lectin containing a β-prism motif normally found in plant lectins . In cancer cells, PAUF acts in an autocrine manner to activate the ERK, JNK and AKT intracellular signaling cascades, resulting in increased expression of the genes involved in tumor progression and metastasis (Lee et al, 2010). Expression of CXCR4, a PAUF-inducing gene, is also positively correlated with PAUF expression in pancreatic cancer tissues from patients (Lee et al, 2010).…”

“…Previously, we identified a novel secretory protein, pancreatic adenocarcinoma up-regulated factor (PAUF), which potentiates metastasis of pancreatic cancer cells via upregulation of migration and invasion (Kim et al, 2009;Lee et al, 2010;Cho et al, 2011). Analysis of the X-ray crystal structure revealed that PAUF is a mammalian lectin containing a β-prism motif normally found in plant lectins .…”

“…In cancer cells, PAUF acts in an autocrine manner to activate the ERK, JNK and AKT intracellular signaling cascades, resulting in increased expression of the genes involved in tumor progression and metastasis (Lee et al, 2010). Expression of CXCR4, a PAUF-inducing gene, is also positively correlated with PAUF expression in pancreatic cancer tissues from patients (Lee et al, 2010). In immune cells, PAUF interacts with the CXCR4-TLR2 complex and inhibits CXCR4-dependent TLR2-mediated NF-κB activation in a paracrine manner .…”

LSINCT5 is over expressed in breast and ovarian cancer and affects cellular proliferation

“…Another gene that had decreased expression after LSINCT5 knock-down was CXCR4, which is the most commonly used marker of several cancers and has also been identified as an important breast cancer marker associated with invasion and metastasis. [35][36][37] Our previous results have shown LSINCT5 to be overexpressed in metastatic and cancer associated lncRNA family. LSINCT5 has increased expression in multiple cancers and tumor tissues including breast and ovarian, compared to their normal counterparts.…”