Upregulation of Wnt5a promotes epithelial-to-mesenchymal transition and metastasis of pancreatic cancer cells

Abstract

BackgroundPancreatic cancer is one of the most lethal cancers worldwide. The aim of this study was to determine the expression pattern, clinical significance, and biological functions of Wnt5a in pancreatic cancer.MethodsImmunohistochemistry was performed to examine Wnt5a expression in 134 surgically resected pancreatic adenocarcinoma and adjacent normal pancreatic tissues. Associations of Wnt5a expression with clinicopathological factors and cancer-specific survival were analyzed. The effects of Wnt5a overexpression or silencing on the invasiveness and epithelial-to-mesenchymal transition (EMT) of pancreatic cancer cells were studied. Silencing of β-catenin by small interfering RNA was done to determine its role in the Wnt5a-mediated tumor phenotype.ResultsThe percentage of Wnt5a positive expression showed a bell-shaped pattern in pancreatic cancer tissues, peaking in well-differentiated carcinomas. The median cancer-specific survival was comparable between patients with positive versus negative expression of Wnt5a. Overexpression of Wnt5a promoted the migration and invasion of pancreatic cancer cells, whereas Wnt5a depletion had an inhibitory effect. In an orthotopic pancreatic cancer mouse model, Wnt5a overexpression resulted in increased invasiveness and metastasis, coupled with induction of EMT in tumor cells. Treatment with recombinant Wnt5a elevated the nuclear β-catenin level in pancreatic cancer cells, without altering the Ror2 expression. Targeted reduction of β-catenin antagonized exogenous Wnt5a-induced EMT and invasiveness in pancreatic cancer cells.ConclusionUpregulation of Wnt5a promotes EMT and metastasis in pancreatic cancer models, which involves activation of β-catenin-dependent canonical Wnt signaling. These findings warrant further investigation of the clinical relevance of Wnt5 upregulation in pancreatic cancer.

Aspartate β-hydroxylase expression promotes a malignant pancreatic cellular phenotype

“…The observation that IN/IGF1/IRS1/RAS/RAF/MAPK/ERK, IN/IGF1/IRS1/PI3K/AKT and WNT/β-catenin pathways upregulate ASPH at the transcriptional level and crosstalk with each other [31-33] links these growth factor signaling cascades that are commonly upregulated in PC [34-45] to Notch activation through ASPH. Overexpression of ASPH activates Notch by promoting cleavage of Notch1 ICN to liberate the C-terminal ICN and subsequently upregulates, at the transcriptional level, a number of downstream Notch responsive genes such as HES1, HEY1, CD44, EpCAM, c-Myc, MMP2/9, cyclin D3, and PCNA.…”

An Arntl2-Driven Secretome Enables Lung Adenocarcinoma Metastatic Self-Sufficiency

“…Many of these Arntl2-regulated secreted factors were also more highly expressed in metastasis-derived cells lines than in non-metastatic primary tumor-derived cell lines (Figure 6C). Several of these top secreted factors, including Wnt5a, Il-11, and Cxcl5 have been previously implicated in regulating metastatic ability in lung and other cancer types (Bo et al, 2013; Hanaki et al, 2012; Kang et al, 2013; Weeraratna et al, 2002; Zhou et al, 2014), while others, such as Smoc2, Grem1, and Ltbp2, are relatively poorly characterized in metastasis (Table S2 and Shvab et al, 2015). Arntl2 knock-down did not lead to changes in canonical epithelial genes Cdh1 and Epcam or lung differentiation genes Muc1 and Abca3 consistent with Arntl2 not directly affecting cancer cell differentiation (Table S2).…”

Wnt5a induces ROR1/ROR2 heterooligomerization to enhance leukemia chemotaxis and proliferation

“…Furthermore, studies have demonstrated that isolated overexpression of ROR2 in 293 cells actually enhanced the capacity of Wnt5a to repress expression of β-catenin target genes (28). As such, the capacity of Wnt5a to act as tumor suppressor versus tumor promoter may depend upon the relative expression of ROR2, ROR1, Because of the restricted expression of ROR1, mAbs such as UC-961 may selectively block the activation of Rho GTPases in ROR1-expressing cancers in response to Wnt5a, which also can be found at high levels in other cancers (53,54). Collectively, our studies imply that UC-961 can block ROR1-dependent signaling, providing additional rationale for the clinical evaluation of this antibody in patients with CLL or other cancers that are complemented by ROR1-dependent, noncanonical Wnt5a signaling.…”