Abstract
BackgroundWingless and Int-related protein (Wnt) ligands are aberrantly expressed in patients with colorectal cancer (CRC). However, the aberrant level of Wnt ligands in serum have not been explored. Here, we aimed to identify the levels of WNT4 in serum and explored its oncogenic role in CRC.MethodsThe Oncomine database was used to analyze the relationship between WNT4 and the prognosis of CRC. ELISA was performed to measure WNT4 levels in serum and conditioned medium from fresh CRC tissues and adjacent normal tissues. Western blot and immunohistochemistry were carried out to measure the expression of WNT4 in human CRC tissues and adjacent normal tissues. The migration and invasion of CRC cells were determined by trans-well assay, and the effects of WNT4 on CRC invasion and metastasis in vivo were verified by tumor xenograft in nude mice. Cancer-associated fibroblasts (CAFs) and angiogenesis in subcutaneous nodules were detected by immunofluorescence (IF). In addition, the suspended spheres formation and tube formation assay were performed to explore the effects of WNT4 on CAFs and angiogenesis respectively.ResultsWNT4 was significantly upregulated in serum of CRC patients, and CRC tissues were identified as an important source of elevated WNT4 levels in CRC patients. Interestingly, elevated levels of WNT4 in serum were downregulated after tumor resection. Furthermore, we found that WNT4 contributed to epithelial-to-mesenchymal transition (EMT) and activated fibroblasts by activating the WNT4/β-catenin pathway in vitro and in vivo. Moreover, angiogenesis was induced via the WNT4/β-catenin/Ang2 pathway. Those effects could be reversed by ICG-001, a β-catenin/TCF inhibitor.ConclusionOur findings indicated that serum levels of WNT4 may be a potential biomarker for CRC. WNT4 secreted by colorectal cancer tissues promote the progression of CRC by inducing EMT, activate fibroblasts and promote angiogenesis through the canonical Wnt/β-catenin signalling pathway.
Highlights
Wingless and Int-related protein (Wnt) ligands are aberrantly expressed in patients with colorectal cancer (CRC)
WNT4 secreted by colorectal cancer tissues promote the progression of CRC by inducing epithelial-to-mesenchymal transition (EMT), activate fibroblasts and promote angiogenesis through the canonical Wnt/β-catenin signalling pathway
WNT4 was upregulated in serum and cancer tissues of CRC patients We first analyzed the expression of WNT4 in CRC tissues and normal tissues from the Oncomine database
Summary
Wingless and Int-related protein (Wnt) ligands are aberrantly expressed in patients with colorectal cancer (CRC). The aberrant level of Wnt ligands in serum have not been explored. We aimed to identify the levels of WNT4 in serum and explored its oncogenic role in CRC. Nowadays, increased attention has been paid to the research of biomarkers for diseases, which could be used for early diagnosis and predict cancer outcome [4]. Measuring biomarkers in blood offers a simple and effective way for disease diagnosis [5]. Among nineteen identified Wingless and Int-related protein (WNT) ligands, WNT4 is highly secretory and its secretion has been reported in wound healing, acute kidney injury, and angiogenesis [6]. We aimed to study WNT4 levels in serum, and explored its oncogenic role in CRC
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