Wnt3a expression is associated with epithelial-mesenchymal transition and promotes colon cancer progression

Abstract

IntroductionEpithelial–mesenchymal transition (EMT) contributes to the progression and metastasis of cancer cells and is associated with a more invasive phenotype of cancer. The Wnt/β-catenin signaling pathway is one of the major pathways involved in EMT regulation. Many studies provide evidence that β-catenin, the key regulator of the canonical Wnt signaling pathway, is important in regulating EMT in cancer. However, the roles of Wnt3a, the representative canonical Wnt ligand, in EMT and colon cancer progression have not yet been fully explored.MethodsThe expression levels of Wnt3a and EMT-associated proteins (E-cadherin, vimentin, and β-catenin) were assessed by immunohistochemistry in human colon cancer tissues to evaluate the clinicopathological significance of Wnt3a, as well as the correlation between Wnt3a and EMT. We then upregulated Wnt3a expression in HCT116 colon cancer cells, established a nude mouse xenograft model, detected the expression of EMT and Wnt/β-catenin signaling-associated proteins, and observed invasion and clone-initiating abilities.ResultsIn 203 human colon cancer tissue samples, Wnt3a protein overexpression was related to colon cancer histological differentiation (P = 0.004), clinical stage (P = 0.008), presence of metastasis and recurrence (P = 0.036), and survival time (P = 0.007) of colon cancer patients. Wnt3a expression was notably concomitant with EMT immunohistochemical features, such as reduced expression of the epithelial marker E-cadherin (P = 0.012), increased expression of the mesenchymal marker vimentin (P = 0.002), and cytoplasmic distribution of β-catenin (P = 0.021). Results of in vitro and in vivo experiments showed that Wnt3a overexpression could alter cell morphology, regulate EMT-associated protein expression, and enhance clone-initiation and invasion. Dkk1 (antagonist of Wnt/β-catenin signaling) could also partially reverse the expression of EMT-associated proteins in Wnt3a-overexpressing cells.ConclusionsWnt3a expression was associated with EMT and promoted colon cancer progression. The EMT-inducing effect was partially due to the stimulative effect of Wnt3a on the Wnt/β-catenin pathway.

Wnt3a protein overexpression predicts worse overall survival in laryngeal squamous cell carcinoma

“…In fact, metastasis was deemed as an essential factor to estimate clinical stages, and it was also prone to occur in less-differentiated malignancies. This result is consistent with those of previous studies investigating colorectal cancer [20,34], hepatocellular carcinoma [25,26], lung cancer [21], and melanoma [28], in which overexpression of Wnt3a could significantly enhance the invasion and migration potential of tumor cells by inducing epithelial-to-mesenchymal transition (EMT) and the metastasis-related protein matrix metalloproteinases (MMP)-2, -7, and -9. In addition, Wnt3a has been reported to be involved in the induction of CSC characteristics both in vitro and in vivo [16,35].…”

“…As previously reported, the aberrant expression of Wnt3a was also found in several human malignancies, including glioblastoma [16,17], mammary adenocarcinoma [18,19], colon carcinoma [20], lung cancer [21], prostate cancer [22], malignant mesothelioma [23], esophageal squamous cell carcinoma [24], hepatocellular carcinoma [25][26][27], and melanoma [28]. In these malignant tumors, Wnt3a expression is closely related to tumor growth, metastasis, chemo-/ radio-resistance and maintenance of CSC characteristics.…”

Wnt3a and wnt5a as Potential Chondrogenic Stimulators for Nucleus Pulposus Cell Induction: A Comprehensive Review

“…83 Similarly, wnt3a has been associated with the progression of a variety of tumors. 84 On the contrary, wnt3a and wnt5a influence on chondrocytes presents a more apparent effect. Chondrocytes resemble NP cells, as both reside in avascular tissues of which the function is to distribute and transfer biomechanical pressure, 85 appointing chondrocytes as a potential alternative to NP cells.…”

Role of Wnt/β-Catenin Signaling in the Chemoresistance Modulation of Colorectal Cancer

“…CRC metastasis could be also promoted by inducing EMT through a β-catenin-dependent pathway [72]. Another study by Qi et al [73] demonstrated that Wnt3a overexpression leads to the distribution of cytosolic β-catenin, downregulation of epithelial markers, and overexpression of mesenchymal markers, in both cellular and animal models of colorectal cancer. Collectively, Wnt/β-catenin signaling may modulate the chemosensitivity of CRC through EMT.…”