Wnt3a Expression Is Associated with Epithelial-Mesenchymal Transition and Impacts Prognosis of Lung Adenocarcinoma Patients

Abstract

Background: Epithelial-mesenchymal transition (EMT) plays an important role in the invasion and migration during cancer metastasis. Wnt3a is one of the ligands in canonical Wnt/β-catenin signaling pathway, which contributes to the carcinogenesis and progression of lung cancer cell lines. The aim of this study was to evaluate the association between Wnt3a and EMT-related proteins (E-cadherin and N-cadherin), and to further investigate its impact on prognosis of lung adenocarcinoma patients.Methods: A total of 147 lung adenocarcinoma patients were included and their clinicopathological characteristics were collected in this retrospective study. The expression levels of Wnt3a, E-cadherin and N-cadherin in post-surgery cancerous and adjacent normal tissues were assessed by immunohistochemistry. The association between Wnt3a and EMT-related proteins and their prognostic values were systematically evaluated. HCC827 and PC9 cell lines were treated with Wnt3a to detect the expression of EMT-related and Wnt/β-catenin signaling-associated proteins, as well as the in vitro migration and invasion abilities.Results: High Wnt3a expression level was significantly associated with low E-cadherin (P<0.001) and high N-cadherin (P<0.001) expression levels in lung adenocarcinoma tissues. Besides, high Wnt3a level predicted poorer lung adenocarcinoma survival by univariate Cox analysis (P=0.001), while the multivariate result was not significant (P=0.355). Subgroup analysis suggested that the prognostic value of Wnt3a expression level was significant in stage T1-T2 (log rank P=0.003) and stage N0 (log rank P=0.031) patients. The multivariate Cox analysis suggested N-cadherin was an independent prognostic factor for lung adenocarcinoma patients (P=0.012). After including these markers into a nomogram, the Harrell's C-index of the nomogram was 0.755. The decision-curve analysis of our nomogram performed net benefit at the threshold probability from 21.6% to 82.0%, and the current model had a better prognostic value than TNM-classification with a lower Akaike information criterion (AIC) value of 166.54. In vitro experiments suggested that Wnt3a could regulate EMT-related proteins and promotes in vitro invasion and migration abilities.Conclusions: Wnt3a could regulate EMT-related proteins and promote the migration and invasion process of lung adenocarcinoma. Although its value as an independent prognostic factor was limited, the combined model suggested good prognostic performance for lung adenocarcinoma patients.

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.…”

PITX2 enhances progression of lung adenocarcinoma by transcriptionally regulating WNT3A and activating Wnt/β-catenin signaling pathway

“…As an important member of WNT gene family, WNT3A enhances β-catenin-dependent transcription through GSK3β inhibition or direct β-catenin phosphorylation at Ser 552 [67]. WNT3A has been reported to promote the migration and invasion process of LUAD and impact prognosis of LUAD patients [41]. And our results suggested that PITX2 directly bound to the promoter region of WNT3A and enhanced its transcription.…”

“…4a). WNT3A, one of the most important ligands in canonical Wnt/β-catenin signaling pathway, has been well established in the progression of LUAD [39][40][41]. Predicted by hTFtarget website, PITX2 potentially targets the promoter region (1092-1101 bp) of WNT3A (Fig.…”

Wnt3a promotes radioresistance via autophagy in squamous cell carcinoma of the head and neck

“…The Wnt ligands, of which there are more than 19 closely related but distinct secreted cysteine‐rich glycoproteins, have been characterized according to their roles in early development and tumourigenesis . Wnt3a, a canonical Wnt ligand, is elevated in hepatocellular carcinoma, prostate cancer, oesophageal squamous cell carcinoma, lung adenocarcinoma and colon or colorectal carcinoma . Moreover, increased Wnt3a protein levels are tightly associated with multiple aggressive cancer phenotypes, such as metastasis, advanced clinical stages and worse patient survival status, revealing that Wnt3a is a valuable prognostic biomarker in human malignancy.…”