Expression of Wnt3a in hepatocellular carcinoma and its effects on cell cycle and metastasis

Abstract

Invasion and metastasis are the primary causes of mortality from hepatocellular carcinoma (HCC). Effective inhibition against participants in the tumourigenesis and metastasis process is critical for treatment of HCC. Wnt3a is involved in the development and metastasis of many malignant tumours. However, the specific mechanisms of Wnt3a-mediated cell proliferation, invasion and metastasis in HCC remain unclear. In this study, we found that Wnt3a and its target gene c-Myc showed higher expression in tumour tissues than normal liver tissues in HCC patients; 71.8% of the cases studied had high Wnt3a and c-Myc expression levels (n=32); Wnt3a expression positively correlated with its target genes MMP-7 and c-Myc. Intriguingly, the expression of Wnt3a, MMP-7 and c-Myc is significantly correlated with Notch3 and Hes1 expression. In vitro experiments showed that Wnt3a was highly expressed in MHcc97H and SK-Hep-1 cells. Therefore, Wnt3a expression was silenced with siRNA, and then, MTT, flow cytometry, wound healing and Transwell assays were performed to analyse cell proliferation, cycle, migration and invasion. The results demonstrated that downregulation of Wnt3a expression inhibited cell viability and induced G0/G1 cell cycle arrest via decreased expression of cyclin D1 and c-Myc and increased expression of p21 and p27. In addition, deletion of Wnt3a significantly inhibited migration and invasion by downregulating MMP-2/-7/-9 expression via the MAPK (p38, ERK1/2 and JNK) pathway. In conclusion, our data show that Wnt3a is involved in HCC development. Wnt3a may be an effective target for treatment of HCC.

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 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.…”

“…(E) Immunohistochemistry staining was used to examine the expression of Wnt3a and Beclin1. *P < 0.05; **P < 0.01; ***P < 0.001Additionally, the Wnt/β-catenin pathway participates in cancer malignant behaviours by interacting with other signalling pathways including Notch1/3,31,32 Hippo,33 nuclear factor-κB,4 and extracellular signal-regulated kinase 1/2, 34 all of which were reported to have dual effects on autophagy. Finally, even the basic expression level of β-catenin is associated with a favourable or unfavourable prognosis in several solid cancers,35 suggesting that canonical βcatenin can act as an oncogene or cancer suppressor depending on the cancer type.…”

Oncogenic Wnt3a: a promising specific biomarker in hepatocellular carcinoma

“…Intriguingly, their expressions are significantly correlated with Notch3 and Hes1 expression. Wnt3a was highly expressed in MHcc97H and SK Hep 1 cells in vitro [61] , as an important regulator of human HCC cell line growth, which could induce activation of the canonical Wnt pathway after binding with SULF2 and GPC-3. Also, it could increase cell proliferation in nude mouse xenografts in vivo [60,61] .…”