The role of WNT5A in oral squamous cell carcinoma

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The role of WNT5A in oral squamous cell carcinoma


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Publication Doctoral Thesis
Title The role of WNT5A in oral squamous cell carcinoma
Author Prgomet, Zdenka
Date 2017
English abstract
Cancer is one of the leading causes of death worldwide and further research into the cancer biology is required to improve treatment and survival. Cancer can start in all sites of the body and is characterized by uncontrolled cell growth and capability of invading surrounding tissue and spreading to other sites of the body. The most common type of cancer occurring in the oral cavity is oral squamous cell carcinoma (OSCC). Tobacco, including the betel quid and other types of smokeless tobacco, is the main risk factor for development of OSCC. Even though therapeutic treatment of OSCC has been improved, the prognosis is still poor, and the 5-year survival remains around 50%. The ongoing research have shown that proteins involved in signaling pathways play an important role in the progression of cancer, however, no reliable biomarkers have yet been identified as predictors of OSCC progression. Over the past years, a protein named WNT5A, has been shown to be involved in different types of cancer, either by promoting or suppressing cancer progression. However, its role in OSCC is still ambiguous. This thesis aimed to provide an insight into the role of WNT5A signaling in OSCC. We started by investigating the functional role of WNT5A in OSCC cells. Due to the lack of the endogenous WNT5A expression, we treated the cells with recombinant WNT5A (rWNT5A) and observed activation of the non-canonical WNT/Ca2+/PKC signaling in OSCC cells. This rWNT5A-induced signaling enhanced migration and invasion of OSCC cells, which was ascertained by different WNT5A inhibitors. These inhibitors eliminated the rWNT5A-induced WNT/Ca2+/PKC signaling and migration of OSCC cells indicating a promoting role of WNT5A in OSCC cells. Before investigating the expression of WNT5A in human OSCC tissues, we evaluated four commercially available WNT5A antibodies for use in immunohistochemistry (IHC) and western blot analysis (WB). Cytoplasmic WNT5A immunostaining pattern was observed with all four antibodies but only the polyclonal AF645 antibody was able to detect WNT5A protein in WNT5A-positive cell lysates. Preabsorption tests revealed that the polyclonal AF645 antibody is the best antibody for detection of WNT5A by WB while the monoclonal 3A4 antibody is the most suitable for use in IHC. Using the monoclonal 3A4 antibody, we investigated the expression of WNT5A in human OSCC tissues. No expression of WNT5A was observed in normal oral epithelium or in mild grade of dysplasia. However, cytoplasmic WNT5A immunostaining was found in 38% of dysplastic tissues and in 81% of the OSCCs. We also noticed that WNT5A was more expressed in advanced OSCCs than in early invasive OSCCs. Furthermore, we did not observe any correlation between expression of WNT5A and two adhesion-proteins, β-catenin and E-cadherin, either in OSCC tissues or in OSCC cells. These findings suggest that WNT5A does not affect the canonical WNT/ β-catenin pathway or downregulation of E-cadherin in OSCC. At last, we investigated if the rWNT5A-induced WNT/Ca2+/PKC signaling affected secretion and activation of matrix metalloproteinases (MMPs) in OSCC cells. We found that rWNT5A-induced activation of MMP2 is not dependent on activation of either β-catenin, ERK1/2, or p38-MAPK, but could instead be induced by WNT5A/Ca2+/PKC pathway. In conclusion, these findings suggest that WNT5A acts as a cancer promoter in OSCC by facilitating cell migration and invasion via the WNT5A/Ca2+/PKC signaling and activation of MMP2.
Publisher Malmö university, Faculty of Odontology
Series/Issue Doctoral dissertation in odontology
ISBN 978-91-7104-754-0
Pages 99
Language eng (iso)
Subject Medicine
Research Subject Categories::ODONTOLOGY
Included papers
  1. I. Migration and invasion of oral squamous carcinoma cells is promoted by WNT5A, a regulator of cancer progression Prgomet Z., Axelsson L., Lindberg P., Andersson T. J Oral Pathol Med. 2015 Nov; 44 (10) 776-84.

  2. II. Optimization, validation and identification of two reliable antibodies for immunodetection of WNT5A Prgomet Z., Andersson T., Lindberg P. Biotech & Histochem. In press. DOI: 10.1080/10520295.2016.1255995

  3. III. Higher expression of WNT5A protein in oral squamous cell carcinoma compared to normal oral epithelium and dysplasia. Prgomet Z., Andersson T., Lindberg P. Submitted to European Journal of Oral Sciences.

  4. IV. WNT5A activates MMP2 in oral squamous cell carcinoma. Prgomet Z., Andersson T., Lindberg P. In manuscript.

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