Migration and invasion of oral squamous carcinoma cells is promoted by WNT5A, a regulator of cancer progression

Abstract

BACKGROUND: Oral squamous cell carcinoma (OSCC) constitutes 90% of all cancers in the oral cavity, and the prognosis for patients diagnosed with OSCC is still poor. The identification of novel therapeutic targets and prognostic markers for OSCC is therefore essential. Previous studies of OSCC revealed an increased expression of WNT5A in the tumor tissue. However, no functional studies of WNT5A-induced effects in OSCC have been performed. METHODS: Two different OSCC cell lines were used for analysis of WNT5A expression by Western blot, whereas WNT5A-induced responses were analyzed by measuring calcium (Ca 2+ ) signaling, PKC activation, migration and invasion. RESULTS: Despite the lack of WNT5A expression, both cell lines responded to recombinant WNT5A (rWNT5A) with activation of the non-canonical WNT/Ca 2+ /PKC pathway. This effect was ascertained to be mediated by WNT5A by use of the WNT5A antagonist, Box5. To investigate how WNT5A affects tumor progression, rWNT5A-induced alterations in BrdU absorbance (reflecting the number of tumor cells) were analyzed. rWNT5A had no effect on BrdU absorbance but instead promoted tumor cell migration and invasion. These results were confirmed by the use of the WNT5A-mimicking peptide Foxy5, while the rWNT5A-induced migration was blocked by secreted Frizzled-related protein 1 (SFRP1), protein kinase C inhibitors or the intracellular Ca 2+ chelator, MAPT. CONCLUSIONS: These novel data clearly show that WNT5A activates the non-canonical WNT/Ca 2+ /PKC pathway and increases migration and invasion of OSCC cells. This may indicate how an increased WNT5A expression in the tumor tissue is likely to promote progression of OSCC.

Wnt5a Increases Properties of Lung Cancer Stem Cells and Resistance to Cisplatin through Activation of Wnt5a/PKC Signaling Pathway

“…Such a Wnt5a/PKC-promoted EMT was also found in epithelial ovarian cancer [18] and oral squamous cell carcinoma (OSCC) [20]. In the epithelial ovarian cancer, an increased expression of Wnt5a and PKC α was significantly correlated with metastasis of the disease, and the PKC α inhibitor could reduce the metastatic capacity [18]; in OSCC, Wnt5a was found to promote the migration and invasion of cancer cells through activation of noncanonical Wnt/Calcium/PKC pathway [20].…”

“…Such a Wnt5a/PKC-promoted EMT was also found in epithelial ovarian cancer [18] and oral squamous cell carcinoma (OSCC) [20]. In the epithelial ovarian cancer, an increased expression of Wnt5a and PKC α was significantly correlated with metastasis of the disease, and the PKC α inhibitor could reduce the metastatic capacity [18]; in OSCC, Wnt5a was found to promote the migration and invasion of cancer cells through activation of noncanonical Wnt/Calcium/PKC pathway [20]. In addition, a recent high-throughput gene expression profiling further revealed that Wnt5a signaling was upregulated in highly metastatic nasopharyngeal carcinoma (NPC) cells and tissues, in which Wnt5a was able to activate PKC signaling and form a positive Wnt5a and phosphorylated PKC loop to promote the stemness characteristics of NPC cells, leading to an enhanced metastatic features and tumorigenicity in vitro and in vivo [21].…”

“…However, more lines of study suggested that activation of noncanonical Wnt signaling, such as the Wnt5a-mediated signaling, was aberrantly enhanced in many epithelial cancers, including the lung cancer [15], breast cancer [16], ovarian cancer [17, 18], and gastric cancer [19]. With respect to Wnt5a signaling, it has been demonstrated to promote cancer cell migration and invasion [20], epithelial-mesenchymal transition (EMT) [18], and metastasis [17, 21, 22], as well as enhance the stemness of cancer stem cells (CSCs) and chemoresistances [21]. With respect to the chemoresistance, Wnt5a has been suggested as a biomarker of poor clinical outcome of patients with ovarian cancer and a mediator of chemoresistance [17].…”

Frizzled2 mediates the migration and invasion of human oral squamous cell carcinoma cells through the regulation of the signal transducer and activator of transcription-3 signaling pathway

“…Since Fzd2 is frequently overexpressed in head and neck SCC cancer cell lines as compared with normal bronchial epithelial cells or primary oral squamous epithelial cells (16), it is likely that the aberrant overexpression of Fzd2 contributes to OSCC carcinogenesis. Notably, Prgomet et al have found that the ectopic expression of Wnt5a, a ligand for Fzd2, promotes OSCC cell migration and invasion (17). However their study did not elucidate whether Fzd2 also participated in OSCC aggressiveness.…”

WNT Signaling in Cutaneous Squamous Cell Carcinoma: A Future Treatment Strategy?

“…However a WNT5A-derived hexapeptide, termed Box5, 12 developed to inhibit WNT/Ca 2+ signaling in melanoma (Jenei, et al 2009), has recently been shown to antagonise WNT5A/Ca 2+ signaling in HNSCC (Prgomet, et al 2015). Future efforts should be focused on identifying which WNT network inhibitors could provide potent therapeutic activity in cSCC.…”