Emerging evidence has established that CXCL14 is important for cell growth, invasion, metastasis, and chemoresistance in multiple cancers [20]. Although it has been reported that upregulated CXCL14 expression promotes OC proliferation, little is known about its biological role in the various pathological processes of OC, including EMT and invasion [14]. Herein, we demonstrated that the CXCL14 level was elevated in carcinoma tissues as compared with para-cancerous tissues. Importantly, high CXCL14 expression is associated with metastasis and poor prognosis. Next, our results indicated that CXCL14 knockdown suppressed OC cell growth, colony formation, and invasion, whereas CXCL14 overexpression produced the opposite results. Further analyses revealed that the canonical Wnt/β-catenin signaling is required for CXCL14-mediated OC cell growth and invasion.
Cancer metastasis is a complicated process, and cancer cells need to acquire metastatic characteristics, such as decreased adhesiveness and increased migration and invasive ability, to escape the confines of the primary tumor site and establish distant metastases [21]. In addition to generating cancer stem cells and resulting in treatment resistance, EMT is considered to be necessary in the initial events of the metastasis cascade by conferring an aggressive phenotype [22]. Thus, the reversal of cancer cell EMT represents a considerable potential therapeutic option for patients with OC.
Importantly, Wnt/β-catenin signaling was involved in the CXCL14-induced EMT process. First, the present findings revealed that reduced CXCL14 expression obstructed EMT, whereas upregulation of CXCL14 contributed to EMT, thus indicating that CXCL14 acts as a crucial regulatory factor of EMT in OC cells. Moreover, β-catenin is a vital element in the Wnt signaling pathway, and β-catenin facilitates the transcriptional activation of EMT-associated genes, including cyclin D1, MMP-7, and Axin2. Additionally, CXCL14 knockdown in SKOV3 cells lowered the expression of Wnt/β-catenin-associated genes, whereas CXCL14 overexpression in OVCAR3 cells augmented their expression. To verify whether CXCL14 triggers OC cell growth and EMT via the Wnt/β-catenin signaling pathway, OC cells were treated with XAV939. Intriguingly, inhibition of Wnt/β-catenin signaling attenuated CXCL14-induced OC cell EMT, as well as cell growth and invasion. Thus, our data suggest that Wnt/β-catenin signaling is necessary for CXCL14-facilitated OC cell growth and invasion.
In tumor tissue cells, owing to various factors, the activation of signal transducer and activator of transcription 3 (STAT3) appears to be in a persistently and abnormally high expression state, which leads to abnormal proliferation of malignant tumor cells. Previous studies have shown that overexpression of CXCL14 increases the phosphorylation level of STAT3 in OC cells, thereby promoting the activation of the STAT3 signaling pathway [14]. Moreover, it is indicated that STAT3 phosphorylation is involved in EMT and tumor metastasis. Specifically, several molecules have been demonstrated to promote tumor metastasis by activating the STAT3 signaling pathway [23, 24]. Accordingly, suppression of STAT3 phosphorylation downregulated the expression of mesenchymal markers (N-cadherin, Snail, and MMP-9) and increased the levels of the epithelial marker, E-cadherin [25]. However, additional investigations are required to identify whether STAT3 is involved in the CXCL14-facilitated OC cell invasion and EMT processes.
It is well recognized that nuclear β-catenin is associated with transcription factor 4 (TCF4) to activate target gene transcription [26]. The key molecular events in Wnt signaling are nuclear β-catenin accumulation and β-catenin/TCF4 complex transcriptional activity [27]. Nuclear β-catenin binds to members of the TCF/LEF family of transcription factors, including Twist and Snail1/2, to trigger EMT [28, 29]. Although β-catenin serves as a downstream effector in CXCL14-induced OC cell growth and invasion, it deserves further exploration of the complex interaction of β-catenin and CXCL14. To gain more insights into CXCL14-induced β-catenin transcriptional activity, the physical interaction between CXCL14 and β-catenin may be worth exploring in future studies.