SOX9 drives the epithelial–mesenchymal transition in non-small-cell lung cancer through the Wnt/β-catenin pathway

Abstract

Background The distant metastasis of cancer cells is a risk factor for tumor lethality and poor prognosis in non-small-cell lung carcinoma (NSCLC). Increased SOX9 expression has been associated with clinical stage and poor prognosis in NSCLC, but the molecular mechanisms by which SOX9 promotes metastasis in NSCLC are still unknown. Methods The relationship between SOX9 expression and T, N, M classification was assessed using the χ 2 test and Spearman’s analysis in 142 immunohistochemically diagnosed specimens of NSCLC. We also generated SOX9-overexpression and SOX9-knockdown cells lines and their corresponding control cell lines by transfection with lentiviral constructs. In vivo assay, SOX9-overexpressing and SOX9-knockdown NSCLC cells were injected in zebrafish to examine distance metastasis. Gene set enrichment analysis (GSEA) was applied to analysis the correlation between SOX9 overexpression and Wnt/β-catenin pathway. Luciferase assay was used to check transcriptional activity of TCF/LEF and western blot and immunofluorescence was employed to detect β-catenin translocation in SOX9-overexpression, SOX9-knockdown and their corresponding control cell lines. Results We found that SOX9 overexpression correlates with the T, N and M stage significantly ( p = 0.03, 0.000, and 0.032 respectively) in 142 immunohistochemically diagnosed specimens of NSCLC. SOX9 overexpression was found to decrease the expression of the epithelial cell markers E-cadherin and γ-catenin and increase the expression of the mesenchymal cell markers N-cadherin and vimentin. An in vivo assay showed distant metastasis of the SOX9-overexpressing cells, which was not observed in the SOX9-knockdown cells. These findings indicate that SOX9 promotes distant metastasis by promoting EMT in NSCLC cells. GSEA showed that SOX9 overexpression was significantly correlated with the Wnt/β-catenin pathway which was corroborated by the expression of EMT-associated proteins in this pathway and its downstream target genes. SOX9 overexpression was also found to enhance the transcriptional activity of TCF/LEF, promote the nuclear translocation of β-catenin and increase the phosphorylation of GSK3β at Ser9. Further, inhibition of β-catenin suppressed the metastasis-promoting effects of SOX9 overexpression. Conclusions This study is the first to report that SOX9 is associated with clinical TNM stage and indicates that SOX9 promotes migration, invasion and the EMT process through the Wnt/β-catenin pathway.

miR‐145 attenuates cardiac fibrosis through the AKT/GSK‐3β/β‐catenin signaling pathway by directly targeting SOX9 in fibroblasts

“…42,49 Furthermore, most studies showed that βcatenin suppression could inhibit fibrosis. 23,28,46 Based on our results, showing that GSK-3β is regulated and phosphorylated by SOX9 and a recent study demonstrating that β-catenin, a downstream effector of SOX9, drove epithelial to mesenchymal transition in non-smalllung cancer, 25 we next explored the effects of miR-145 and SOX9 on the β-catenin pathway in CFs. We found that SOX9 and β-catenin were elevated in hypoxic CFs, both of which exhibited enhanced nuclear localization.…”

Cancer Stem Cell Transcriptome Landscape Reveals Biomarkers Driving Breast Cancer Heterogeneity

“…Several genes connected with ESR1 have been associated with breast cancer stemness. For example, we previously reported the suppressive role of FOXA1 on breast cancer stemness [17]; SOX9 is as a stem cell factor [18] that drives the epithelial mesenchymal transition (EMT) in non-small cell lung cancer through Wnt pathway [19] and maintains human breast luminal progenitor and breast cancer stem cells through SOX9 mediated signaling [20], and both the SOX9/FXYD3/SRC [21] and the SOX9/SOX2 [20] axes are critical for breast cancer stem cell functionalities; PLA2G7 is associated with ER negativity in clinical breast cancer samples and regulates EMT in vitro [22]. The prognostic values of several markers have been reported, including PTPN6 and KRT19 in breast cancers [23][24][25], EPPK1 in non-small cell lung cancers [26], SERPINB5 in colorectal cancers [27], and NCCRP1 in squamous cell carcinoma [28].…”

Circ_0109046 promotes the malignancy of endometrial carcinoma cells through the microRNA‐105/SOX9/Wnt/β‐catenin axis

“…Increasing evidence has suggested that SOX9 may regulate the Wnt/β-catenin signaling pathway during tumorigenesis. [21][22][23][24] We therefore, detected whether there is a similar regulatory network in EC.…”