xav939 and Neoplasm-Metastasis

The Wnt/β-catenin pathway plays vital roles in diverse biological processes, including cell differentiation, proliferation, migration, and insulin sensitivity. A recent study reported that the DNA-binding transcriptional factor SIX3 is essential during embryonic development in vertebrates and capable of downregulating target genes of the Wnt/β-catenin pathway in lung cancer, indicating negative regulation of Wnt/β-catenin activation. However, regulation of the SIX3-Wnt/β-catenin pathway axis remains unknown. We measured the expression of TRIM27 and SIX3 as well as investigated whether there was a correlation between them in lung cancer tissue samples. Herein, we found that the E3 ubiquitin ligase, TRIM27, ubiquitinates, and degrades SIX3. TRIM27 induces non-small cell lung cancer (NSCLC) cell proliferation and metastasis, and the expression of β-catenin, S100P, TGFB3, and MMP-9 were significantly inhibited by SIX3. Furthermore, XAV939 is a selective β-catenin-mediated transcription inhibitor that inhibited TRIM27- and SIX3-mediated NSCLC cell proliferation, migration, and invasion. Clinically, lung tissue samples of cancer patients showed increased TRIM27 expression and decreased SIX3 expression. Taken together, these data demonstrate that TRIM27 acts as an oncogene regulating cell proliferation and metastasis in NSCLC through SIX3-β-catenin signaling.

Topics: A549 Cells; beta Catenin; Calcium-Binding Proteins; Carcinoma, Non-Small-Cell Lung; Cell Movement; Cell Proliferation; DNA-Binding Proteins; Eye Proteins; Female; Heterocyclic Compounds, 3-Ring; Homeobox Protein SIX3; Homeodomain Proteins; Humans; Lung Neoplasms; Male; Matrix Metalloproteinase 9; Middle Aged; Neoplasm Metastasis; Neoplasm Proteins; Nerve Tissue Proteins; Nuclear Proteins; Oncogenes; Signal Transduction; Transforming Growth Factor beta3; Ubiquitination

Triple-negative breast cancer (TNBC) accounts for 15% of overall breast cancer. A lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2 receptor) makes TNBC more aggressive and metastatic. Wnt signaling is one of the important pathways in the cellular process; in TNBC it is aberrantly regulated, which leads to the progression and metastasis. In this study, we designed a therapeutic strategy using a combination of a low dose of paclitaxel and a Wnt signaling inhibitor (XAV939), and examined the effect of the paclitaxel-combined XAV939 treatment on diverse breast cancer lines including TNBC cell lines (MDA-MB-231, MDA-MB-468, and BT549) and ER+ve cell lines (MCF-7 and T-47D). The combination treatment of paclitaxel (20 nM) and XAV939 (10 µM) exerted a comparable therapeutic effect on MDA-MB-231, MDA-MB-468, BT549, MCF-7, and T-47D cell lines, relative to paclitaxel with a high dose (200 nM). The paclitaxel-combined XAV939 treatment induced apoptosis by suppressing Bcl-2 and by increasing the cleavage of caspases-3 and PARP. In addition, the in vivo results of the paclitaxel-combined XAV939 treatment in a mice model with the MDA-MB-231 xenograft further confirmed its therapeutic effect. Furthermore, the paclitaxel-combined XAV939 treatment reduced the expression of β-catenin, a key molecule in the Wnt pathway, which led to suppression of the expression of epithelial-mesenchymal transition (EMT) markers and angiogenic proteins both at mRNA and protein levels. The expression level of E-cadherin was raised, which potentially indicates the inhibition of EMT. Importantly, the breast tumor induced by pristane was significantly reduced by the paclitaxel-combined XAV939 treatment. Overall, the paclitaxel-combined XAV939 regimen was found to induce apoptosis and to inhibit Wnt signaling, resulting in the suppression of EMT and angiogenesis. For the first time, we report that our combination approach using a low dose of paclitaxel and XAV939 could be conducive to treating TNBC and an external carcinogen-induced breast cancer.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinogenesis; Cell Line, Tumor; Cell Movement; Epithelial-Mesenchymal Transition; Female; Heterocyclic Compounds, 3-Ring; Humans; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Neovascularization, Pathologic; Paclitaxel; Triple Negative Breast Neoplasms; Wnt Signaling Pathway

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.. 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.. 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.

Topics: Animals; beta Catenin; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Movement; Cell Nucleus; Epithelial-Mesenchymal Transition; Heterocyclic Compounds, 3-Ring; Humans; Lung Neoplasms; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Staging; SOX9 Transcription Factor; Wnt Signaling Pathway; Zebrafish

Gastric cancer (GC) is one of the most common malignant tumors of the digestive system. The etiology of GC is complex, and much more attention should be paid to genetic factors. In this study, we explored the role and function of LINC00052 in GC. We applied qRT-PCR and Northern blot to detect the expression of LINC00052 and found it was highly expressed during GC. We also investigated the effects of LINC00052 on tumor prognosis and progression and found that LINC00052 indicated poor prognosis and tumor progression. By performing MTT, colony formation, and Transwell assays, we found that LINC00052 promoted MGC-803 cell proliferation and metastasis. Pull-down and RIP assays showed that LINC00052 could interact with β-catenin and methyltransferase SMYD2, and immunoprecipitation detection showed that LINC00052 promoted β-catenin methylation to maintain its stability, so as to activate the Wnt/β-catenin pathway. Furthermore, XAV939 (inhibitor of β-catenin) was used to treat MGC-803 cells, and we found that LINC00052 promoted proliferation and metastasis, possibly by activation of the Wnt/β-catenin pathway. In conclusion, our research demonstrated a carcinogenic role for LINC000052 in GC, which may represent a new approach for the prevention and therapy of this cancer.

Topics: Adult; beta Catenin; Cell Line, Tumor; Cell Proliferation; Disease Progression; Female; Heterocyclic Compounds, 3-Ring; Humans; Male; Middle Aged; Neoplasm Metastasis; Prognosis; RNA, Long Noncoding; Stomach Neoplasms; Survival Rate; Transfection; Wnt Signaling Pathway