ING5 inhibits cell proliferation and invasion in esophageal squamous cell carcinoma through regulation of the Akt/NF-κB/MMP-9 signaling pathway.

The inhibitor of growth 5 (ING5) is a new candidate tumor suppressor gene (TSG) of the ING family. So far, there have been many reports about its functions related to cancer development. However, the biological roles of ING5 in esophageal squamous cell carcinoma (ESCC) remain unclear. In the present study, we demonstrated that ING5 was lowly expressed in ESCC tissues and cell lines. Overexpression of ING5 inhibited ESCC cell proliferation and invasion in vitro as well as suppressed tumor growth and metastasis in vivo. We also found that overexpression of ING5 significantly decreased the levels of p-AKT, NF-κB and MMP-9 in ECA109 cells. Taken together, these findings demonstrated that ING5 inhibited cell proliferation and invasion in ESCC through regulation of the Akt/NF-κB/MMP-9 signaling pathway. Thus, ING5 might be considered a promising target for ESCC treatment.

Zhang GJ ，Zhao J ，Jiang ML ，Zhang LC ... -  《-》

Catalytically defective receptor protein tyrosine kinase PTK7 enhances invasive phenotype by inducing MMP-9 through activation of AP-1 and NF-κB in esophageal squamous cell carcinoma cells.

Shin WS ，Hong Y ，Lee HW ，Lee ST ... -  《Oncotarget》

BRCA1-Associated Protein Increases Invasiveness of Esophageal Squamous Cell Carcinoma.

We performed a screen for genes whose expression correlates with invasiveness of esophageal squamous cell carcinoma (ESCC) cells. We studied the effects of overexpression and knockdown of these genes in cell lines and expression levels in patient samples. We selected genes for analysis from 11 loci associated with risk of ESCC. We analyzed the effects of knocking down expression of 47 of these genes using RNA interference on-chip analysis in ESCC cells and HeLa cells. Cells with gene overexpression and knockdown were analyzed in migration and invasion assays or injected into nude mice and metastasis of xenograft tumors was quantified. We collected ESCC and non-tumor esophageal tissues from 94 individuals who underwent surgery in China from 2010 and 2014; clinical information was collected and survival time was measured from the date of diagnosis to the date of last follow-up or death. Levels of messenger RNAs (mRNAs) were quantified by RNA sequencing, and levels of proteins were determined from immunoblot analyses. Patient survival was compared with mRNA levels using Kaplan-Meier methods and hazard ratios were calculated by Cox models. We identified 8 genes whose disruption increased migration and 10 genes whose disruption reduced migration. Knockdown of BRCA1-associated protein gene (BRAP) significantly reduced migration of KYSE30, KYSE150, and HeLa cells. In patient tumors, 90% of ESCCs examined had higher levels of BRAP protein than paired non-tumor tissues, and 63.8% had gains in BRAP DNA copy number. Levels of BRAP mRNA in ESCC tissues correlated with patient survival time, and high expression increased risk of death 2.4-fold compared with low expression. ESCCs that had metastasized to lymph node had significantly higher levels of BRAP mRNA than tumors without metastases. Knockdown of BRAP in ESCC and HeLa cell lines significantly reduced migration and invasiveness; these cell lines formed less metastases in mice than control cells. Nuclear translocation of the nuclear factor-κB (NF-κB) P65 subunit and phosphorylation of inhibitor of NF-κB kinase subunit β (IKBKB or IKKβ) increased in cells that overexpressed BRAP and decreased in cells with BRAP knockdown. In immunoprecipitation assays, BRAP interacted directly with IKKβ. Expression of matrix metalloproteinase 9 and vascular epithelial growth factor C, which are regulated by NF-κB, was significantly reduced in cells with knockdown of BRAP and significantly increased in cells that overexpressed BRAP. Expression of BRAP is increased in ESCC samples compared with non-tumor esophageal tissues; increased expression correlates with reduced patient survival time and promotes metastasis of xenograft tumors in mice. BRAP overexpression leads to increased activity of NF-κB and expression of matrix metalloproteinase 9 and vascular epithelial growth factor C.

Zhao Y ，Wei L ，Shao M ，Huang X ，Chang J ，Zheng J ，Chu J ，Cui Q ，Peng L ，Luo Y ，Tan W ，Tan W ，Lin D ，Wu C ... -  《-》

Aurora-A modulates MMP-2 expression via AKT/NF-κB pathway in esophageal squamous cell carcinoma cells.

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies. It is necessary to identify new markers for predicting tumor progression and therapeutic molecular targets. It has been reported that overexpressions of Aurora-A and matrix metalloproteinases 2 (MMP-2) may promote the malignant development of tumor. However, the relationship between Aurora-A and MMP-2 expression in tumor patients has not been investigated. In addition, the underlying mechanisms that Aurora-A regulates MMP-2 expression are still not fully elucidated. In this study, we demonstrated that Aurora-A and MMP-2 were overexpressed in ESCC tissues compared with paired normal adjacent tissues (P < 0.0001). Overexpression of Aurora-A was associated with the lymph node metastasis of ESCC (P = 0.01). Significantly, Aurora-A protein expression was positively correlated with MMP-2 protein expression in ESCC tissues (r = 0.66, P < 0.0001) as well as in ESCC cell lines. The level of Aurora-A expression was also positively correlated with the invasion capability of ESCC cells. Furthermore, Aurora-A overexpression significantly increased ESCC cell invasion by the upregulation of MMP-2 expression. In addition, Aurora-A overexpression promoted nuclear factor-kappaB (NF-κB) activation, and Aurora-A-mediated MMP-2 upregulation was abrogated by NF-κB inhibitor. Further analysis showed that activation of NF-κB was severely attenuated by AKT inhibitor in cells overexpressing Aurora-A. Taken together, these data indicate that Aurora-A overexpression upregulates MMP-2 expression through activating AKT/NF-κB signaling pathway in ESCC cells. These findings reveal that Aurora-A may be used as an important indicator for the judgment of malignant behavior of ESCC, and may be an attractive target for cancer therapy.

Wang X ，Li X ，Li C ，He C ，Ren B ，Deng Q ，Gao W ，Wang B ... -  《-》

Elevated serine protease HtrA1 inhibits cell proliferation, reduces invasion, and induces apoptosis in esophageal squamous cell carcinoma by blocking the nuclear factor-κB signaling pathway.

Xia J ，Wang F ，Wang L ，Fan Q ... -  《-》