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KLK11 suppresses cellular proliferation via inhibition of Wnt/?-catenin signaling pathway in esophageal squamous cell carcinoma.

ABSTRACT: Studies have demonstrated that kallikrein-associated peptidase 11 (KLK11) is dysregulated in various cancers. However, the potential roles of KLK11 in esophageal squamous cell carcinoma (ESCC) are still unknown. In our study, we found that the expression of KLK11 in advanced ESCC was significantly down regulated than that in the adjacent tissues, and patients with higher KLK11 expression had markedly increased overall survival rates compared with those with lower KLK11 expression. In addition, up regulation of KLK11 decreased the proliferation capacity of TE-1 and EC18 cells, and down regulation of KLK11 increased the proliferation capacity. To explore the possible mechanism of KLK11 in regulating the proliferation of ESCC, the expression of the related factors in Wnt/?-catenin pathway and cell cycle-mediated factors, such as GSK-3?/p-GSK-3?, ?-catenin, Ki67, p-Rb/Rb, CDK6, CDK4 and Cyclin D1, were determined. Furthermore, KLK11 was found to be negatively correlated with the expression of ?-catenin in the nucleus, as showed by decreased expression of cyclin D1 and Ki67 through deactivation of the Wnt/?-catenin signaling pathway. XAV-939, a Wnt/?-catenin inhibitor, partially decreased the effects of KLK11 deficiency on ESCC cell proliferation. Finally, we validated that KLK11 inhibited ESCC proliferation in vivo. Our results showed that the inhibitory effects of KLK11 on the proliferation of TE-1 and EC18 cells might be associated with inhibition of Wnt/?-catenin signaling pathway. KLK11 played a key role in inhibiting ESCC carcinogenesis and progression and became a potential biomarker for poor prognosis in patients with ESCC.

SUBMITTER: He X

PROVIDER: S-EPMC6834484 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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KLK11 suppresses cellular proliferation via inhibition of Wnt/β-catenin signaling pathway in esophageal squamous cell carcinoma.

He Xin X Meng Fan F Qin Lingyu L Liu Zhile Z Zhu Xiongjie X Yu Zhongjian Z Zheng Yanfang Y

American journal of cancer research 20191001 10

Studies have demonstrated that kallikrein-associated peptidase 11 (KLK11) is dysregulated in various cancers. However, the potential roles of KLK11 in esophageal squamous cell carcinoma (ESCC) are still unknown. In our study, we found that the expression of KLK11 in advanced ESCC was significantly down regulated than that in the adjacent tissues, and patients with higher KLK11 expression had markedly increased overall survival rates compared with those with lower KLK11 expression. In addition, u ...[more]

PMID: 31720087

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Project description:BackgroundEsophageal squamous cell carcinoma (ESCC) is the predominant subtype of esophageal cancer in East Asia, with approximately half of ESCC cases occurring in China. ESCC poses a serious threat to the quality of life of patients. MicroRNAs (miRNAs) are extremely important in the occurrence and development of ESCC. Current studies have shown that miR-212-3p is expressed at low levels in esophageal adenocarcinoma tumor tissues; however, its function and mechanism in ESCC have not been studied.MethodsThe expression levels of miR-212-3p and SOX4 were detected by quantitative polymerase chain reaction (qPCR) in ESCC tissues and adjacent tissues, and ESCC cell lines from 60 patients. The interaction of miR-212-3p and SOX4 was determined using a dual-luciferase reporter gene system. EC9706 Cells were transfected with miR-212-3p mimic, NC mimic, si-NC and si-SOX4 and miR-212-3p mimic + overexpressing-SOX4, and the effects on miR-212-3p and SOX4 expression were observed, respectively. An MTT assay was carried out to detect the proliferation ability of ESCC. The invasion ability and apoptosis level of the cells were determined by Transwell assay and flow cytometry, respectively. qPCR was used to detect expression of miR-212-3p and SOX4. Western blot was performed to observe the expression of SOX4, Wnt1, β-catenin, c-Myc, and Cyclin D1.ResultsmiR-212-3P was observed to be down-regulated in ESCC tissues and cells, while SOX4 expression was up-regulated; the two were negatively correlated. The dual-luciferase reporter gene further confirmed that miR-212-3p targeted SOX4. miR-212-3p overexpression and interference with SOX4 significantly inhibited the proliferation and invasion of ESCC EC970 cells, and promoted apoptosis. Furthermore, the results of Western blot confirmed that miR-212-3p overexpression and interference with SOX4 down-regulated the expression of Wnt1, β-catenin, c-Myc, and Cyclin D1. Meanwhile, SOX4 overexpression reversed the effect of up-regulation of miR-212-3p on EC970 function.ConclusionsmiR-212-3p mediates the apoptosis and invasion of ESCC cells through inhibiting the Wnt/β-catenin signal pathway by targeting SOX4.

Project description:BackgroundAlthough there are many treatments for breast cancer, such as surgery, radiotherapy, chemotherapy, estrogen receptor antagonists, immune checkpoint inhibitors and so on. However, safer and more effective therapeutic drugs for breast cancer are needed. Sinensetin, a safer therapeutic drugs, come from citrus species and medicinal plants used in traditional medicine, while its role and underlying mechanism in breast cancer remain unclear. Our study aimed to investigate the role and mechanism of sinensetin in breast cancer.MethodsCell Counting Kit-8 (CCK-8) was used to determine the safe concentration of sinensetin in MCF-10A, MCF7 and MDA-MB-231 cells; 120 μM sinensetin was used in subsequent experiments. Real time polymerase chain reaction (RT-PCR), Western blotting, Terminal Deoxynucleotidyl Transferase mediated dUTP Nick-End Labeling (TUNEL) apoptosis assay, Transwell invasion assay and Clone formation assay were used in this study to determine cell viability, mRNA expression, protein levels, apoptosis, proliferation, invasion and so on.ResultsHerein, our results showed that 120 μM sinensetin suppressed the cell viability and promoted apoptosis of MCF7 and MDA-MB-231 cells. Treatment with 120 µM sinensetin for 24 h showed no significant toxicity to normal mammary cells; 120 μM sinensetin decreased cell proliferation, invasion, and epithelial-mesenchymal transition (EMT), and downregulated β-catenin, lymphatic enhancing factor 1 (LEF1), T-cell factor (TCF) 1/TCF7, and TCF3/TCF7L1 expression in MCF7 and MDA-MB-231 cells. The Wnt agonist SKL2001 reversed the inhibitory effect of sinensetin on cell survival, metastasis, and EMT. Sinensetin-induced downregulation of β-catenin, LEF1, and TCF1/TCF7 expression were upregulated by SKL2001 in MCF7 and MDA-MB-231 cells.ConclusionsIn summary, sinensetin suppressed the metastasis of breast cancer cell via inhibition of Wnt/β-catenin pathway and there were no adverse effects on normal breast cells. Our study confirmed the role of sinensetin in breast cancer cells and provided a better understanding of the underlying mechanism.

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KLK11 suppresses cellular proliferation via inhibition of Wnt/?-catenin signaling pathway in esophageal squamous cell carcinoma.

Publications

KLK11 suppresses cellular proliferation via inhibition of Wnt/β-catenin signaling pathway in esophageal squamous cell carcinoma.

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