CTEN Inhibits Tumor Angiogenesis and Growth by Targeting VEGFA Through Down-Regulation of ß-Catenin in Breast Cancer.

C-terminal tensin-like (CTEN) belongs to the tensin gene family, which encodes proteins that localize to focal adhesions and modulate integrin function. Accumulating studies have reported that CTEN expression can be upregulated or downregulated in different types of cancers, suggesting that CTEN has both oncogenic and tumor suppressor functions. In this study, by analyzing the expression level of CTEN in the human breast cancer (BRCA) samples from the clinically annotated genomic database, The Cancer Genome Atlas, we found that CTEN was downregulated in different BRCA subclasses, including luminal, human epidermal growth factor receptor 2 positive and triple-negative BRCA. Consistently, the protein level of CTEN was also reduced in BRCA based on the Proteomic Tumor Analysis Consortium. In contrast, vascular endothelial growth factor A (VEGFA), a signal protein that stimulates the formation of blood vessels, was upregulated in BRCA. CTEN overexpression in human umbilical vein endothelial cells and MCF7 significantly suppressed the expression of VEGFA, inhibited cell proliferation, migration, and tube formation in vitro. Mechanistically, CTEN bind to casitas B-lineage lymphoma (c-Cbl), an E3 ubiquitin-protein ligase, and decreased the ß-catenin expression. In turn, the downregulation of ß-catenin reduced the expression of VEGFA. Rescuing ß-catenin expression effectively ameliorated the effect of CTEN overexpression in cell proliferation, migration, and tube formation. In conclusion, CTEN inhibited tumor angiogenesis by targeting VEGFA through c-Cbl-mediated down-regulation of ß-catenin and may serve as a tumor suppressor in BRCA.

Overexpression of CTEN is associated with gefitinib resistance in non-small cell lung cancer.

COOH-terminus tensin-like molecule (CTEN) is a member of the tensin family, which is considered to be one of the novel proto-oncogenes involved in tumorigenesis and cancer progression. However, the mechanisms of CTEN in acquired resistance of non-small cell lung cancer (NSCLC) remain relatively unknown. The aim of the present study was to understand the roles of CTEN in acquired gefitinib resistance of NSCLC. The present study investigated the expression level of CTEN using reverse transcription-quantitative polymerase chain reaction and Western blot analysis. Cell Counting kit-8 and colony-formation assays were performed to evaluate the proliferative and colony-formative abilities of PC9 and PC9/GR cells in vitro. Mouse xenograft models were used to assess the growth of PC9/GR cells in vivo. A gefitinib-resistant NSCLC cell line (PC9/GR) was established, and the protein and mRNA expression levels of CTEN were observed to be higher in PC9/GR cells than in PC9 cells. Notably, the sensitivity of PC9/GR cells to gefitinib was observed to be decreased when CTEN was overexpressed, while PC9/GR cells with CTEN-downregulation showed markedly enhanced sensitivity to gefitinib. In vitro proliferation and colony formation assays revealed that increased CTEN markedly promoted the cell proliferative and colony-forming capacities of PC9 and PC9/GR cells, and CTEN-silencing inhibited the cell proliferative and colony-forming abilities of the PC9 and PC9/GR cells. Notably, deficient expression of CTEN notably retarded the growth of PC9/GR xenografts in vivo. In addition, the plasma mRNA expression of CTEN was notably elevated in patients with NSCLC with acquired gefitinib resistance. Overexpression of CTEN is associated with acquired gefitinib resistance in NSCLC. CTEN may be investigated as a potential therapeutic target for the treatment of patients with NSCLC with acquired gefitinib resistance.

Simvastatin downregulates HER2 via upregulation of PEA3 to induce cell death in HER2-positive breast cancer cells.

Simvastatin is a widely used cholesterol-adjusting drug that selectively inhibits the 3-hyrdoxy-3-methylglutaryl-coenzyme A reductase, leading to decreased cholesterol biosynthesis. Notably, through this activity, simvastatin exerts antiproliferative and proapoptotic effects on various cancer cells, including non-small cell lung and breast cancer. Although statin-induced breast cancer cell death is nitric oxide inducible and arginase dependent, we report alternative mechanisms relative to the antitumor function of simvastatin in breast cancer cells. Simvastatin induced cell death in MDA-MB-361, SK-Ov3, and SKBR3, HER2-overexpressing cell lines, in both time- and dose-dependent manners, but did not exert cytotoxicity in MCF10A and MDA-MB-231, HER2 low/negative cell lines. The protein expression of HER2 decreased after the cells were treated with simvastatin; however, HER2 protein and mRNA stabilities were not changed. Furthermore, simvastatin inhibited the activity of the HER2 promoter. Simvastatin-induced cytotoxicity and promoter activity repression were reversed by mevalonate and GGPP, the immediate metabolic products of the acetyl CoA/3-hyrdoxy-3-methylglutaryl CoA reductase reaction and the isoprenoid of the mevalonate cascade, respectively. In addition, simvastatin treatment induced the expression of PEA3, which is a HER2 promoter inhibitor. The use of siRNA to downregulate expression of PEA3 inhibited the simvastin-induced HER2 repression and cell death. These findings provide alternative mechanisms for the antitumor effects of simvastatin, suggesting that simvastatin could also be used as a combination therapy with other chemotherapy agents in HER2-positive patients.

[Efficacy and side-effects of docetaxel combined with cisplatin on the treatment of local advanced esophageal cancer with concomitant radiation therapy].

OBJECTIVE: To investigate the therapeutical effect and side-effect of docetaxel combined with cisplatin (DDP) on the treatment of local advanced esophageal cancer with concomitant radiation therapy. METHODS: Ninety patients with LOCAL advanced esophageal squamous cell carcinoma were divided into two groups: (DDP + 5-Fu) group and (docetaxel + DDP) group. Chemotherapy was carried out every 4 weeks for a total of 4 courses. The radiation dose was 50.4 Gy/28FX. RESULTS: The median survival time of patients in the (DDP + 5-Fu) group was 16 months and that in (docetaxel + DDP) group was 21 months (P = 0.0278). The 3-year survival rate in the (docetaxel + DDP) group was obviously higher than that in the (DDP + 5-Fu) group (23.9% vs. 12.1%). The ORR in (docetaxel + DDP) group (84.5%) was significantly higher than that in the (DDP + 5-Fu) group (71.1%) (P = 0.025). No significant differences were observed in the incidence of side-effects in the two groups. CONCLUSIONS: The conventional dose chemotherapy of docetaxel + DDP with concomitant radiation therapy showed a better partial remission rate and long-term survival rate for the treatment of local advanced esophageal cancer than the traditional chemotherapy (DDP + 5-Fu) with concomitant radiation therapy and the side-effects are not increased.