Abnormally elevated ubiquilin­1 expression in breast cancer regulates metastasis and stemness via AKT signaling.

Ubiquilin­1 (UBQLN1) is an essential factor for the maintenance of proteostasis in cells. It is important for the regulation of different protein degradation mechanisms, including the ubiquitin­proteasome system, autophagy and endoplasmic reticulum­associated protein degradation pathways. However, the role of UBQLN1 in cancer progression remains largely unknown. In the present study, the expression, functions and molecular mechanisms of UBQLN1 in breast cancer tissue samples and cell lines were explored. Immunohistochemical and bioinformatics analyses revealed that UBQLN1 expression was significantly upregulated in breast cancer tissues and cell lines. UBQLN1 expression in breast cancer was significantly associated with lymph node metastasis and TNM stage. Moreover, a high UBQLN1 expression was a predictor of an unfavorable survival in patients with breast cancer. In vitro, UBQLN1 silencing markedly inhibited cell migration and invasion, epithelial­to­mesenchymal transition (EMT) and MMP expression. UBQLN1 silencing attenuated the stem cell­like properties of breast cancer cells, including their mammosphere­forming abilities. UBQLN1 knockdown also enhanced breast cancer cell chemosensitivity to paclitaxel. The expression levels of the stem cell markers. Aldehyde dehydrogenase 1 (ALDH1), Oct­4 and Sox2 were significantly decreased in the cells in which UBQLN1 was silenced, whereas breast cancer stem cells exhibited an increased expression of UBQLN1. Mechanistically, UBQLN1 knockdown inhibited the activation of AKT signaling, as revealed by the increased PTEN expression and the decreased expression of phosphorylated AKT in cells in which UBQLN1 was silenced. On the whole, the present study demonstrates that UBQLN1 is aberrantly upregulated in breast cancer and predicts a poor prognosis. The silencing of UBQLN1 inhibited the invasion, EMT and stemness of breast cancer cells, possibly via AKT signaling.

RRY Inhibits Amyloid-ß1-42 Peptide Aggregation and Neurotoxicity.

BACKGROUND: Current understanding of amyloid-ß protein (Aß) aggregation and toxicity provides an extensive list of drugs for treating Alzheimer's disease (AD); however, one of the most promising strategies for its treatment has been tri-peptides. OBJECTIVE: The aim of this study is to examine those tri-peptides, such as Arg-Arg-Try (RRY), which have the potential of Aß1-42 aggregating inhibition and Aß clearance. METHODS: In the present study, in silico, in vitro, and in vivo studies were integrated for screening tri-peptides binding to Aß, then evaluating its inhibition of aggregation of Aß, and finally its rescuing cognitive deficit. RESULTS: In the in silico simulations, molecular docking and molecular dynamics determined that seven top-ranking tri-peptides could bind to Aß1-42 and form stable complexes. Circular dichroism, ThT assay, and transmission electron microscope indicated the seven tri-peptides might inhibit the aggregation of Aß1-42 in vitro. In the in vivo studies, Morris water maze, ELISA, and Diolistic staining were used, and data showed that RRY was capable of rescuing the Aß1-42-induced cognitive deficit, reducing the Aß1-42 load and increasing the dendritic spines in the transgenic mouse model. CONCLUSION: Such converging outcomes from three consecutive studies lead us to conclude that RRY is a preferred inhibitor of Aß1-42 aggregation and treatment for Aß-induced cognitive deficit.

Cytokine TNF-α promotes invasion and metastasis of gastric cancer by down-regulating Pentraxin3.

As a novel multifaceted player in cancer, Pentraxin3(PTX3) was recognized to be a possible factor related with tumor development. Recent researches have indicated that PTX3 is involved in immune response, inflammation, as well as cancer, and is greatly controlled by numerous cytokines. Tumor necrosis factor (TNF-α) is an imperative cytokine that demonstrates an extensive array of biological consequences in gastric cancer advancement. Here, we inspected the expression of PTX3 in gastric carcinoma tissues along with gastric cell lines and established that PTX3 was suggestively inferior in gastric cancer tissue and cells. The treatment of the gastric cell lines BGC-823 as well as SGC-7901 with rhTNF-α caused substantial decrease in the expression of PTX3. Furthermore, PTX3 controlled the capability of cell migration, invasion as well as epithelial-mesenchymal transition (EMT) in gastric cancer cell lines mediated by TNF-α. Additionally, PTX3 upregulation inhibited tumorigenicity in vivo and could be reversed by exogenous TNF-α. Conversely, overexpression of PTX3 inhibited progress both in vitro as well as in vivo in gastric cancer mediated by TNF-α. Further studies are necessary to demonstrate the mechanism of interaction between PTX3 and cytokines.

ITGA3 interacts with VASP to regulate stemness and epithelial-mesenchymal transition of breast cancer cells.

BACKGROUND: The interaction of integrin and extracellular matrix (ECM) has a profound implication on pathological conditions such as tumor growth and infiltration. Related reports have confirmed that integrin α3 (ITGA3) influences the development of bladder cancer, head and neck cancer, colorectal cancer and other cancers. However, the mechanism of ITGA3 in breast cancer is unknown. METHODS: The impact of ITGA3 on the biological features of breast cancer cells was explored using the Transwell and wound healing assays. In addition, its influence on stemness of breast cancer cells was examined with the sphere formation assay. The possible mechanism by which ITGA3 regulates breast cancer was explored using Western blot. The interaction between ITGA3 and VASP was determined by co-immunoprecipitation and immunofluorescence staining assays. RESULTS: Results show that downregulation of ITGA3 promotes breast cancer cell proliferation, apoptosis, invasion and migration. Indeed, suppression of ITGA3 negatively regulates the stemness of breast cancer cells and EMT process. Our findings indicate that ITGA3 interacts with VASP and regulates its expression, and knockdown of ITGA3 inhibits the activity of the PI3K-AKT axis. CONCLUSION: Our results show that ITGA3-VASP modulates breast cancer cell stemness, EMT and PI3K-AKT pathways. Therefore, ITGA3 might be a druggable target for clinical breast cancer management.