Recent studies have shown that metal and metal oxide have a potential function in antitumor therapy. Our previous studies demonstrated that cuprous oxide nanoparticles (CONPs) not only selectively induce apoptosis of tumor cells in vitro but also inhibit the growth and metastasis of melanoma by targeting mitochondria with little hepatic and renal toxicities in mice. As a further study, our current research revealed that CONPs induced apoptosis of human melanoma stem cells (CD271+/high cells) in A375 and WM266-4 melanoma cell lines and could significantly suppress the expression of MITF, SOX10 and CD271 involved in the stemness maintenance and tumorigenesis of melanoma stem cells. CD271+/high cells could accumulate more CONPs than CD271-/low through clathrin-mediated endocytosis. In addition, lower dosage of CONPs exhibited good anti-melanoma effect by decreasing the cell viability, stemness and tumorigenesis of A375 and WM266-4 cells through reducing the expression of SOX10, MITF, CD271 and genes in MAPK pathway involved in tumor progression. Finally, CONPs obviously suppressed the growth of human melanoma in tumor-bearing nonobese diabetic-severe combined immunodeficiency (NOD-SCID) mice, accompanied with tumors structural necrosis and fibrosis remarkably and decreased expression of CD271, SOX10 and MITF. These results above proved the effectiveness of CONPs in inhibiting melanoma progress through multiple pathways, especially through targeting melanoma stem cells.

/pdf/cuprous-oxide-nanoparticle-inhibited-melanoma-progress-by-2f9k75kyrt.pdf

Cuprous oxide nanoparticle-inhibited melanoma progress by targeting melanoma stem cells

Extensive review on breast cancer its etiology, progression, prognostic markers, and treatment

Acetylation dependent translocation of EWSR1 regulates CHK2 alternative splicing in response to DNA damage

The nuclear envelope component proline-rich protein 14 (PRR14) is involved in the nuclear morphological alteration and activation of the mTOR (mammalian target of rapamycin) signaling pathway, and has been repeatedly shown to be upregulated in patients with Parkinson's disease (PD). The aim of this study was to explore whether PRR14 can be used as a potential biomarker for the diagnosis of PD. We compared PRR14 expression in PD patients and normal controls in gene expression omnibus (GEO) data. Quantitative enzyme-linked immunosorbent assay (ELISA) was used to detect PRR14 expression in PD patients and age- and sex-matched controls. The relationship between serum PRR14 and clinical phenotype was evaluated using correlation analysis and logistic regression. The expression of PRR14 in whole blood, substantia nigra, and medial substantia nigra was significantly higher in PD patients than in the healthy control group. Compared to plasma, serum was more suitable for the detection of PRR14. Furthermore, serum PRR14 level in PD patients was significantly higher than that in age- and sex-matched controls. The area under the curve for serum PRR14 level in the ability to identify PD versus age- and sex-matched controls was 0.786. In addition, serum PRR14 level was found to correlate with constipation in PD patients. Our findings demonstrate for the first time that serum PRR14 is a potential biomarker for PD.

/pdf/preliminary-findings-on-proline-rich-protein-14-as-a-20s8mevo0k.pdf

Preliminary Findings on Proline-Rich Protein 14 as a Diagnostic Biomarker for Parkinson's Disease.

Nuclear envelope component PRR14 has been detected to be upregulated in varieties of cancers, especially in breast cancer. But its role in breast carcinogenesis is poorly understood. In this study, we show PRR14 contributes to breast carcinogenesis mainly through overexpression, which derives from elevated transcription and gene amplification. Increased PRR14 expression promotes breast cancer cell proliferation and tumor formation. Biochemical analysis reveals, in addition to previously reported activation of PI3-kinase/Akt/mTOR pathway, PRR14 overexpression regulates cell cycle in breast cancer by inhibiting CHEK2's activation, followed with the deregulation of DNA damage pathway. In correspondence, CHEK2 and PRR14 show opposite impact on breast cancer patients receiving chemotherapy. Collectively, our study is the first to document the oncogenetic role of PRR14 in breast cancer, which protects cells from apoptosis and stimulates proliferation by activating the PI3-kinase/Akt/mTOR pathway and inhibiting the CHEK2 pathway. Both of these pathways are of great influence in breast cancer and PRR14 appears to be their novel interacting node, which renders patients more resistance to chemotherapy and provides a potential therapeutic target in breast cancer.

/pdf/oncogene-prr14-promotes-breast-cancer-through-activation-of-4zqwch3r8x.pdf

Oncogene PRR14 promotes breast cancer through activation of PI3K signal pathway and inhibition of CHEK2 pathway.

Gross changes in nuclear morphology are a standard criteria used in the diagnosis of many cancers. Cancerous cells are characterized by enlarged nuclei and prominent nucleoli. However, the specific nuclear components involved, the underlying mechanisms, and the implications for cancer progression, are far from clear. The nuclear lamina, a scaffold-like network of protein filaments surrounding the nuclear periphery, is required in the regulation of most nuclear activities, including nuclear shape, DNA replication, RNA transcription, nuclear and chromatin organization, cell cycle regulation, cell development and differentiation, and apoptosis et al. During tumorigenesis, the components of the nuclear lamina undergo significant alterations and are suggested biomarkers in certain types of cancer, such as lamin A/C in colorectal cancer and lamin B1 in liver cancer. It can therefore be hypothesized that the nuclear lamina plays a key role in connecting nuclear morphologic change with its functional alteration during tumorigenesis. PRR14 has previously been identified as a novel component of the nuclear lamina, tethering heterochromatin to the nuclear lamina during the cell cycle. Our group confirmed this observation in myoblast C2C12 cells and demonstrated that this bridge is not only physical but functional as well; PRR14 directly binds to HP1α, a constitutive component of heterochromatin, and myogenesis is tightly regulated by this binding. Disruption of this interaction almost completely blocked myogenesis and the majority of cells underwent apoptosis. CouldPRR14 beamissing link in the commonmechanismmediating nuclear morphological change and its functional alteration during tumorigenesis? In our recent paper published inOncogene, we have shown that the expression level of PRR14 is significantly increased in lung cancer with, or without, gene copy number variation. Indeed, PRR14 is commonly elevated in many cancer types besides lung cancer (Figure 1a). Elevated expression of PRR14 at the protein level has yet to be confirmed due to a lack of an appropriate antibody. However, in the future, it would be meaningful to monitor PRR14 protein expression levels during the process of tumorigenesis. From comparative analysis of differentially expressed transcripts, between high-PRR14 and low-PRR14 expressing samples, within different types of lung cancer collections in TCGA (lung adenocarcinoma and lung squamous cell carcinoma), we conclude that PRR14 expression is positively associated with both gene expression and generic transcription pathways. In addition, PRR14 overexpression results in markedly enlarged cell size. Thus, we hypothesized that PRR14 may be a novel oncogene activating the PI3-kinase/ Akt/mTOR signal pathway, which is known to regulate mammalian cell size through generic gene expression and a commonly activated pathway in lung cancer. Consistent with this, the high expression of PRR14 significantly associates with a decreased 5-year survival rate in more than 1900 lung cancer patients. And the PI3K/Akt/mTOR pathway activation was confirmed through analysis of phosphorylation status of its downstream effectors. Furthermore, we demonstrated that the activation of the pathway was achieved by direct interaction of PRR14 with GRB2, a regulator of PI3K signaling pathway. Consequently, elevated PRR14 promoted, and reduced PRR14 impeded, lung cancer cell proliferation as well as tumor formation. As expected, elevated PRR14 was specifically associated with a heightened sensitivity to the inhibitors of PI3K (GDC-0941) and its downstream effector mTOR (Torin2 and LY294002), but showed no effect on the mitogen-activated protein kinase (MAPK) inhibitor (U0126; Figure 1b). Fortunately, we got two PRR14 variants with higher affinity for GRB2 in tumors and they demonstrated a higher capacity to activate PI3K/AKT/mTOR signaling pathway and form tumors, which further confirmed our hypothesis. GRB2 is also involved in Ras signaling pathway, and AKT/ mTOR and MAPK pathways are both its downstream signal pathways. To exclude the possibility that PRR14 activates AKT/mTOR pathway through Ras instead of PI3K pathway, the phosphorylation status of ERK was used as a readout of the MAPK pathway activity, an alternate downstream pathway of Ras from the Akt/mTOR pathway. The phosphorylation status of ERK was not significantly altered. ThePI3K pathway has been demonstrated to regulate diverse cellular processes including proliferation, adhesion, survival and motility, and its aberrant activation is frequently observed in various cancers conferring sensitivity and resistance to conventional therapies. Therefore, the PI3K pathway is considered a well-validated target for cancer treatment. Although the activity of the pathway has been extensively explored, previous research has mainly focused on the cytoplasmic component, whereas its functions and effector proteinswithin the nucleus are poorly understood. Noticeably, both previous and our research has demonstrated that PRR14,with nuclear localization signal in both its Nand C-terminals, is predominately localized within the cell nucleus including the nuclear lamina during mitosis. Our findings may therefore provide a novel and common nuclear target in the PI3K pathway.

Discovery of a novel target for cancer: PRR14

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Oncogene PRR14 promotes breast cancer through activation of PI3K signal pathway and inhibition of CHEK2 pathway.

Discovery of a novel target for cancer: PRR14