Tumor-derived microvesicles are rich in metastasis-related proteases and play a role in the interactions between tumor cells and tumor microenvironment in tumor metastasis. Because shed microvesicles ...may remain in the extracellular environment around tumor cells, the microvesicle membrane protein may be the potential target for cancer therapy. Here we report that chromosome segregation 1-like (CSE1L) protein is a microvesicle membrane protein and is a potential target for cancer therapy. v-H-Ras expression induced extracellular signal-regulated kinase (ERK)-dependent CSE1L phosphorylation and microvesicle biogenesis in various cancer cells. CSE1L overexpression also triggered microvesicle generation, and CSE1L knockdown diminished v-H-Ras-induced microvesicle generation, matrix metalloproteinase (MMP)-2 and MMP-9 secretion and metastasis of B16F10 melanoma cells. CSE1L was preferentially accumulated in microvesicles and was located in the microvesicle membrane. Furthermore, anti-CSE1L antibody-conjugated quantum dots could target tumors in animal models. Our findings highlight a novel role of Ras-ERK signaling in tumor progression and suggest that CSE1L may be involved in the "early" and "late" metastasis of tumor cells in tumorigenesis. Furthermore, the novel microvesicle membrane protein, CSE1L, may have clinical utility in cancer diagnosis and targeted cancer therapy.
Colorectal cancer has high rates of recurrence and metastasis. Many patients with similar histopathological features show significantly different clinical outcomes, and these differences are ...primarily related to metastases undetected by current diagnostic methods. There is no useful serological marker for metastatic disease. We investigated the cellular apoptosis susceptibility (CSE1L/CAS) protein in comparison with carcinoembryonic antigen (CEA) as a marker for metastatic colorectal cancer. Using serum from 103 patients with stage I, II, III, and IV disease, CSE1L was detected in 36.0% (9 of 25), 57.7% (15 of 26), 71.4% (30 of 42), and 88.9% (8 of 9) of patients, respectively; a pathological CEA level was found in 16.0% (4 of 25), 42.3% (11 of 26), 47.6% (20 of 42), and 77.8% (7 of 9) of patients, respectively; a combined CSE1L/CEA assay was detected in 48.0% (12 of 25), 65.4% (17 of 26), 88.1% (37 of 42), and 100% (9 of 9) of patients, respectively. Lymphatic metastasis is an important predictor of poor prognosis and crucial for determination of therapeutic strategy. Serum CSE1L was detected in 74.5% (38 of 51) of patients with lymph node metastasis, whereas a pathological CEA level was found in only 52.9% (27 of 51) of the same patients ( P < 0.001); the combined CSE1L/CEA assay increased sensitivity to 90.2% (46 of 51). Animal experiments showed CSE1L reduction in B16-F10 melanoma cells correlated with decreased metastasis to the colorectal tract in C57BL/6 mice. These results indicate that assay of serum CSE1L may facilitate diagnosis of colorectal cancer lymphatic metastases; furthermore, CSE1L is a possible therapeutic target.
This letter proposes a partial-time-shifted pilot scheme to find a better tradeoff between the user accommodation and orthogonality of pilots for the massive multiple-input multiple-output system. To ...this end, the pilot symbols rather than the pilot sequences are applied. In addition, the neighboring cells are allowed to transmit the pilot signals using the overlapped symbol periods. Despite the stronger interference, the larger user accommodation as well as the near-far effect incurred by using the pilot symbols can contribute to the higher sum transmission rates for both the uplink and downlink cases.
The unfolded protein response (UPR) is a conserved and adaptive cellular response to increase cell survival during ER stress. XBP-1 spliced form (XBP-1S) generated by IRE1 endoribonuclease is a key ...transcriptional regulator in UPR to activate genes involved in protein folding and degradation to restore ER function. Although Akt activation was suggested to be a pro-survival pathway activated during ER stress, the signal to trigger Akt is still not clear. In this study, we report IGF1 transcription and Akt phosphorylation are enhanced in XBP-1S stably overexpressed clone of zebrafish embryonic cell line (ZF4). In addition, zebrafish IGF1 intron1 with predicted UPRE (XBP-1S binding sites) and ERSE (ATF6/XBP-1S binding site) linked with basal promoter could be activated by XBP-1S, not by XBP-1 unspliced form (XBP-1U). Furthermore, we demonstrate that expression of endogenous IGF1 is transiently induced as XBP-1 splicing during ER stress in parallel to ER chaperone GRP78/Hspa5 and ER resided E3 ubiquitin ligase Synoviolin in ZF4 cells by quantitative PCR. Our results suggest zebrafish XBP-1S not only activates genes responsible for protein folding, transporting, glycosylation and ER associated degradation but also activates anti-apoptosis signal via IGF1/Akt pathway in unfolded protein response to cope with ER stress.
Abstract Background Ras plays an important role in colorectal cancer progression. CSE1L (chromosome segregation 1-like) gene maps to 20q13, a chromosomal region that correlates with colorectal cancer ...development. We investigated the association of CSE1L with Ras in colorectal cancer progression. Methods The effect of CSE1L on metastasis-stimulating activity of Ras was studied in an animal model with tumor cells expressing CSE1L -specific shRNA and v-H-Ras. CSE1L expression was evaluated by the immunohistochemical analysis of 127 surgically resected colorectal tumors. K-Ras mutations were analyzed by direct sequencing. Results CSE1L knockdown reduced Ras-induced metastasis of B16F10 melanoma cells in C57BL/6 mice. v-H-Ras expression altered the cellular trafficking of CSE1L and increased CSE1L secretion. Most colorectal tumors were positive for CSE1L staining (98.4%, 125 of 127). Colorectal tumors with K-Ras mutation or high cytoplasmic CSE1L expression were correlated with T status (depth of tumor penetration; P = .004), stage ( P = .004), and lymph node metastasis ( P = .019). Conclusions CSE1L may be a target for treating Ras-associated tumors. Analysis of K-Ras mutation and CSE1L expression may provide valuable clinical and pathological information to aid in the determination of treatment options for colorectal cancer.
Hypochlorous acid (HOCl), used as a liquid or a fog, has broad antimicrobial and deodorizing effects. Our facility was thefirst in Taiwan that was built with a system to supply stabilized, biosafe ...HOCl solution (50 ppm available chlorine concentration,pH 6) into a new animal barrier facility that housed genetically modified mice. The HOCl system creates an extremelyclean environment that allows us to raise mice in static, filter-top cages and to handle them on open tables without the needfor biologic safety cabinets (BSC). Our animal facility (AF) sometimes receives mice from outside sources that are infectedwith pathogens, notably murine norovirus (MNV), Helicobacter spp., and trichomonads. We found that our standard operationprocedure (SOP) prevented cross-contamination to other mice, including those in adjacent cages. After the removal of infectedmice from a room, the remaining mice remained uninfected, without the need for extensive environmental decontamination.Learning this allowed us to use a test-and-removal method to eliminate pathogens. In addition, infected mouse strains thatwere not commercially available were rederived by using cross-fostering. After finding unexpected infections, we were ableto identify all infected mice by widespread screening. We then removed contaminated cages and performed cross-fosteringas needed. This approach was able to successfully eliminate murine norovirus, Helicobacter spp., and trichomonads. Overthe 12 y in which we managed this AF, we refined our husbandry methods and our approach to the detection and eradicationof pathogens by using HOCl fog and solution, the test-and-removal, and cross-fostering.
Metastatic markers are highly useful diagnostic and prognostic indicators of cancer metastasis. Herein, we report that secretory
CSE1L/CAS, a cellular apoptosis susceptibility protein, is a new ...marker for metastatic cancer. CAS was colocalized with matrix
metalloproteinase-2 in vesicles surrounding the outside of MCF-7 cell membranes, and the COOH-terminal domain of CAS was associated
with matrix metalloproteinase-2-containing vesicles. Immunohistochemical staining for CAS was positive in the stroma and gland
lumens of human metastatic cancer tissues. CAS was also detected in conditioned medium from B16-F10 melanoma cells and more
frequently in the sera of patients with metastatic cancer than in sera from patients with primary cancer. Specifically, the
prevalence of serum CAS in serum samples from 146 patients was 58.2% (32 of 55), 32.0% (8 of 25), and 12.1% (8 of 66) for
patients with metastatic, invasive, and primary cancers, respectively. Our results suggest that CAS is a secretory protein
associated with cancer metastasis, which may have clinical utility in metastatic cancer screening and diagnosis. (Cancer Epidemiol
Biomarkers Prev 2009;18(5):1570–7)
Colorectal carcinomas spread easily to nearby tissues around the colon or rectum, and display strong potential for invasion and metastasis. CSE1L, the chromosome segregation 1-like protein, is ...implicated in cancer progression and is located in both the cytoplasm and nuclei of tumor cells. We investigated the prognostic significance of cytoplasmic vs. nuclear CSE1L expression in colorectal cancer.
The invasion- and metastasis-stimulating activities of CSE1L were studied by in vitro invasion and animal experiments. CSE1L expression in colorectal cancer was assayed by immunohistochemistry, with tissue microarray consisting of 128 surgically resected specimens; and scored using a semiquantitative method. The correlations between CSE1L expression and clinicopathological parameters were analyzed.
CSE1L overexpression was associated with increased invasiveness and metastasis of cancer cells. Non-neoplastic colorectal glands showed minimal CSE1L staining, whereas most colorectal carcinomas (99.2%, 127/128) were significantly positive for CSE1L staining. Cytoplasmic CSE1L was associated with cancer stage (P=0.003) and depth of tumor penetration (P=0.007). Cytoplasmic CSE1L expression also correlated with lymph node metastasis of the disease in Cox regression analysis
CSE1L regulates the invasiveness and metastasis of cancer cells, and immunohistochemical analysis of cytoplasmic CSE1L in colorectal tumors may provide a useful aid to prognosis.
The strong immunogenicity induction is the powerful weapon to prevent the virus infections. This study demonstrated that one-step synthesis of DNA polyplex vaccine in microneedle (MN) patches can ...induce high immunogenicity through intradermal vaccination and increase the vaccine stability for storage outside the cold chain. More negative charged DNA vaccine was entrapped into the needle region of MNs followed by DNA polyplex formation with branched polyethylenimine (bPEI) pre-coated in the cavities of polydimethylsiloxane (PDMS) molds that can deliver more DNA vaccine to immune-cell rich epidermis with high transfection efficiency. Our data in this study support the safety and immunogenicity of the MN-based vaccine; the MN patch delivery system induced an immune response 3.5-fold as strong as seen with conventional intramuscular administration; the DNA polyplex formulation provided excellent vaccine stability at high temperature (could be stored at 45ºC for at least 4 months); the DNA vaccine is expected to be manufactured at low cost and not generate sharps waste. We think this study is significant to public health because there is a pressing need for an effective vaccination in developing countries.
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