SOX2 upregulates side population cells and enhances their chemoresistant ability by transactivating ABCC1 expression contributing to intrinsic resistance to paclitaxel in melanoma.

Paclitaxel is the last choice for the treatment of advanced melanoma as a second-line chemotherapeutic agent, but there are still many cases of intrinsic resistance to paclitaxel in melanoma and the reasons that cause paclitaxel resistance remain unclear. Here, we identified that high expression of SRY-box transcription factor 2 (SOX2) and high ratio of side population (SP) cells reduced the sensitivity to paclitaxel in melanoma cells. The knockout and the induction of SOX2 completely depleted and significantly upregulated the ratios of melanoma SP cells, respectively. These data suggest that SOX2, a pluripotent transcription factor for inducing cancer stem cells in melanoma, is also sufficient and necessary for the induction of melanoma SP cells. ATP-binding cassette (ABC) subfamily C member 1 (ABCC1) is one of ABC transporters which causes SP cells to be resistance to chemotherapeutic agents by efficiently pumping drugs out of cells. The knockout and the induction of ABCC1 significantly increased and decreased the sensitivity of melanoma cells to paclitaxel. High expression of ABCC1 was identified in melanoma cell lines with high expression of SOX2 and in their SP cells. SOX2 was identified to induce ABCC1 transcription. Taken together, SOX2 upregulates SP cells and enhances their chemoresistant ability by increasing ABCC1 expression, which contributes to intrinsic resistance to paclitaxel in melanoma. Our findings will lead to new insights into melanoma biology and therapy resistance, and eventually to new therapeutic targets.

CADM1 inhibits ovarian cancer cell proliferation and migration by potentially regulating the PI3K/Akt/mTOR pathway.

Previous studies have shown that cell adhesion molecule 1 (CADM1), an immunoglobulin superfamily member, is frequently inactivated but functions as a tumor suppressor in many solid tumors. However, the characterization of CADM1 expression in ovarian cancer cells and the mechanisms of its tumor suppressor function are not fully understood. We generated ovarian cancer cell lines in which CADM1 was stably upregulated or downregulated. CADM1 expression was significantly decreased in ovarian cancer tissue and cells lines. Functionally, knockdown of CADM1 promoted the growth, migration and invasion of ovarian cancer cells. Conversely, further experimental evidence indicated that overexpression of CADM1 inhibited the migration and invasion of ovarian cancer cells potentially through inhibition of the PI3K/Akt/mTOR signaling pathway by regulating upstream regulators (LXR/RXR, IGF1, IFI44L and C4BPA) and downstream effectors (APP, EDN1, TGFBI and Rap1A). In conclusion, CADM1 inhibits ovarian cancer cell proliferation and migration by potentially regulating the PI3K/Akt/mTOR signaling pathway. CADM1 could be a potential therapeutic target for ovarian cancer.

Downregulating SynCAM and MPP6 expression is associated with ovarian cancer progression.

Synaptic cell adhesion molecules (SynCAMs) are single transmembrane proteins that belong to the immunoglobulin superfamily of cell adhesion molecules. In the present study, a decrease in SynCAM levels in ovarian tumor tissues compared with normal tissues is reported; the downregulation was accompanied by the grade malignancy. The observations suggested that SynCAM may be essential for important novel functions in ovarian cancer. Further experiments showed that low SynCAM expression inhibited membrane palmitoylated protein 6 (MPP6) expression, a member of the palmitoylated membrane protein subfamily of peripheral membrane-associated guanylate kinases. In addition, low levels of MPP6 in ovarian tumor tissues correlated with shorter patient survival. A SynCAM-regulated pathway may provide molecular targets for the treatment of ovarian cancer and novel biomarkers to be used in clinical diagnosis.

Nectin-3 is a new biomarker that mediates the upregulation of MMP2 and MMP9 in ovarian cancer cells.

Nectin-3 is a cell adhesion molecule that functions in tight junctions. Recent reports have implicated nectin-3 in pancreatic adenocarcinoma and lung adenocarcinoma. However, there has been little exploration of the expression, cellular invasion and migration of nectin-3 in ovarian cancer (OC). We evaluated the distribution of cells that were positive for nectin-3 using immunohistochemistry in specimens of human OC and correlated these results with overall survival (OS). The nectin-3 expression was significantly increased accompanied by a degree of malignancy in ovarian tumors; moreover, the expression of matrix metallopeptidases (MMP) 2 and 9 was upregulated. In addition, an increased level of nectin-3 was related to a poorer OS. In summary, we have demonstrated that cellular migration and invasion via nectin-3 mediate the upregulation of MMP2 and MMP9 in OC cells. Nectin-3 may be a new biomarker for OC diagnosis.

Tumor suppressor in lung cancer 1 gene expression in epithelial ovarian cancer.

OBJECTIVES: Loss of Tumor Suppressor in Lung Cancer 1(TSLC1) was observed in many different cancers, but there were only limited research on TSLC1 gene and its roles in cancer suppression in ovarian cancer. This study explores the relationship between TSLC1 gene expression and the ovarian epithelial cancer. MATERIALS AND METHODS: Expression levels of TSLC1 were detected by immunohistochemical staining on formal-fixed paraffin embedded pathological specimen. A total of 259 samples were collected, including 24 benign ovarian tumor and 235 malignant ovarian cancers among them. RESULTS: Suppressed expression of TSLC1 protein was observed in 87.8% of poorly differentiated, 85.1% of moderately differentiated, and 46% of well differentiated ovarian epithelial cancers, respectively. There were none suppressed TSLC1 expression in benign ovarian tumor. Kruskal-Wallis test showed a significant association between the expression levels of TSLC1 gene and the degree of ovarian cancer differentiation (P < 0.001). CONCLUSIONS: Decreased expression of TSLC1 is associated with the differentiation in ovarian epithelial cancer. TSLC1 might be used as a molecular marker of severity in early stage ovarian cancer, and to help differentiating benign and malignant ovarian tumors.

[Drug resistance of methicillin resistant Staphylococcus strains in burn ward and relative analysis].

OBJECTIVE: To study the distribution and drug resistance of methicillin resistant Staphylococcus strains in various specimens of inpatients in burn wards, and to provide reference for clinical treatment. METHODS: Bacteria were isolated from specimens of wound exudate, blood, sputum, and bronchoalveolar lavage fluid etc., which were collected from patients hospitalized in our burn wards from January 2008 to December 2010. The bacteria were routinely cultured and identified. Drug resistance of the Staphylococci to 15 antibiotics commonly used in clinic was identified by K-B disk diffusion method. Data were processed with statistical software WHONET 5.5. The homology of 40 strains of methicillin resistant Staphylococcus aureus (MRSA) was analyzed by pulsed-field gel electrophoresis (PFGE). RESULTS: Altogether 386 strains of Staphylococcus were isolated, including 196 strains of Staphylococcus aureus and 190 strains of coagulase negative Staphylococcus. The mean annual isolation rates of MRSA and methicillin resistant coagulase negative Staphylococcus (MRCoNS) were respectively 73.00% (143/196) and 74.20% (141/190). The resistance rates of MRSA and MRCoNS to ß-lactams drugs, such as penicillin, oxacillin, cefazolin, and cefuroxime were 100.00% in every year. No Staphylococcus strains resistant to vancomycin, teicoplanin, or linezolid were found. Three different PFGE patterns A, B, and C were identified among 40 MRSA strains, including 33 strains of type A (30 strains in sub-type A1 and 3 strains in sub-type A2), 6 strains of type B (respectively 3 strains in sub-types B1 and B2), and 1 strain of type C. CONCLUSIONS: The isolation rates of MRSA and MRCoNS were high in our burn wards from January 2008 to December 2010. All of them showed strong drug resistance property, and they were multidrug resistant. The most prevalent strain was PFGE type A.

[Effect of insulin on burn wound healing in aging diabetes mellitus rats].

OBJECTIVE: To investigate the effect of topical application of insulin on the burn wound healing in aging diabetes mellitus (DM) rats and to explore its mechanism. METHODS: Seventy-five SPF Wistar rats (female and/or male), aged 12-24 months and weighing 300-350 g, were selected and randomly divided into group A (burn control group, n=25), group B (DM burn control group, n=25), and group C (DM insulin treatment group, n=25). The rats in group B and group C were fed with high-fat, high-protein, and high-sugar forage for 1 month and received intraperitoneal injection of streptozotocin (STZ) to establish experimental model of aging DM. The rats were fed with high-fat, high-protein, and high-sugar forage for another 8 weeks. Then, the deep second-degree burn model was established in the rats of group B and group C. The wounds in group A and B underwent local subcutaneous injection of 2 mL isotonic saline and group C received local subcutaneous injection of 0.1 U insulin. The rate of wound healing was calculated 7, 14, and 21 days after burn injury. At 1, 3, 7, 14, and 21 days after burn injury, HE staining observation, immunohistochemistry staining for CD34, detection of sugar and hydroxyproline (HOP) content in wound tissue, and microvessel density (MVD) calculation were performed. RESULTS: At 7, 14, and 21 days after burn injury, the wound healing rates of group A and group C was significantly higher than that of group B (P < 0.05), and there was no significant difference between group A and group C (P > 0.05). Histology observation at 21 days after burn injury: in group A, certain degree of epithelization was evident in the wound epithelium; in group B, large quantity of necrotic tissue was evident; in group C, complete epithelization occurred in the wound epithelium with better epithelial cell differentiation and more neonatal collagen. For the sugar content in the wound tissue, group A was significantly lower than group B or group C at 1, 3, 7, 14, and 21 days (P < 0.05) and group C was significantly lower than group B at 7, 14, and 21 days (P < 0.05). For the HOP content in the wound tissue and the MVD count, group A or group C was significantly higher than group B (P < 0.05) and there was no significant difference between group A and group C (P > 0.05). CD34 expression: in group A, it was (+) at 7 days, (++) at 14 days, and (+++) at 21 days; in group B, it was (+) at 14 and 21 days; in group C, it was (++) at 7 days and (+++) at 14 and 21 days. CONCLUSION: Topical application of insulin can promote the synthesis of wound collagen, accelerate the wound angiogenesis, and speed up the wound healing in aging DM rats.

[Detection of integron, homology and genotype of carbapenemases in multi-drug resistant Acinetobacter Baumannii isolated from burn wound].

OBJECTIVE: To investigate the relationship among antibiotic resistance, integron, homology of multi-drug resistant Acinetobacter Baumannii isolated from burn ward. METHODS: Thirty-one strains of multi-drug resistant Acinetobacter baumannii were isolated from samples of burn wound exudate in hospitalized patients of Gansu Province People's Hospital. The minimum inhibitory concentrations (MIC) of these strains against 11 antibiotics was examined by agar dilution method. Homology of these strains was analyzed by pulse-field gel electrophoresis (PFGE). Class 1, 2 and 3 integrase, integron genes and genotype of carbapenemases were amplified by PCR and verified by DNA sequencing. RESULTS: Acinetobacter baumannii were highly resistant to all antibiotics except imipenem, meropenem, cefoperazone-sulb-actam, piperacillin-tazobactam (antibiotic resistance rate was 45.2%, 48.4%, 48.4%, 41.0%, respectively). All strains were classified into 3 types of clones (A, B, C clone included 18, 7, 6 strains respectively) based on PFGE pattern. Integrons of 20 strains of Acinetobacter Baumannii harbored aadA1, aadA5, aacA4, aac3, catB8, aacC1, aac (6')-Ib, drfA17 and drf8 gene. CONCLUSION: Multi-drug resistance Acinetobacter baumannii (major in clone A) spread widely in burn ward of Gansu Province People's Hospital. Integrons of Acinetobacter baumannii mediated drug resistance against aminoglycoside antibiotics, chloramp-phenicol. All carbapenem-resistant Acinetobacter Baumannii can produce OXA-23 carbapenemase.

[Investigation of 728 strains of infectious bacteria in burn ward and analysis of their antibiotic resistance].

OBJECTIVE: To study the infectious strains of bacteria in our burn ward in recent 5 years, and analyze their antibiotic resistance. METHODS: Bacteria were isolated from the wound excretions of 306 burn patients hospitalized during 2001 to 2006 for analyzing their strains and their antibiotic resistance. RESULTS: 378 strains were Grams positive bacteria, among them Staphylococcus aureus was the predominant strain. Further analysis showed that methicillin resistant staphylococcus aureus (MRSA) ranked the first in occurrence, followed by methicillin-resistance Staphylococcus epidermidis (MRSE) and Enterococcus fecalis, 338 strains were Gram negative bacteria, and among them Acinetobacter baumannii was predominant, and Enterobacter cloacae and Pseudomonas aeruginosa ranked the 2nd and 3rd. Twelve strains were fungi. CONCLUSION: Drug resistance to antibiotics in our burn ward may be related to the beta-lactamases from acinetobacter baumannii and multiple-drug-resistance of MRSA.

[The isolation of acinetobacter strain from burn wound and the analysis of its antibiotic resistance].

OBJECTIVE: To investigate the distribution and drug resistance of acinetobacter isolated from burn wounds. METHODS: The acinetobacter strains were isolated and identified by routine methods. Based on the recommendation of NCCLS, AmpC enzyme was determined by cefoxiti three-dimensional test, ESBLs by disk diffusion method and bacterial susceptibility by Kirby-Bauer agar diffusion method. RESULTS: Among the 69 strains of acinetobacter clinically isolated from burn wounds, 52 were baumannii (75.6%). The acinetobacter strains were identified to be highly resistant to 17 kinds of antibiotics. The drug resistance rate of beta-lactamase-producing strains (68.25%) was higher than that of non-beta-lactamase-producing strains (20.33%). The strains isolated in our burn ward exhibited multiple drug resistance which was mainly due to the production of many kinds of beta-lactamases. Among the 38 strains of beta-lactamase-producing acinetobacter, those producing AmpC beta-lactamase (AmpC BLA) accounted for 42.1%. CONCLUSION: Acinetobacter strain was one of the pathogens in burn wound infection, and its isolation and identification of its drug resistance could be beneficial to the doctors to make right choice of antibiotics.