Novel Immunotherapies for Osteosarcoma.

Osteosarcoma (OS) is the most common primary malignant bone sarcoma mainly affecting adolescents and young adults, which often progresses to pulmonary metastasis and leads to the death of OS patients. OS is characterized as a highly heterogeneous cancer type and the underlying pathologic mechanisms triggering tumor progress and metastasis are incompletely recognized. Surgery combined with neoadjuvant and postoperative chemotherapy has elevated 5-year survival to over 70% for patients with localized OS tumors, as opposed to only 20% of patients with recurrence and/or metastasis. Therefore, novel therapeutic strategies are needed to overcome the drawbacks of conventional treatments. Immunotherapy is gaining momentum for the treatment of OS with an increasing number of FDA-approved therapies for malignancies resistant to conventional therapies. Here, we review the OS tumor microenvironment and appraise the promising immunotherapies available in the management of OS.

Physcion-8-O-ß-d-glucoside interferes with the nuclear factor-κB pathway and downregulates P-glycoprotein expression to reduce paclitaxel resistance in ovarian cancer cells.

OBJECTIVE: This study assessed whether physcion-8-O-beta-D-monoglucoside (PG) sensitises paclitaxel (PTX)-resistant ovarian cancer cells and explored the underlying mechanism. METHODS: Ovarian cancer SK-OV-3 cells were used to establish PTX-resistant SK-OV-3 (SK-OV-3/PTX) cells. The Cell Counting Kit-8 assay and crystal violet staining were used to determine cell viability. P-glycoprotein (P-gp) and nuclear factor (NF)-κB expression and cell distributions were detected using immunofluorescence. Cell apoptosis and protein expression changes were detected using flow cytometry and western blotting, respectively. Effect of PG in vivo was evaluated using a xenograft tumour model. P-gp expression in tumour tissues was detected using immunohistochemical staining. KEY FINDINGS: PG (1-10 µm) did not significantly affect SK-OV-3/PTX cell proliferation but significantly downregulated P-gp expression. PG pretreatment (1-10 µm) enhanced PTX cytotoxicity. PG treatment decreased the quantity of phosphorylated-NF-κB p65 in SK-OV-3/PTX cell total proteins and upregulated IKBα expression. Simultaneously, it decreased NF-κB p65 levels in nuclear proteins. PG (1-10 µm) inhibited NF-κB p65 entry into the nucleus. PTX plus PG significantly inhibited SK-OV-3/PTX xenograft tumour growth. PG (1-10 µm) reduced P-gp expression in transplanted tumour tissue. CONCLUSIONS: PG can enhance the sensitivity of PTX-resistant ovarian cancer cells SK-OV-3/PTX to PTX, and this effect is related to inhibiting NF-κB from entering the nucleus and down-regulating the expression of P-gp protein.

miRNA­199b­3p suppresses growth and progression of ovarian cancer via the CHK1/E­cadherin/EMT signaling pathway by targeting ZEB1.

Ovarian cancer is one of the most common gynecological malignancies and its pathogenesis and progression are regulated by multiple genes. MicroRNAs (miRNAs) are endogenous non­coding RNAs that regulate body function by altering post­transcriptional gene expression. Previous studies have suggested that miRNAs are closely associated with the pathogenesis and progression of several malignancies, including breast cancer, hepatocellular carcinoma and glioma, among others. Therefore, miRNAs are promising novel targets for the diagnosis, treatment and determination of prognostic factors in patients with ovarian cancer. In the present study, the role of miRNA­133b­3p in ovarian cancer progression and its possible mechanism of action were investigated. The results demonstrated that the expression of miRNA­199b­3p and zinc finger E­box binding homeobox (ZEB)1 were increased in patients with ovarian cancer. The overall survival (OS) and disease­free survival (DFS) of patients with ovarian cancer and high miRNA­199b­3p expression were prolonged compared with those of patients with low miRNA­199b­3p expression. Additionally, the OS and DFS of patients with ovarian cancer and low ZEB1 expression were longer compared with those of patients with high ZEB1 expression. Furthermore, miRNA­199b­3p overexpression reduced cell proliferation and promoted apoptosis in an in vitro model of ovarian cancer. miRNA­199b­3p overexpression also suppressed ZEB1 and checkpoint kinase 1 expression and induced E­cadherin expression and epithelial­to­mesenchymal transition in this model. Furthermore, the effects of miRNA­199b­3p­mediated apoptosis and migration were attenuated by ZEB1 and E­cadherin, respectively. The results of the present study indicated that miRNA­199b­3p suppressed ovarian cancer progression by targeting ZEB1, which may represent a promising therapeutic target for ovarian cancer.

LncRNA PLAC2 Positively Regulates CDK2 to Promote Ovarian Carcinoma Cell Proliferation.

BACKGROUND: PLAC2 has been reported to participate in glioma, but its role in ovarian carcinoma (OC) is unclear. This study investigated the role of lncRNA PLAC2 in OC. METHODS: A 5-year follow-up study of 64 patients was carried out in Weihai Municipal Hospital after the admission of patients. A total of 64 OC patients were selected from 178 OC patients admitted in the aforementioned hospital from August 2011 to January 2014. Cell transfections, cell cycle analysis, cell proliferation assay and Western blot were carried out during the research. RESULTS: The expression levels of PLAC2 and CDK2 were both upregulated in OC and they were positively correlated. During the 5-year follow-up, patients with high levels of PLAC2 and CDK2 showed significantly lower overall survival rate. In OC cells, overexpression of PLAC2 resulted in upregulated, while silencing of PLAC2 resulted in downregulated expression of CDK2. Cell proliferation assay showed that overexpression of PLAC2 resulted in increased, while silencing of PLAC2 resulted in decreased proliferation rate of OC cells. In addition, overexpression of CDK2 attenuated the effects of silencing of PLAC2. CONCLUSION: PLAC2 positively regulates CDK2 to promote OC cell proliferation.

Weighted gene correlation network analysis reveals novel regulatory modules associated with recurrent early pregnancy loss.

At present, the etiology and pathogenesis of recurrent early pregnancy loss (REPL) are not completely clear. Therefore, identifying the underlying diagnostic and prognostic biomarkers of REPL can provide new ideas for the diagnosis and treatment of REPL. The chip data of REPL (GSE63901) were downloaded from the NCBI Gene Expression Omnibus (GEO) database. Weighted Gene Co-Expression Network Analysis (WGCNA) was used to construct a co-expression module for studying the relationship between gene modules and clinical features. In addition, functional analysis of hub genes in modules of interest was performed. A total of 23 co-expression modules were identified, two of which were most significantly associated with three clinical features. The MEbrown module was positively correlated with cyclin E level and the out-of-phase trait while the MEred module was positively correlated with the effect of progesterone. We identified 17 hub genes in the MEred module. The functional enrichment analysis indicated that such hub genes were mainly involved in pathways related to cellular defense response and natural killer (NK) cell-mediated cytotoxicity. In the MEbrown module, we identified 19 hub genes, which were mainly enriched in cell adhesion molecule production, regulation of cellular response to growth factor stimulus, epithelial cell proliferation, and transforming growth factor-ß (TGF-ß) signaling pathway. In addition, the hub genes were validated by using other datasets and three true hub genes were finally obtained, namely DOCK2 for the MEred module, and TRMT44 and ERVMER34-1 for the MEbrown module. In conclusion, our results screened potential biomarkers that might contribute to the diagnosis and treatment of REPL.

Effects of ectopic HER-2/neu gene expression on the COX-2/PGE2/P450arom signaling pathway in endometrial carcinoma cells: HER-2/neu gene expression in endometrial carcinoma cells.

OBJECTIVES: To investigate the role of HER-2/neu-mediated COX-2/P450arom signal in estrogen-dependent endometrial carcinoma. METHODS: The recombinant eukaryotic expression vector, pcDNA3.1-HER-2/neu, was constructed and transfect to Ishikawa endometrial carcinoma cells. The expression of COX-2 and P450arom in transfected cells were detected by real-time PCR and western blotting. The levels of estrogen in cell supernatants were detected by ELISA. RESULTS: Over-expression of HER-2/neu in transfected cells was confirmed by real-time PCR and western blotting. The levels of autocrine estrogen in transfected cells was significantly increased which combination with the enhancement of COX-2 and P450arom expression in transfected cells. CONCLUSION: HER-2/neu induced the improvement of autocrine estrogen in endometrial carcinoma cell through triggering the COX-2/P450arom signal.

Relevance of Bcl-x expression in different types of endometrial tissues.

OBJECTIVES: To explore the roles of Bcl-xl and Bcl-xs in the development and progression of endometrial carcinoma, and to analyze the correlation between Bcl-xl and Bcl-xs. METHODS: RT-PCR and Western-blot assay were applied to detect the expressions of Bcl-xl and Bcl-xs in endometrial tissues of various histomorphologic types. RESULTS: The Bcl-xl expression levels of simple and atypical hyperplasia endometrial tissues were not significantly different from that of normal endometrial tissue (both P > 0.05). On contrary, Bcl-xl expression in endometrial carcinoma tissue was significantly higher than the normal endometrial tissue (P = 0.00), which was correlated with the pathological grading of endometrial carcinoma (F = 5.33, P = 0.02). In addition, Bcl-xs mRNA level in simple hyperplasia endometrial tissue had no significant difference compared to that in normal endometrial tissue (P = 0.12), while the levels of atypical hyperplasia and endometrial carcinoma endometrial tissues were significantly different from the normal endometrial tissue (both P = 0.00). Furthermore, level of Bcl-xs mRNA was correlated with the clinical staging and lymph node metastasis of the endometrial carcinoma (P < 0.05). The expressions of Bcl-xl and Bcl-xs were negatively correlated with each other (r = -0.76). CONCLUSION: The abnormal expressions of Bcl-xs and Bcl-xl were one of the molecular mechanisms for the pathogenesis of endometrial carcinoma, and altered ratio between these two might involve in the onset of endometrial carcinoma.