The Clinical Implications of Human Telomerase Reverse Transcriptase Expression in Grade and Prognosis of Gliomas: a Systematic Review and Meta-analysis.

Human telomerase reverse transcriptase (hTERT), a ribonucleoprotein, is reported as an important complex, which is required for stability of DNA molecular structure at the rear of the chromosome. Until now, hTERT has been linked to cell immortalization and tumorigenesis. A couple of articles have been published about the telomerase function in the gliomas; however, these results are conflicting in some degree. Thus, it is crucial to perform a meta-analysis to identify their real actions. We included eligible articles, and estimated odds ratios (ORs) with 95 % confidence intervals (95 % CIs). In our meta-analysis, all 15 eligible articles included 932 patients. Results from 10 studies on WHO grade showed that high hTERT gene or protein expression in glioma tissues was obviously related to high WHO grade (III + IV) (OR 2.45, 95 % CI 1.92-3.13; p = 0.000). What is more, hTERT expression was not associated with old age (OR 0.91, 95 % CI 0.72-1.16; p = 0.448) as well as gender (OR 1.06, 95 % CI 0.82-1.37; p = 0.664). Importantly, hTERT expression was significantly associated with 5-year overall survival (OS; n = 3; hazard ratio (HR) 2.25, 95 % CI 1.36-3.70; p = 0.002) of glioma patients. No heterogeneity was found in all studies. In conclusion, this meta-analysis suggests that hTERT is significantly associated with high glioma grade and poor 5-year overall survival, and pathological test of hTERT mRNA and protein in glioma tissues should be suggested as criteria of glioma grade in the clinical practice.

Crk-like adapter protein regulates CCL19/CCR7-mediated epithelial-to-mesenchymal transition via ERK signaling pathway in epithelial ovarian carcinomas.

Recent studies have suggested that Crk-like adapter protein (CrkL) and epithelial-to-mesenchymal transition (EMT) induced by CCL19/CCR7 play an important role in ovarian epithelial carcinogenesis. However, the regulatory mechanisms of CrkL on the CCL19/CCR7 signaling pathways in epithelial ovarian carcinomas (EOC) are not well characterized. Here, CCR7 and CrkL proteins were tested in 30 EOC tissues and cell lines. In vitro, the roles of CrkL in CCL19-stimulated SKOV-3 cell invasion and migration were investigated. In this work, CCR7 and CrkL over-expressed in EOC tissues and cell lines and correlated with FIGO stage and lymph node metastasis. Moreover, CCR7 and CrkL serve as an independent prognostic factor. In SKOV-3 cells, CrkL knockdown markedly suppressed the CCL19-stimulated expression of p-ERK and EMT biomarkers (N-cadherin, Snail and MMP9), compared with control. In contrast, p-AKT expression level did not change. On the other hand, functional analysis revealed CrkL knockdown could significantly decrease SKOV-3 cell invasion number of transwell invasion assay, and wound closure area of wound healing assay, compared to control. In conclusion, CrkL regulates CCL19/CCR7-induced EMT via ERK signaling pathway in EOC patients, which further suggested CrkL could be suggested as an efficient target in ovarian cancer treatment.

Crk-like adapter protein is required for TGF-ß-induced AKT and ERK-signaling pathway in epithelial ovarian carcinomas.

Crk-like adapter protein (CrkL) was identified as an important biomarker in epithelial ovarian carcinomas. At the same time, the transforming growth factor ß (TGF-ß) pathway plays a key role in oncogenesis of advanced cancers. However, more detailed regulation mechanisms are still unclear. So we investigated the role of CrkL in TGF-ß pathways in epithelial ovarian carcinomas. The small interfering RNA (siRNA) was used to suppress CrkL in serous papillary cystic adenocarcinoma (SKOV-3) cell line, TGF-ß downstream signal molecules AKT and ERK phosphorylation status was tested using the Western blot. Wound healing assay was used to evaluate the capacity of cell migration and proliferation. In this study, CrkL can be activated by TGF-ß1 treatment and inhibited by siCrkL. CrkL knockdown markedly suppressed the phosphorylated ERK (p-ERK) as well as the phosphorylated AKT (p-AKT) (p < 0.001) compared with control or TGF-ß1 alone. On the other hand, CrkL knockdown could significantly affect SKOV3 wound closure (p < 0.001) using wound healing assay compared to siControl. In conclusion, CrkL protein is required for TGF-ß signal pathways through AKT and ERK pathway, which can mediate the development of epithelial ovarian carcinomas. CrkL plays a key regulation role in TGF-ß signaling pathway of epithelial ovarian carcinomas, and this study suggested CrkL could be suggested as an efficient target in ovarian cancer treatment.

The clinical implications of Crk-like adaptor protein expression in papillary thyroid microcarcinoma.

Papillary thyroid microcarcinoma (PMC) is the most common subtype of thyroid carcinomas with satisfactory prognosis. Crk-like (CrkL) adaptor protein was identified in the development of many carcinomas. However, the clinical implications of CrkL protein in PMC were still unknown. Here, we conducted immunohistochemistry to test and analyze CrkL expression in papillary thyroid carcinoma (PTC) (50 cases), PMC (50 cases), and nodular goiter (50 cases), and then western blot further identified the expression of CrkL proteins. In our present study, the positive rate and the mean optical density (MOD) value of CrkL expression in PTC and PMC tissues were statistically significantly different, compared with nodular goiter (p = 0.021, 0.037) and normal thyroid tissues (p = 0.003, 0.009), respectively. In addition, CrkL expression was not associated with age, gender, and tumor number. Conversely, significant differences between CrkL expression and metastasis (p < 0.01) and violation of capsule (p < 0.01) were observed. Notably, western blot indeed identified that the metastasis group of either PTC or PMC tissues had about twofold increased expression of CrkL compared with their non-metastasis groups (p < 0.05). In conclusion, CrkL is highly expressed in papillary thyroid carcinoma and papillary thyroid microcarcinoma and closely correlated to metastasis. Therefore, it is essential to carry out neck lymph node clearance in patients with papillary thyroid microcarcinoma.

The essential roles of CCR7 in epithelial-to-mesenchymal transition induced by hypoxia in epithelial ovarian carcinomas.

The chemokine receptor CCR7 and its ligands CCL19/21 mediate the tumor mobility, invasion, and metastasis (Wu et al. Curr Pharm Des. 15:742-57, 2009). Hypoxia induced epithelial-to-mesenchymal transition (EMT) to facilitate the tumor biology. Here, we addressed the roles of CCR7 in epithelial ovarian carcinoma tissues and hypoxia-induced serous papillary cystic adenocarcinoma (SKOV-3) EMT. The expression level of CCR7 protein was analyzed by immunohistochemistry in 30 specimens of epithelial ovarian carcinomas. Western blot was used to investigate the expression of hypoxia-induced CCR7, HIF-1α, and EMT markers (N-cadherin, Snail, MMP-9). In addition, wound healing and Transwell assay were introduced to observe the capacity of migration and invasiveness. Our data showed CCR7 expression was observed in 22 cases of tissues and closely associated with lymph node metastasis and FIGO stage (III + IV). At 6, 12, 24, and 36 h following hypoxia, CCR7 and HIF-1α proteins were both obviously upregulated in a time-dependent method, compared with normal oxygen. In vitro, SKOV-3 expressed N-cadherin, Snail, and MMP-9 once either CCL21 stimulation or hypoxia induction, while hypoxia accompanied with CCL21 induction exhibited strongest upregulation of N-cadherin, Snail, and MMP-9 proteins. Besides, wound healing and Transwell assay further identified that hypoxia with CCL21 stimulation can remarkably promote cell migration and invasiveness. Taken together, CCR7 can constitutively express in epithelial ovarian carcinomas and be induced rapidly in response to hypoxia, which indeed participates in EMT development and prompts the cell migration and invasion. Thus, this study suggested that the epithelial ovarian cancer invasion and metastasis can be inhibited by antagonizing CCR7.

The correlation of bone morphogenetic protein 2 with poor prognosis in glioma patients.

Glioma is the most common type of human intracranial cancers and has poor prognosis. Bone morphogenetic protein 2 (BMP2) plays important roles in cancer cell signalings (Vecht et al. Oncologist 19:751-9, 2014). Here, we aimed to investigate the correlation of BMP2 with patient prognosis as well as pathological indicators. Immunohistochemistry was used to test BMP2 proteins in 45 gliomas of distinct malignancy grade, and Kaplan-Meier survival analysis was performed to assess prognostic significance. BMP2 protein was also detected in cell lines by Western blot. We observed that BMP2 protein was stained in 44.4% (20 out of 45) of all glioma tissues, including 32.1% of low-grade (I + II) gliomas and 52.9% of high-grade (III + IV) gliomas. Grade IV gliomas potently expressed BMP2 proteins. Western blot showed BMP2 protein expressed in cell lines NHA, A172, T98G, U87, and U251. In addition, BMP2 expression was significantly associated with WHO grade (p = 0.024). According to log-rank test and Cox regression model, BMP2 can be suggested as an independent prognostic factor, apart from WHO grade. Taken together, BMP2 is differently highly expressed in different grades of gliomas and correlated to WHO grade. BMP2 also independently indicates poor prognosis in old glioma patients, which is indicative of an effectively therapeutic target.

Cell surface nucleolin is crucial in the activation of the CXCL12/CXCR4 signaling pathway.

Recently, CXCL12-CXCR4 has been focused on therapeutic strategies for papillary thyroid carcinoma (PTC) and other cancers. At the same time, cell surface nucleolin is also over-expressed in PTC and others. Interestingly, a few reports suggest that either CXCR4 or cell surface nucleolin is a co-receptor for HIV-1 entry into CD4+ T cells, which indicates that there is a relationship between CXCR4 and nucleolin. In this study, antibody and siRNA were used to identify effects of cell surface nucleolin and CXCR4 on cell signaling; soft-agar colony formation assay and Transwell assay were used to determine roles of nucleolin and CXCR4 in cell proliferation and migration. Importantly, co-immunoprecipitation was used to demonstrate the relationship between CXCR4 and nucleolin. Results showed CXCR4 and nucleolin were co-expressed in PTC cell line K1, B-CPAP, and TPC-1. Either cell surface nucleolin or CXCR4 was necessary to prompt extracellular signal-regulated kinase phosphorylation. When blocked, CXCR4 or nucleolin can significantly affect TPC-1 proliferation and migration (p < 0.01). Co-immunoprecipitation analysis identified that nucleolin can bind and interact with CXCR4 to activate CXCR4 signaling. This study suggests that nucleolin is crucial in the activation of CXCR4 signaling, which affects cell growth, migration, and invasiveness. Further, nucleolin may interact with other receptors. Our study also offers new ideas for cancer therapy.