Overexpression of SPAG9 correlates with poor prognosis and tumor progression in hepatocellular carcinoma

Sperm-associated antigen 9 (SPAG9) was reported as a novel biomarker for several cancers and associated with the malignant behavior of cancer cells. However, its expression pattern and biological role in human hepatocellular carcinoma (HCC) have not been reported. In the present study, we analyzed SPAG9 expression in human HCC tissues by immunohistochemistry and found that SPAG9 overexpression is correlated with tumor stage (p?p?=?0.019), tumor size (p?=?0.034), AFP levels (p?=?0.006), and tumor relapse (p?=?0.0017). Furthermore, SPAG9 overexpression is correlated with poor overall survival (p?p?=?0.002). Transfection of SPAG9 small interfering RNA (siRNA) was performed in Bel-7402 cell line. Colony formation and MTT showed that SPAG9 siRNA knockdown inhibited HCC cell proliferation. We also found that SPAG9 depletion could increase cell apoptosis. In addition, the level of cyclin D1 and cyclin E protein expression was downregulated after siRNA treatment. In conclusion, SPAG9 is overexpressed in human HCC and serves as a prognostic marker. SPAG9 contributes to cancer cell growth through regulation of cyclin proteins.     

Rsf-1 overexpression in human prostate cancer,implication as a prognostic marker

Rsf-1 (HBXAP) was recently reported to be overexpressed in various cancers and associated with the malignant behavior of cancer cells. However, the expression of Rsf-1 and its clinical significance in human prostate cancer have not been reported. In the present study, we analyzed the expression pattern of Rsf-1 in human prostate cancer tissues and found that Rsf-1 was overexpressed in 45 % of prostate cancer specimens. There was a significant association between Rsf-1 overexpression and tumor stage (p?=?0.0039) and preoperative PSA level (p?=?0.015). Furthermore, Rsf-1 overexpression correlated with poor biomedical recurrence-free survival in prostate cancer patients (p?<?0.001). Rsf-1 overexpression could serve as an independent predictor for poor recurrence-free survival (p?=?0.012). In addition, small interfering RNA (siRNA) knockdown in DU145 cells with high endogenous Rsf-1 expression decrease cell proliferation, colony formation, and invasion. In conclusion, Rsf-1 is overexpressed in human prostate cancers and serves as a novel prognostic marker. Rsf-1 contributes to prostate cancer cell growth and invasion, which makes it a candidate therapeutic target.     

Rsf-1 overexpression correlates with poor prognosis and cell proliferation in colon cancer

Rsf-1 (HBXAP) was recently reported to be overexpressed in various cancers and associated with the malignant behavior of cancer cells. However, the expression of Rsf-1 and its biological roles in colon cancer have not been reported. The molecular mechanism of Rsf-1 in cancer aggressiveness remains ambiguous. In the present study, we analyzed the expression pattern of Rsf-1 in colon cancer tissues and found that Rsf-1 was overexpressed in 50.4?% of colon cancer specimens. There was a significant association between Rsf-1 overexpression and TNM stage (p?=?0.0205), lymph node metastasis (p?=?0.0025), and poor differentiation (p?=?0.0235). Furthermore, Rsf-1 overexpression correlated with a poor prognosis in colon cancer patients (p?=?0.0011). In addition, knockdown of Rsf-1 expression in HT29 and HCT116 cells with high endogenous Rsf-1 expression decrease cell proliferation and colony formation ability. Further analysis showed that Rsf-1 knockdown decreased cyclin E expression and phospho-Rb level. In conclusion, Rsf-1 is overexpressed in colon cancers and contributes to malignant cell growth by cyclin E and phospho-Rb modulation, which makes Rsf-1 a candidate therapeutic target in colon cancer.     

High expression of Golgi phosphoprotein-3 is associated with poor survival in patients with hepatocellular carcinoma

Golgi phosphoprotein 3 (GOLPH3) is recently demonstrated to function as an oncogene involved in the development and progression of cancers. However, little is known about GOLPH3 expression and its clinical significance in hepatocellular carcinoma (HCC). The levels of GOLPH3 messenger RNA (mRNA) and protein in HCC cell lines and fresh tissues were determined by quantitative RT-PCR and western blotting. Additionally, the protein expression of GOLPH3 was detected in 167 paraffin-embedded HCC samples by immunohistochemistry. GOLPH3 mRNA and protein was overexpressed in HCC cell lines and tissues than the immortalized normal hepatocyte cell line LO2 and the adjacent nontumorous live tissues, respectively. High GOLPH3 expression was positively correlated with high serum AFP level (P?=?0.015) and more tumor recurrence or metastasis (P?=?0.010). In addition, HCC patients with high GOLPH3 expression had poorer overall survival (hazard ratio (HR), 1.87; 95 % confidence interval (CI), 1.19–2.94; P?=?0.006) and poorer disease-free survival (HR, 1.90; 95 % CI, 1.21–2.98; P?=?0.005) than those with low GOLPH3 expression. The cumulative 5-year survival rate was only 35.19 % (95 % CI, 26.18–44.20 %) in the high GOLPH3 expression group, whereas it was 55.93 % (95 % CI, 43.26–68.60 %) in the low GOLPH3 expression group. Furthermore, multivariate Cox regression analysis demonstrated that the expression of GOLPH3, tumor size, and tumor multiplicity were independent prognostic predictors for HCC patients. GOLPH3 was overexpressed in HCC at both the mRNA and protein levels, and high expression of GOLPH3 could be served as a novel and potential prognostic biomarker for HCC patients.     

Overexpression of hSNF2H in glioma promotes cell proliferation,invasion, and chemoresistance through its interaction with Rsf-1

hSNF2H partners with Rsf-1 to compose the Rsf complex to regulate gene expression. Recent studies indicated that hSNF2H was overexpressed in several human cancers. However, its expression pattern and biological mechanism in glioma remain unexplored. In this study, we found that hSNF2H was overexpressed in 32 % of glioma specimens. hSNF2H overexpression correlated with advanced tumor grade (p?=?0.0338) and Rsf-1 positivity in glioma tissues (p?=?0.016). Small interfering RNA (siRNA) knockdown was performed in A172 and U87 cell lines. MTT, colony formation assay, and cell cycle analysis showed that knockdown of hSNF2H inhibited cell proliferation, colony formation ability, and cell cycle transition. Matrigel invasion assay showed that hSNF2H depletion inhibited invasive ability of glioma cells. In addition, we demonstrated that hSNF2H depletion decreased temozolomide resistance of A172 and U87 cell lines and increased temozolomide induced apoptosis. Furthermore, hSNF2H depletion decreased cyclin D1, cyclin E, p-Rb, MMP2, cIAP1, Bcl-2 expression, and phosphorylation of IκBα and p65, suggesting hSNF2H regulates apoptosis through NF-κB pathway. Immunoprecipitation showed that hSNF2H could interact with Rsf-1 in both cell lines. To validate the involvement of Rsf-1, we checked the change of its downstream targets in Rsf-1 depleted cells. In Rsf-1 depleted cells, changes of cyclin E, Bcl-2, and p-IκBα were not significant using hSNF2H siRNA treatment. In conclusion, our study demonstrated that hSNF2H was overexpressed in human gliomas and contributed to glioma proliferation, invasion, and chemoresistance through regulation of cyclin E and NF-κB pathway, which is dependent on its interaction with Rsf-1.     

Role of ZIC1 methylation in hepatocellular carcinoma and its clinical significance

Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies in humans, and its prognosis is generally poor even after surgery. The zinc finger of the cerebellum (ZIC1) gene is a novel tumor suppressor gene that plays a crucial role in vertebrate development. Altered expression of ZIC1 is observed in various types of human cancers. The aims of the present study were to investigate the methylation status of ZIC1 in HCC and evaluate its clinical implication. The methylation status of ZIC1 was analyzed in 132 pairs of HCC and corresponding noncancerous tissues by methylation-specific polymerase chain reaction (PCR) (MSP). The expression of ZIC1 messenger RNA (mRNA) in HCC tissues was examined by real-time PCR. Methylation frequency of ZIC1 in HCC was significantly higher than that in the corresponding noncancerous tissues (P?P?=?0.022), histological differentiation (P?=?0.033), and tumor stage (P?=?0.009). The downregulation of the ZIC1 mRNA expression in HCC was correlated with the ZIC1 methylation (P?P?mRNA and associated with poor survival in HCC. Overall, aberrant methylation is an important mechanism for ZIC1 inactivation in HCC, and ZIC1 methylation may be a promising biomarker for the diagnosis and prognosis of HCC.     

Prognostic significance of VEGFR1/Flt-1 immunoexpression in colorectal carcinoma

Colorectal carcinoma (CRC) is a major cause of morbidity and mortality. Vascular endothelial growth factor 1/Fms-like tyrosine kinase 1 (VEGFR1/Flt-1) regulates monocyte migration, recruits endothelial cell progenitors, increases the adhesive properties of natural killer cells and induces of growth factors. Flt-1 is expressed on tumour cells and has been implicated in tumour growth and progression. The objective of this study is to address the relation of Flt-1 expression to tumour prognostication. Paraffin blocks from 143 primary CRC and 48 regional nodal metastases were retrieved from the archives of the Department of Pathology at King Abdulaziz University. Tissue microarrays were designed and constructed. Immunohistochemistry for Flt-1 was performed. Staining intensity and extent of staining were assessed and combined. Results were dichotomised as low expression and high expression. Flt-1 was overexpressed in primary tumours and nodal metastasis (p?p?=?0.690). Flt-1 immunoexpression was not associated with the clinicopathological parameters. Flt-1 overexpression was an independent predictor of positive margin status, positive lymphovascular invasion and local disease recurrence (p?p?p?=?0.003, respectively). Flt-1 was not associated with survival (log-rank?=?0.003, p?=?0.959). Flt-1 was overexpressed in primary CRC and their nodal metastases. Flt-1 expression was an independent predictor of margin status, lymphovascular invasion and local disease recurrence. Therefore, expression profiling of Flt-1 seems to have a prognostic potential in CRC. However, to elucidate the association of overexpression of Flt-1 with tumour characteristics and prognostication, more in vivo and in vitro molecular investigations are recommended.     

NUCKS1 overexpression is a novel biomarker for recurrence-free survival in cervical squamous cell carcinoma

Nuclear casein kinase and cyclin-dependent kinase substrate 1 (NUCKS1) is overexpressed in various cancer tissues and may therefore contribute to oncogenesis. However, the status of NUCKS1 expression in cervical squamous cell carcinoma (CSCC) remains unknown. Immunohistochemistry was used to determine the expression of NUCKS1 protein in 30 cervical intraepithelial neoplasias (CINs) and 125 CSCCs compared with 20 normal cervical specimens. The correlationships of NUCKS1 protein overexpression with the clinicopathologic characteristics and clinical outcomes in patients with CSCC were analysed. The status of NUCKS1 expression was negative or weak in normal tissues, but high in 21 (70.0 %) CINs and in 44 (35.2 %) CSCCs. NUCKS1 overexpression was associated with advanced International Federation of Gynaecology and Obstetrics stage (P?=?0.016), poor histologic grade (P?=?0.040), large tumour size (P?=?0.016), parametrial involvement (P?=?0.025), deep stromal infiltration (P?=?0.043), lymph node metastasis (P?=?0.034) and recurrence (P?P?=?0.034). In conclusion, NUCKS1 overexpression may be associated with tumour progression and recurrence in CSCCs and may thus serve as a new molecular marker for the prediction of RFS in these patients.     

The NQO1 C609T polymorphism and hepatocellular carcinoma risk

NAD(P)H quinine oxidoreductase 1 (NQO1) enzyme plays a crucial role in the protection against oxidative stress. The polymorphism of NQO1 C609T has been implicated in the development of hepatocellular carcinoma (HCC). However, the findings were inconsistent due to different ethnicity, sample size, and source of controls in individual studies. To better estimate the association of NQO1 C609T polymorphism with HCC risk, we performed a meta-analysis of all currently available studies on the susceptibility to HCC. The meta-analysis included three independent studies with a total of 1, 595 subjects. The association was assessed under five different gene models. The overall analysis suggested that the variant allele and genotypes were significantly related to increased risk of HCC (OR_{T vs. C}?=?1.47, 95 % CI 1.07–2.00, P _OR?=?0.016; OR_{TT vs. CC}?=?2.06, 95 % CI 1.06–3.98, P _OR?=?0.032; OR_{TC vs. CC}?=?1.33, 95 % CI 1.06–1.67, P _OR?=?0.012; OR_{TT?+?TC vs. CC}?=?1.46, 95 % CI 1.19–1.81, P _OR?TT vs. CC?+?TC?=?1.62, 95 % CI 1.25–2.09, P _OR?NQO1 C609T variant allele and genotypes are more susceptible to HCC, particularly for Asians.     

Prognostic Value of Matrix Metalloproteinase-1/ Proteinase-Activated Receptor-1 Signaling Axis in Hepatocellular Carcinoma

Matrix metalloproteinase-1 (MMP-1) is proposed to be involved in both tumor cell invasion and metastasis. MMP-1 proteolytically activates protease activated receptor-1 (PAR-1), which also plays an important role in tumor development and progression. However, it is currently unknown whether MMP-1 activation of PAR-1 has relevance to the progression of hepatocellular carcinoma (HCC). To address this problem, we investigate the clinicopathological and prognostic value of MMP-1/PAR-1 signaling axis in HCC. Immunohistochemistry assay was used to determine the expression of MMP-1 and PAR-1 proteins in normal and HCC tissues. The correlations of MMP-1 and PAR-1 expression with clinicopathological parameters were assessed by Chi-squared test. Patient survival and their differences were determined by Kaplan-Meier method and log-rank test. Cox regression was adopted for multivariate analysis of prognostic factors. MMP-1 and PAR-1 immunoreactivities were negative or low in normal liver tissues, but high in HCC tissues. PAR-1 expression was significantly correlated with that of MMP-1 (r?=?0.896, p?P?P?P?P?相似文献   

ARMC8α promotes proliferation and invasion of non-small cell lung cancer cells by activating the canonical Wnt signaling pathway

ARMC8 proteins are novel armadillo repeat containing proteins, which are well conserved in eukaryotes and are involved in a variety of processes such as cell migration, proliferation, tissue maintenance, signal transduction, and tumorigenesis. Armadillo repeat proteins include well-known proteins such as β-catenin and p120ctn. Our current knowledge of ARMC8, especially its role in cancer, is limited. In this study, we quantified ARMC8 expression in 112 non-small cell lung cancer (NSCLC) tissues and adjacent non-cancerous tissues, and seven lung cancer cell lines using immunohistochemistry staining and Western blotting. ARMC8 level was significantly higher in NSCLC tissues than in the adjacent normal tissues (67.9 % versus 5.4 %, p?p?=?0.022), lymph node metastasis (p?=?0.001), and poor prognosis (p?NSCLC patients. Cox regression analysis demonstrated that ARMC8 was an independent prognostic factor for NSCLC. Consistent with this, ARMC8α downregulation by siRNA knockdown inhibited growth, colony formation, and invasion in A549 lung cancer cells, while ARMC8α overexpression promoted growth, colony formation, and invasion in H1299 lung cancer cells. In addition, ARMC8α knockdown downregulated canonical Wnt-signaling pathway activity and cyclin D1 and matrix metalloproteinase (MMP)-7 expression. Consistent with this, ARMC8α overexpression upregulated canonical Wnt-signaling pathway activity and cyclin D1 and MMP-7 expression. These results indicate that ARMC8α upregulates cyclin D1 and MMP7 expression by activating the canonical Wnt-signaling pathway and thereby promoting lung cancer cell proliferation and invasion. Therefore, ARMC8 might serve as a novel therapeutic target in NSCLC.     

The diagnostic,predictive, and prognostic role of serum epithelial cell adhesion molecule (EpCAM) and vascular cell adhesion molecule-1 (VCAM-1) levels in breast cancer

The purpose of this study was to determine the clinical significance of vascular cell adhesion molecule-1 (VCAM-1) and epithelial cell adhesion molecule (EpCAM) in breast cancer (BC) patients. Ninety-six BC patients and 30 age- and sex-matched healthy controls were enrolled into this study. Pretreatment serum markers were determined by the solid-phase sandwich (enzyme-linked immunosorbent assay (ELISA)). The median age at diagnosis was 48 years (range 29–80 years). Majority of the patients (71 %) had luminal subtype, and 38.5 % had metastatic disease. Twenty-nine (30 %) patients showed tumor progression, and 20 (21 %) patients died during follow-up. Median progression-free survival (PFS) and overall survival (OS) were 8.6?±?1.7 and 35.5?±?1.5 months, respectively. The baseline serum EpCAM levels of the patients were significantly higher than those of the controls (p?VCAM-1 between the patients and controls (p?=?0.47). No significant correlation was detected between the levels of the serum markers and other clinical parameters (p?>?0.05). Patients with HER-2-positive and triple-negative tumors had significantly poorer PFS (p?=?0.04 and p?=?0.001, respectively), while metastatic disease and chemotherapy unresponsiveness had significantly adverse effect on OS analysis (p?p?VCAM-1 levels nor serum EpCAM levels were identified to have a prognostic role on either PFS or OS (VCAM-1 p?=?0.76 and p?=?0.32; EpCAM p?=?0.16 and p?=?0.69, respectively). Even though any predictive or prognostic role could not be determined for both markers, serum levels of EpCAM were found to have diagnostic value in BC patients.     

RETRACTED ARTICLE: Downregulation of miR-148b as biomarker for early detection of hepatocellular carcinoma and may serve as a prognostic marker

MicroRNAs (miRNAs) have a large number of various target genes in different cancer types, which may result in many biological functions. Thus, identifying the molecular mechanisms of miRNAs may effect on the complexity of cancer progression via regulation of gene. In the current study, we utilized real-time PCR to quantify the diction of miR-148b in trail hepatocellular carcinoma (HCC) specimen and normal tissues. Furthermore, we evaluated the relationship of miR-148b and clinicopathological features with survival of HCC patients. Therefore, we evaluated the level of miR-148b expression in 101 HCC patients and also in 40 normal control cases. The result suggested lower expression in tumor tissues than normal control tissues (0.96?±?0.14; 1.84?±?0.20, P?<?0.05). Our findings suggest that the declined expression of miR-148b can considerably be linked to tumor node metastasis (TNM) stage (stages III and IV; P?=?0.021) and vein invasion (P?=?0.029). Nevertheless, miR-148b expression was not related to sex (P?=?0.674), age (P?=?0. 523), size of tumor (P?=?0.507), liver cirrhosis, and histologic grade (P?=?0.734). Survival analysis showed that low expression was remarkably related to overall survival (P?=?0.012). Furthermore, multivariate survival test suggested that decline of miR-148b diction was linked to poor survival in HCC patients. Our results suggested that miR-148b is decreased in HCC. Therefore, we concluded that miR-148b may play its role in the prognosis of HCC.     

KPT-330 inhibitor of XPO1-mediated nuclear export has anti-proliferative activity in hepatocellular carcinoma

Purpose

Exportin-1 (XPO1, CRM1) mediates the nuclear export of several key growth regulatory and tumor suppressor proteins. Cancer cells often overexpress XPO1 resulting in cytoplasmic mislocalization and aberrant activity of its target proteins. Orally bioavailable selective inhibitors of nuclear export (SINE) that irreversibly bind to and inhibit the function of XPO1 have been recently developed. The aim of this study was to investigate the efficacy of the clinical staged, orally available, SINE compound, KPT-330 in hepatocellular carcinoma (HCC).

Methods

In silico, meta-analysis showed that XPO1 is overexpressed in HCC. Six HCC cell lines were treated with KPT-330, and cell proliferation and expression of cell growth regulators were examined by cell proliferation assays and Western blot analysis, respectively. The in vivo anti-cancer activity of KPT-330 was examined in a HCC xenograft murine model.

Results

KPT-330 reduced the viability of HCC cell lines in vitro and this anti-proliferative effect was associated with cell cycle arrest and induction of apoptosis. The expression of the pro-apoptotic protein PUMA was markedly up-regulated by KPT-330. In addition, SINE treatment increased the expression of the tumor suppressor proteins p53 and p27, while it reduced the expression of HCC promoting proteins, c-Myc and c-Met. XPO1 levels itself were also down-regulated following KPT-330 treatment. Finally, a HCC xenograft murine model showed that treatment of mice with oral KPT-330 significantly inhibited tumor growth with little evidence of toxicity.

Conclusion

Our results suggest that SINE compounds, such as KPT-330, are promising novel drugs for the targeted therapy of HCC.     

Combination of radiofrequency ablation with transarterial chemoembolization for hepatocellular carcinoma: an up-to-date meta-analysis

The aim of this meta-analysis was to compare the effectiveness of combination of radiofrequency ablation (RFA) and transarterial chemoembolization (TACE) with that of RFA alone in patients with hepatocellular carcinoma (HCC). Randomized controlled trials comparing RFA plus TACE with RFA alone for HCC were included into this meta-analysis, and the search strategy followed the requirement of the Cochrane Library Handbook. Overall survival rate and recurrence-free survival rate were analyzed and compared by using Review Manager (version 5). We identified 7 randomized controlled trials comprising 571 patients who were treated by RFA plus TACE versus RFA alone for HCC. Meta-analyses showed that the combination of RFA and TACE was associated with a significantly higher overall survival rates (OR_{1 year}?=?2.39, 95 % CI, 1.35–4.21, P?=?0.003; OR_{3 years}?=?1.85, 95 %CI 1.26–2.71, P?=?0.002), and recurrence-free survival rate (OR_{1 year}?=?2.00, 95 % CI 1.26–3.18, P?=?0.003; OR_{3 years}?=?2.13, 95 %CI 1.41–3.20, P?TACE can improve the overall survival rate and the recurrence-free survival rate for patients with HCC.     

Diversin is overexpressed in human gliomas and its depletion inhibits proliferation and invasion

Previous study indicated diversin overexpression in human cancers. However, its expression pattern in human gliomas and the molecular mechanisms of diversin on cancer progression have not been characterized. In the present study, diversin expression was investigated in 105 glioma specimens using immunohistochemistry. Negative staining was observed in normal glial cells, and positive staining was found in 33 out of 105 (31.4 %) glioma specimens. Diversin overexpression correlated with advanced tumor grade (p?siRNA) knockdown was performed in U87 and TG905 cell lines with high endogenous diversin expression. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and colony formation assay showed that diversin knockdown inhibited glioma cell growth. Matrigel invasion assay showed that diversin depletion inhibited cell invasion. In addition, messenger RNA (mRNA) and protein levels of matrix metallopeptidase 9 (MMP9) were downregulated after siRNA treatment. In conclusion, diversin is overexpressed in human glioma and regulates glioma cell proliferation and invasion, possibly through MMP9.