Increased chemokine receptor IL-17RA expression is associated with poor survival in gastric cancer patients

Background: Previous researchers have identified that the chemokine interleukin-17 (IL-17) was associated with survival time of patients with gastric cancer, but the roles of its receptors (IL-17R) in gastric cancer remain unknown. Our studies were designed to clarify the function of IL-17RA and to explore their potential role in gastric cancer. Materials and methods: The expression of IL-17RA was determined in primary gastric cancer tissues (n=101) using Real-time RT-PCR, immunohistochemistry, and western blotting. To investigate the functional significance of IL-17RA expression, IL-17RA expression and clinical parameters, multivariate survival was analyzed in patients with gastric cancer. Results: IL-17RA was overexpression in gastric cancer tissues compared with adjacent normal tissues (P<0.05). The elevated expression level of IL-17RA was observed correlated significantly with tumor progression (P=0.003), Lymphatic invasion (P=0.019), lymphoid nodal status (P=0.001), distant metastasis (P<0.001) of gastric cancer patients, TNM stage (P=0.0013) and was one of the independent prognostic factors for patient’s overall survival. Conclusions: These results demonstrated that the expression of IL-17RA plays an important role in gastric cancer progression, migration and prognosis of gastric cancer. The IL-17-IL-17RA signaling mechanism may be a potential novel target.     

High expression of integrin-linked kinase predicts aggressiveness and poor prognosis in patients with gastric cancer

Integrin-linked kinase (ILK), an intracellular serine/threonine protein kinase, has been reported to be highly expressed in many human malignancies, including gastric cancer. However, the prognostic significance of ILK expression in gastric cancer remains to be elucidated. In the present study, ILK expression in 95 gastric tumor tissues and 30 adjacent non-cancerous gastric mucosa was evaluated by immunohistochemistry and correlated with clinicopathological characteristics and patients’ outcome. The results showed that high ILK expression was observed in 47.4% (45/95) of gastric cancer tissues, but only in 20.0% (6/30) of adjacent gastric mucosa. Clinicopathological analysis indicated that high ILK expression was significantly associated with poor tumor differentiation (P = 0.024), advanced TNM stage (P = 0.006), tumor invasion (P = 0.001), and lymph node metastasis (P = 0.014). Kaplan–Meier survival curves demonstrated that patients with high ILK expression had substantially shorter overall survival that those with low ILK expression (P = 0.043, log-rank test). Furthermore, Cox multivariate regression analysis identified ILK expression as an independent prognostic factor for overall survival of gastric cancer patients (hazard ratio, 1.95; 95% confidence interval, 1.02–3.13; P = 0.026). In conclusion, our data suggest that ILK may contribute to the malignant progression of gastric cancer and serve as a novel prognostic indicator for gastric cancer patients.     

Decreased expression of SEMA3A is associated with poor prognosis in gastric carcinoma

Background/purpose: SEMA3A (semaphorin-3A), is a secreted protein that belongs to the semaphorin family and can function as both a chemoattractive agent or a chemorepulsive agent. SEMA3A has been shown to be a tumor suppressor in various cancers. This study investigated the expression of SEMA3A in gastric cancer and its prognostic value for gastric cancer patients. Methods: We examined the expression of SEMA3A in paired cancerous and matched adjacent noncancerous gastric mucosa tissues by real-time quantitative RT-PCR (qRT-PCR) and western blotting. In vitro, we evaluate the effects of SEMA3A on gastric cancer cell proliferation and migration by MTT, transwell and wound-healing assays. Furthermore, we analyzed SEMA3A expression in 128 patients who underwent resection procedures using immunohistochemistry. The relationships between the SEMA3A expression levels, the clinicopathological factors, and patient survival were investigated. Results: Our results revealed decreased SEMA3A mRNA (P = 0.0037) and protein (P = 0.033) expression in tumor tissue samples compared with matched adjacent non-tumorous tissue samples. Overexpression of SEMA3A inhibits gastric cancer cell proliferation and migration in vitro. Immunohistochemical staining data showed that SEMA3A expression was significantly decreased in 54.68% of gastric cancer cases. In addition, the chi-square test revealed that low SEMA3A expression was significantly correlated with poor differentiation (P = 0.015), Vascular invasion (P = 0.001), depth of invasion (P < 0.001), lymph node metastasis (P = 0.029), distant metastasis (P = 0.002) and advanced TNM stage (P = 0.003). SEMA3A expression was positively correlated with clinical TNM stage, that suggested the more advanced clinical TNM stage corresponding to the lower expression level of SEMA3A (r_s = -0.322, P < 0.001) by Spearman rank correlation analysis. Kaplan-Meier survival analysis demonstrated that low expression of SEMA3A was significantly correlated with a poor prognosis for gastric cancer patients (P < 0.001). The multivariate analysis revealed that SEMA3A expression was an independent prognostic factor of the overall survival rate of patients with gastric cancer. Conclusion: SEMA3A expression decreased significantly as gastric cancer progressed and metastasized, suggesting that SEMA3A might serve as a candidate tumor suppressor and a potential prognostic biomarker in gastric carcinogenesis.     

Expression of Tim-3 in gastric cancer tissue and its relationship with prognosis

As a negative regulatory molecule, T-cell immunoglobulin–and mucin domain-3 (Tim-3) plays a crucial role in the tumor immunological tolerance. In the present study, we aimed to determine the Tim-3 expression in gastric cancer tissue and its relationship with clinicopathological parameters and prognosis. The Tim-3 expression was assessed in 52 gastric cancer specimens and 15 gastritis tissues by flow cytometry, and gastritis tissues served as the control. As a result, we found that the Tim-3 expressions on CD4⁺T cells and CD8⁺T cells in gastric cancer tissue was significantly higher than those in gastritis tissue (P=0.022, P=0.047, respectively). The median expression level of Tim-3 on CD4⁺T cells were significantly correlated with clinicopathological parameters, such as tumor size, lymph node metastasis, the depth of tumor invasion and TNM staging (P=0.042, P=0.026, P=0.001, P=0.003, respectively), while it was not correlated with sex, age and histological subtype (all P>0.05). In CD8⁺T cells, the Tim-3 expression was relevant to tumor invasion and TNM staging (P=0.035, P=0.017, respectively), while it was irrelevant to other clinicopathological parameters (all P>0.05). Additionally, Kaplan-Meier survival curves showed that the median overall survival time of patients with lower Tim-3 expression was greater than that of patients with higher Tim-3 expression in CD4⁺T cells and CD8⁺T cells (χ²=18.036, P<0.001 and χ²=18.036, P<0.001, respectively). Moreover, the multivariate analysis revealed that the Tim-3 expression and TNM stage were independent prognostic factors for gastric cancer patients (P=0.029, P=0.043 and P=0.003, respectively). These results suggest that Tim-3 played an important role in the development and progression of gastric cancer, and it could be used as an independent prognostic factor for gastric cancer patients.     

Expression of ITGB1 predicts prognosis in colorectal cancer: a large prospective study based on tissue microarray

Background: ITGB1 is a heterodimeric cell-surface receptor involved in cell functions such as proliferation, migration, invasion and survival. The aim of this study was to assess ITGB1 expression in colorectal cancer and correlate it with clinicopathological features, as well as to evaluate its potential prognostic significance. Materials and methods: In this study, we examined the expression of ITGB1 using tissue microarrays containing analyzed specimens by immunohistochemistry. ITGB1 expression was further correlated with clinicopathological and prognostic data. The prognostic significance was assessed using Kaplan-Meier survival estimates and log-rank tests. A multivariate study with the Cox’s proportional hazard model was used to evaluate the prognostic aspects. Results: ITGB1 expression was present in 88.5% of the analyzed specimens. Significant differences in ITGB1 expression were found between normal mucosa and carcinomas (P<0.001). High ITGB1 expression was associated with poor prognosis, and it independently correlated with shortened overall survival and disease-free survival in colorectal cancer patients (P<0.001). More so, ITGB1 expression, bowel wall invasion, lymph node metastasis and distant metastasis were independent prognostic factors for overall survival. Additionally, significant differences in ITGB1 expression were observed in adenomas and tumors from patients with familial adenomatous polyposis compared to normal colon mucosa (P<0.05) Conclusion: The results of this study indicate that ITGB1 overexpression in colorectal tumors is associated with poor prognosis, as well as aggressive clinicopathological features. Therefore, ITGB1 expression could be used as potential prognostic predictor in colorectal cancer patients.     

Focal adhesion kinase (FAK) gene amplification and its clinical implications in gastric cancer

Focal adhesion kinase, a nonreceptor tyrosine kinase, is known to be associated with tumor progression in various tumors. Because the clinical implications of focal adhesion kinase overexpression in gastric cancer have been inconsistent, we extended previous studies and evaluated focal adhesion kinase gene amplification as well as its protein expression. Immunohistochemical tissue array analysis showed that focal adhesion kinase immunoreactivity was present in both the cytoplasm and membrane of gastric cancer cells. Diffuse immunoreactivity of focal adhesion kinase protein in cytoplasm or membrane was found in 240 (54%) or 263 (59%) of 444 surgical samples, respectively, and positively correlated with tumor size, depth of tumor infiltration, nodal metastasis, distant metastasis, lymphatic invasion, and venous invasion (P < .001). Regarding focal adhesion kinase gene amplification, fluorescence in situ hybridization analysis showed focal adhesion kinase gene amplification in 34 (8.9%) of 384 gastric cancer specimens, whereas there was no amplification in any case of atrophy, intestinal metaplasia, or adenoma/dysplasia. Focal adhesion kinase gene amplification was positively associated with age (P = .012), tumor size (P = .007), nodal metastasis (P = .021), distant metastasis (P = .029), lymphatic invasion (P = .006), venous invasion (P = .032), and perineural invasion (P = .023). Focal adhesion kinase protein expression and gene amplification were positively correlated with each other, and each of them was found to be an independent poor prognostic factor (P < .01). In conclusion, our results showed that either focal adhesion kinase protein expression or focal adhesion kinase gene amplification was significantly correlated with cancer progression and poor prognosis in gastric cancer. Thus, focal adhesion kinase gene amplification could supplement its protein expression for the diagnosis and treatment of gastric cancer.     

Prognostic relevance of cyclooxygenase-2 (COX-2) expression in Chinese patients with prostate cancer

Cyclooxygenase-2 (COX-2), an inducible isoform of cyclooxygenase, has been reported to be correlated with tumorigenesis, tumor progression and metastasis. The present study was designed to investigate the clinicopathological and prognostic significance of COX-2 in Chinese patients with prostate cancer. Firstly, RT-PCR and Western blot assays were performed to detect the expression of COX-2 mRNA and protein in prostate cancer cell lines and 20 tissue samples (tumor or corresponding non-tumor). Next, immunohistochemistry was performed to detect the expression of COX-2 protein in 88 prostate cancer tissue samples. Finally, the correlation between COX-2 expression and clinicopathological factors and patient survival was evaluated. We found that the expression levels of COX-2 mRNA and protein showed significant difference among four prostate cancer cell lines. Moreover, the levels of COX-2 mRNA and protein were significantly higher in prostate cancer tissues than in corresponding non-tumor tissues. COX-2 staining was positive in the cytoplasm of prostate cancer cells. High-COX-2 expression was correlated with the Gleason score (P=0.009), tumor stage (P=0.012), and lymph-node status (P=0.036). Furthermore, patients with high-COX-2 expression showed lower disease-free (P=0.014) and overall survival (P=0.047) rates than those with low-COX-2 expression. Univariate and multivariate analyses suggested that the status of COX-2 protein expression was an independent prognostic indicator for patients’ survival. Taken together, higher COX-2 protein expression might provide an independent prognostic marker for Chinese patients with prostate cancer who have undergone surgery.     

Expression and clinical significance of FOS-like antigen 1 in gastric adenocarcinoma

BackgroundThe overexpression of FOS-like antigen 1 (FOSL1) in several types of cancers was reported before. However, the expression and clinical significance of FOSL1 in gastric cancer (GC) have not been elucidated.Materials and methodsThe expression of FOSL1 in 105 cases of GCs was detected with immunohistochemistry, and the mRNA of FOSL1 was investigated with quantitative real-time polymerase chain reaction(qRT-PCR) in 15 pairs of GCs and tumor adjacent tissues. With Chi-square test or Fisher test, we analyzed the correlation between FOSL1 expression and clinicopathological factors. With univariate analysis, we evaluated the correlations between clinicopathological factors including FOSL1 and overall survival (OS) rates. With multivariate analysis, we identified the independent prognostic risk factors of GC.ResultsThe percentages of patients with low and high FOSL1 expression in our study accounted for 43.81% and 56.19%, respectively. The mRNA levels of FOSL1 in GCs were significantly higher than those in tumor adjacent tissues. FOSL1 expression was demonstrated to be significantly correlated with lymphatic invasion (P = 0.036) and TNM stage (P = 0.016). High expression of FOSL1 was significantly correlated with lower 5-year OS (P = 0.002), and FOSL1 expression was identified as an independent prognostic biomarker of GC (P = 0.001).ConclusionsFOSL1 is an independent prognostic biomarker of GC. Detecting FOSL1 expression could help stratify GC patients with high-risk and guide the precious treatment.     

Overexpression of leucine‐rich repeat‐containing G protein‐coupled receptor 5 in gastric cancer

Gastric cancer is one of the most common malignancies worldwide and patients with advanced gastric cancer still have poor clinical outcomes. The overexpression of leucine‐rich repeat‐containing G protein‐coupled receptor 5 (LGR5) mRNA in colorectal cancer and its correlation with clinicopathological factors were recently reported by us. In this study, we show LGR5 mRNA overexpression in human gastric cancer specimens by quantitative RT‐PCR and in situ hybridization and assess a correlation with clinicopathological factors. The mean expression of LGR5 mRNA in cancerous tissues was five times higher than that in normal tissue (P = 0.0002). Furthermore, LGR5 mRNA expression show marked variation among cases and significantly increased in cases where lymphatic invasion was present compared with those where it was absent (P = 0.0056). Although the mean expression level of LGR5 was observed to be higher in nodal metastasis and venous invasion positive cases compared to negative cases, a significant difference was not observed. These results suggest that LGR5 can be a biomarker for malignancy in gastric cancer.     

Decreased HCRP1 expression is associated with poor prognosis in breast cancer patients

Background: Downregulation of hepatocellular carcinoma related protein 1 (HCRP1) has been reported to be associated with a poor prognosis in a variety of malignant tumors. The purpose of this study was to assess HCRP1 expression in breast cancer and to examine its possible correlation with commonly used prognostic factors, particularly epidermal growth factor receptor (EGFR). Methods: Immunohistochemical analysis was performed on tumors from 194 patients with primary breast cancer. HCRP1 expression was analyzed along with major clinicopathological variables. Results: HCRP1 protein expression was shown to be correlated with age (P = 0.001), histological grade (P = 0.005), tumor progression (P = 0.013), and death (P = 0.001), but not with tumor size, lymph-node metastasis, or Ki67 status. Kaplan-Meier survival curves showed that lower HCRP1 expression was significantly correlated with increased short-term survival (P < 0.001), and both univariate and multivariate analyses revealed that HCRP1, tumor size, lymph-node metastasis, and human epidermal growth factor receptor-2 (HER-2) were independent prognostic factors (all P < 0.05). In addition, low HCRP1 expression was much more frequent in triple negative breast cancer (TNBC; 63.89%) than in luminal (16.95%) and HER-2 overexpression phenotypes (7.5%; P < 0.001), and significant correlations between HCRP1 and survival time were observed for the TNBC group (P < 0.004). Furthermore, an inverse relationship between HCRP1 and EGFR expression was found both for the complete set of all cases (P < 0.001), and for each phenotype analyzed individually (P < 0.05). Conclusion: Our results suggest that HCRP1 may play an important role in EGFR regulation and that its decreased expression is an independent predictor of breast cancer, especially in TNBC patients.     

Low PBRM1 identifies tumor progression and poor prognosis in breast cancer

Background: To investigate the expression and role of PBRM1 in breast cancer, and to evaluate the clinical and prognostic significance of PBRM1 protein in patients with breast cancer. Methods: The expression of PBRM1 was examined in breast cancer tissue and paired non-cancerous tissues by real-time PCR. Moreover, PBRM1 protein expression was evaluated by immunohistochemistry in 150 paraffin-embedded breast cancer specimens. The correlation between PBRM1 expression and clinicopathological features were statistically analyzed. Results: The status of PBRM1 protein in breast cancer tissues is much lower than that in paracarcinoma tissues. Low PBRM1 expression was positively correlated with tumor stage (P =0.003) and lymph node metastasis (P =0.013). The overall (P =0.003) and recurrent-free survival (P =0.001) of the patients with high PBRM1 expression was significantly lower than the low PBRM1 expression group. Multivariate analysis showed that the expression of PBRM1 was an independent factor of overall survival for the patients with breast cancer (P =0.030). Conclusions: PBRM1 might involve in the development and progression of breast cancer as a tumor suppressor, and thereby may be a valuable prognostic marker for breast cancer patients.     

PINCH Expression and Its Clinicopathological Significance in Gastric Adenocarcinoma

Objective: Particularly interesting new cysteine-histidine rich protein (PINCH) is an important component of the local adhesion complexes and upregulated in several types of malignancies, and involved in the incidence and development of tumours. PINCH expression is also independently correlated with poorer survival in patients with colorectal cancer. However, there is no study of PINCH in gastric cancer, therefore, the aim of this project was to investigate PINCH expression and its clinicopathological significance in gastric adenocarcinoma. Patients and methods: PINCH expression was immunohistochemically examined in normal gastric mucous (n = 30) and gastric adenocarcinoma (n = 73), from gastric cancer patients. Results: PINCH expression in the associated-stroma of gastric cancers was heterogeneous, and its positive rate (75%) was higher than that of normal gastric mucosa (43%, X² = 9.711, p = 0.002). The stronger staining was observed at the invasive edge of tumour when compared to the inner area of tumour. The rate of positive PINCH (88%) in the cases with lymph node metastasis was higher than that (52%) in the cases without metastasis (X² = 11.151, p = 0.001). PINCH expression was not correlated with patients’ gender, age, tumour size, differentiation and invasion depth (p > 0.05). Comclusion: PINCH protein might play an important role in the tumourigenesis and metastasis of gastric adenocarcinoma.     

High expression of matrix metalloproteinase-9 indicates poor prognosis in human hilar cholangiocarcinoma

High expression of matrix metalloproteinase-9 (MMP-9) was found to be correlated with tumor progression and poor prognosis in a variety of carcinomas. However, few studies have investigated the role of MMP-9 in human hilar cholangiocarcinoma. In this study, a total of 58 patients with hilar cholangiocarcinoma who underwent curative resection were included in this study. The expression of MMP-9 was analyzed by immunohistochemistry using the streptavidin peroxidase complex method. The correlation of MMP-9 overexpression with clinicopathological features and survival time of patients was investigated. The results showed that MMP-9 overexpression was prominent in cancer cells and mainly localized in the cytoplasm. MMP-9 overexpression was observed in 46.5% tumors, which showed no correlation with clinicopathological parameters. Patients with high MMP-9 expression had a significantly poorer overall survival rate than those with negative or low MMP-9 expression (P = 0.038). Multivariate analysis confirmed that MMP-9 overexpression was an independent prognostic factor (P = 0.007). In conclusion, overexpression of MMP-9 is a valuable independent prognostic indicator in hilar cholangiocarcinoma.     

Alterations in vitamin D signaling pathway in gastric cancer progression: a study of vitamin D receptor expression in human normal,premalignant, and malignant gastric tissue

Amount of studies in cells and animal models have proved vitamin D has multifarious antitumor effects. However, epidemiological studies showed inconsistent result on gastric cancer. The antitumor role is mainly mediated by the vitamin D receptor (VDR). Our hypothesis is that VDR may be abnormally (poorly) expressed in gastric cancer tissue. Present study is aimed at discovering and analyzing VDR expression in a series of human gastric tissues, including normal, premalignant, and malignant gastric tissue, and correlated VDR to the clinicopathological parameters of gastric cancer patients. VDR expression was detected by immunohistochemistry. The χ² test was used to analyze the VDR expression as well as the relationship between VDR and the clinicopathological factors of gastric cancer patients. Compared with normal (82.61%) and premalignant tissues (73.64%), VDR was lower expressed in cancer tissues (57.61%), with a statistically significant difference (P = 0.001). Among cancer tissues, VDR was higher expressed in well and moderate differentiated tissues contrasted with tissues with poor differentiation, and higher expressed in small tumors (< 5 cm) compared with large tumors (≥ 5 cm), with a statistically significant difference respectively (P = 0.016, P = 0.009). A decline linear trend appeared when analyzing the statistical difference of VDR expression among normal, premalignant, and malignant gastric tissues. VDR expression has been on the decline from the premalignant stage, finally low expressed in gastric cancer tissues, especial in poorly differentiated tissues. VDR could be a potential prognostic factor for patients with gastric cancer.     

TGFBI protein high expression predicts poor prognosis in colorectal cancer patients

Transforming growth factor-beta-induced (TGFBI) serves as a linker protein and plays a role in the activation of morphogenesis, cell proliferation, adhesion, migration, differentiation and inflammation. High expression levels of the human TGFBI gene are correlated with numerous human malignancies. In order to explore the roles of TGFBI in the tumor progression of colorectal cancer, colorectal cancer specimens from 115 patients with strict follow-up were selected for the analysis of TGFBI by immunohistochemistry. The correlations between TGFBI expression and the clinicopathological features of colorectal cancers were evaluated. In the colorectal cancer tissues, TGFBI was mainly localized in the cytoplasm and stroma and scarcely in the nucleus. TGFBI expression in the cytoplasm and stroma was not found to be associated with age, gender, tumor histopathological grading, PT category and tumor location (P > 0.05 for each). However, high TGFBI expression in the cytoplasm and stroma correlated with lymph node metastasis, distant metastasis and Dukes stage (P < 0.05 for each). The survival rate was significantly lower in patients with high TGFBI expression than in those with low TGFBI expression. Furthermore, we found that tumor node metastasis (TNM) staging (HR: 2.963; 95% CI: 1.573-1.664; P = 0.000), differentiation (HR: 1.574; 95% CI: 1.001-2.476; P = 0.049) and high TGFBI cytoplasmic expression (HR: 3.332; 95% CI: 1.410-7.873; P = 0.000) proved to be independent prognostic factors for survival in colorectal cancer. In conclusion, TGFBI plays an important role in the progression of colorectal cancers and it is an independent poor prognostic factor for colorectal cancer patients.     

Metastasis-associated protein 1 (MTA1) in gastric cancer tissues is positively associated with poorer prognosis

Background

The present study examined the clinical significance of metastasis-associated protein 1 (MTA1) in the progression and patient survival of gastric cancer.

Prognostic significance of phosphorylated 4E-binding protein 1 in non-small cell lung cancer

Phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) binding protein (4E-BP1) results in release of eIF4E, which sequentially relieves translational repression and enhances oncogenic protein synthesis. We assessed the expression of phosphorylated 4E-BP1 (p-4E-BP1) in non-small cell lung cancer (NSCLC) and its correlation with clinicopathological parameters and patient survival. In addition, we investigated whether phosphorylation site made a difference in outcome. Tissue microarray blocks were generated from 73 NSCLC samples and immunohistochemically stained for p-4E-BP1 Thr37/46 and p-4E-BP1 Thr70. Both p-4E-BP1 Thr37/46 and p-4E-BP1 Thr70 were more highly expressed in squamous cell carcinoma than in adenocarcinoma (P = 0.006 and P = 0.003, respectively). Expression of p-4E-BP1 Thr70 was higher in tumours with a diameter larger than 3 cm (P = 0.024) and nodal metastasis (P = 0.053). High p-4E-BP1 Thr70 expression significantly correlated with worse overall survival (P = 0.001) and was an independent prognostic factor (hazard ratio 2.64, P = 0.004). p-4E-BP1 Thr37/46 had no prognostic significance. Phosphorylation site affected the prognostic significance of p-4E-BP1. p-4E-BP1 Thr70 is a candidate biomarker to predict poor prognosis in patients with NSCLC.