Overexpression of UQCRC2 is correlated with tumor progression and poor prognosis in colorectal cancer

Ubiquinol-cytochrome c reductase complex core protein 2 (UQCRC2) is an important subunit of mitochondrial respiratory complex III. However, its role in tumorigenesis and tumor progression remains unknown, especially with regards to colorectal cancer (CRC). In this research, we measured the expression of UQCRC2 protein by immunohistochemistry assay in 89 paired paraffin-embedded tumor tissues and corresponding adjacent normal tissues from patients with colorectal adenocarcinoma and investigated possible correlations of UQCRC2 expression with clinicopathological parameters and prognosis. We found that UQCRC2 was significantly upregulated in CRC tissues compared with adjacent normal tissues, and immunohistochemical UQCRC2 status was correlated to the depth of invasion (T), lymph node metastasis (N), advanced TNM stage. Multivariate analysis indicated that UQCRC2 remained an independent prognostic factor for poorer overall survival. Furthermore, we determined the role of UQCRC2-knockdown in CRC cells (RKO and HCT116) using lentivirus-mediated small hairpin RNAs (shRNAs). The effects of UQCRC2 knockdown on CRC cells (RKO and HCT116) proliferation were analyzed by cell proliferation and colony formation assay, and cell cycle and apoptosis were assessed by flow cytometry. We found that silencing UQCRC2 suppressed cell proliferation and colony formation in RKO and HCT116 cells, led to a cell cycle arrest and induced cell apoptosis in vitro. These results provided novel insights into the potential role of UQCRC2 in the tumorigenesis and progression of CRC, and revealed that UQCRC2 may serve as a new prognostic and therapeutic target in CRC.     

Cytoplasmic Pin1 expression is correlated with poor prognosis in colorectal cancer

Objective

The aim of this study was to determine the clinicopathological significance and prognostic role of Pin1 expression and subcellular localization in colorectal cancer (CRC).

Downregulation of miR-9 correlates with poor prognosis in colorectal cancer

IntroductionmicroRNAs (miRNAs) are frequently dysregulated in many human cancers including colorectal cancer (CRC) and are useful candidate biomarkers in liquid biopsy of cancer for their stability in the blood.MethodsWe compared the expression of microRNA-9 (miR-9) in tissues (n = 357) and sera (n = 109) of CRC patients to determine whether miR-9 in serum reflects that in the cancer tissue in parallel. Also, we examined the miR-9 role in CRC by in vitro functional studies in four CRC cell lines.ResultsOn multivariate analysis of colorectal cancer tissues and sera, miR-9 low expressions were significantly associated pN stage (tissues; p < 0.01, serum; p = 0.013), and clinical stage (tissues; p < 0.01, serum; p = 0.031). Moreover, patients with low miR-9 expression had shorter survival than those with high miR-9 expression (log-rank test, tissue; p = 0.021, serum; p = 0.011). miR-9 level in serum reflects that in the tumor. The CRC cells with low miR-9 expression was significantly increased cell proliferation, migration, invasion and colony formation than cells with high miR-9 expression.ConclusionSerum miR-9 is an useful early detection marker in liquid biopsy of CRC and overexpression of miR-9 in CRC may be a novel prognostic marker as well.     

Matrix metalloproteinase 9 is associated with Gleason score in prostate cancer but not with prognosis

Prostate cancer is the most common cancer in North American men. Among men diagnosed with prostate cancer in more than three cores or with high grade prostate cancer, many experience long disease-free survival. However, these patients still undergo radical treatment while they could benefit from active surveillance with complementary therapy. Matrix metalloproteinase 9 degrades type IV collagen and activates tumorigenic factors and is thus a potential prognostic factor and therapeutic target. This study was thus aimed at investigating the role of matrix metalloproteinase 9 on prostate cancer progression. We correlated matrix metalloproteinase 9 immunohistochemical expression by cancer, stromal and benign epithelial cells with prostate cancer disease-free survival among a cohort composed of 187 pT3NxM0 prostate cancer patients. Median follow-up was 4.63 years and a recurrence occurred in 67 men (35.3%). Matrix metalloproteinase 9 immunostaining was cytoplasmic and expressed at different levels in cancer (94.1%), stromal (87.7%) and benign epithelial cells (94.1%). High levels (>50% of cells) of matrix metalloproteinase 9 expression by prostate cancer cells was strongly associated with high Gleason score (P = .0009). In stromal cells and in benign epithelial cells, high matrix metalloproteinase 9 expression levels were respectively associated with low pT3 substage (P = .046) and with low initial serum prostate-specific antigen levels (P = .006). Matrix metalloproteinase 9 expression level by any cell type was not associated with prostate cancer disease-free survival. These results show that matrix metalloproteinase 9 is overexpressed by cancer cells in high grade tumors and by stromal and benign epithelial cells in lower substage tumors.     

Matrix metalloproteinase 13 activity is associated with poor prognosis in colorectal cancer

AIMS: The matrix metalloproteinases (MMPs) are a family of proteolytic enzymes collectively capable of degrading all extracellular matrix components, in particular fibrillar collagen. The importance of this group of proteins in the processes of tumour invasion and metastasis is now widely acknowledged. MMP-13 (collagenase 3) has a central role in the MMP activation cascade. The purpose of this study was to investigate the presence and activity of MMP-13 in colorectal cancer and relate these to clinicopathological features. METHODS: Immunohistochemistry for MMP-13 was performed on formalin fixed, paraffin wax embedded sections of a large series of colorectal cancers (n = 249), all of which had uniform clinical and pathological information available. Immunoreactivity to MMP-13 was detected with a monoclonal antibody to MMP-13 using a Dako TechMate 500 automated immunostaining system. The presence and cellular localisation of MMP-13 was assessed using a semiquantitative scoring system. Gelatin zymography was used to detect and measure MMP-13 activity. The zymography was performed on a subset of the cases studied by immunohistochemistry using two groups of 10 paired Dukes's C tumours and normal samples, selected by either having "good" or "poor" survival. RESULTS: Immunoreactivity to MMP-13 was identified in 91% of cases and immunoreactivity was localised to the cytoplasm of tumour cells. A high MMP-13 staining score showed a trend towards poorer survival. Tumours had significantly greater MMP-13 activity compared with normal colonic mucosa (p < 0.001). Furthermore, the tumour to normal tissue ratio was significantly higher in the poor survival group (p = 0.02). CONCLUSIONS: These results show that MMP-13 is frequently present and active in colorectal cancer and suggest that the activity of MMP-13 is associated with poorer survival in colorectal cancer.     

Matrix metalloproteinase-1 is associated with poor prognosis in oesophageal cancer

The matrix metalloproteinases (MMPs) are a family of closely related proteolytic enzymes which are involved in the degradation of different components of the extracellular matrix. There is increasing evidence to indicate that individual MMPs have an important role in tumour invasion and tumour spread. Monoclonal antibodies specific for MMP-1, MMP-2, or MMP-9 have been produced, using as immunogens peptides selected from the amino acid sequences of individual MMPs. The presence of MMP-1, MMP-2, and MMP-9 in oesophageal cancer was investigated by immunohistochemistry on formalin-fixed, wax-embedded sections of oesophageal cancers. The relationship of individual MMPs to prognosis and survival was determined. MMP-1 was present in 24 per cent of oesophageal cancers, while MMP-2 and MMP-9 were present in 78 and 70 per cent of tumours, respectively. The presence of MMP-1 was associated with a particularly poor prognosis (log rank test 8·46, P<0·004) and was an independent prognostic factor (P=0·02). The identification of individual MMPs in oesophageal cancer provides a rational basis for use in the treatment of oesophageal cancer of MMP inhibitors which are currently undergoing clinical trial. © 1998 John Wiley & Sons, Ltd.     

High extracellular matrix metalloproteinase inducer/CD147 expression is strongly and independently associated with poor prognosis in colorectal cancer

As in most solid tumors, colorectal cancer prognosis strongly depends on the extent of local invasion and lymph node and distant metastases. Extracellular matrix metalloproteinase inducer (EMMPRIN) is a transmembrane glycoprotein that activates matrix metalloproteinases, a group of enzymes that play an important role in tumor invasion and metastasis formation. This study investigates the EMMPRIN expression in a large cohort of patients with colorectal cancer. Immunohistochemical analysis of tissue microarrays from 285 patients shows that increased EMMPRIN protein expression does not correlate with clinicopathologic parameters and is an independent prognostic factor of poor survival, with mean survival times of 103 months in EMMPRIN negative/low versus 57 months in EMMPRIN intermediate/high patients (P < .001). This pronounced association of increased EMMPRIN levels and--on average--a 45% reduction in overall survival could help improve the risk stratification in patients with colorectal cancer; moreover, the lack of correlations with classical measures of cancer invasion/spreading may suggest the relevance of alternative EMMPRIN pathways beyond matrix metalloproteinase activation.     

Increasing of FKBP9 can predict poor prognosis in patients with prostate cancer

BackgroundFK506 binding protein 9 (FKBP9) has been reported and identified for a long time, but its relationship with cancer is rarely studied. For example, the role of FK506 binding protein 9 in prostate cancer (PCa) is still unclear. Therefore, we decided to detect the expression level of FKBP9 in PCa and explore its clinical significance.MethodsThe expression level of FKBP9 protein was detected by immunohistochemistry. In addition, it was demonstrated by high-throughput sequencing of mRNA levels in the TCGA (cancer genome atlas) dataset of 499 patients. Kaplan-meier analysis and Cox proportional hazard regression model were used to evaluate the relationship between FKBP9 expression and survival in prostate cancer patients.ResultsThe expression of FKBP9 was localized in the cytoplasm, which in normal prostate tissues was obviously lower than that in PCa tissues (P = 0.001). High expression of FKBP9 was related with lymph node metastasis (P = 0.022) and distant metastasis (P = 0.028). Kaplan-Meier survival analysis revealed that the BCR-free survival of PCa patients with high FKBP9 level was significantly shortened (P=0.041).ConclusionsFKBP9 may be a cancer promoter that enhances PCa progression, and the level of FKBP9 may be used as an independent precursor of PCa patients.     

Over-expression of lncRNA DANCR is associated with advanced tumor progression and poor prognosis in patients with colorectal cancer

Despite advances made in the diagnosis and treatment of human colorectal cancer (CRC), the long-term survival for CRC remains poor. Long non-coding RNA anti-differentiation ncRNA (lncRNA DANCR) was identified to be involved in carcinogenesis of hepatocellular carcinoma. While its expression in CRC and potential role in tumor progression is still unknown. In the present study, we investigated the expression level of lncRNA DANCR as well as its association with CRC progression and prognosis. The expression of lncRNA DANCR was detected by quantitative real-time PCR (qRT-PCR) in 104 CRC specimens. The prognostic value of lncRNA DANCR was further analysis. Our results showed that lncRNA DANCR expression was increased in CRC tissues compared with that in adjacent normal tissues (P<0.05). In addition, tumors with high lncRNA DANCR expression was correlated with TNM stage, histologic grade, and lymph node metastasis (P<0.05). Kaplan-Meier analysis showed that patients with high lncRNA DANCR expression had a shorter overall survival (OS) and disease-free survival (DFS) compared with the low lncRNA DANCR expression group (P<0.05). Moreover, in a multivariate Cox model, our results showed that lncRNA DANCR expression was an independent poor prognostic factor for both OS and DFS in CRC. Our data indicated that lncRNA DANCR expression might be a novel potential biomarker for CRC prognosis.     

Low expression of RSK4 predicts poor prognosis in patients with colorectal cancer

Background: Colorectal cancer (CRC) is one of the leading causes of cancer-related death all over the world. Ribosomal s6 kinase4 (RSK4), an X-linked gene, firstly was found as to be a potential tumor suppressive gene in a variety of cancers and is widely participated in signaling pathway. However its role in CRC is unclear. This study is to explore the correlation between the protein expression of RSK4 and clinical pathologic characteristics in colorectal tumors, which might serve as a prognostic determinant of colorectal cancers. Methods: Biopsies of 103 colorectal cancer and 46 matched adjacent noncancerous tissues were collected for analysis of RSK4 protein by immunohistochemistry. The correlation between RSK4 protein expression and the clinical pathological features of colorectal cancers were evaluated by Chi-square test and Fisher’s exact test. The survival rates were analyzed by the Kaplan-Meier method, and the relationship between prognostic factors and patient survival was analyzed by the Cox proportional hazard models. Results: RSK4 was conversely correlated with some pathological classifications (P<0.05 for N, G and clinical staging), and there were no statistically significant differences in age, CEA expression in blood, CA199 and tumors t-staging (x² test, P>0.05 for all categories) respectively. Furthermore, patients with high protein level of RSK4 showed prolonged overall survivals (P<0.05). Moreover, multivariate analysis showed that low expression level of RSK is an independent risk factor for high mortality in colorectal cancer. Conclusions: Low RSK4 expression is correlated with advanced clinical pathologic classifications and is a poor overall survival in colorectal cancer patients. These findings suggest that RSK4 may serve as a useful marker in prognostic evaluation for patients with colorectal cancer.     

Neutrophil gelatinase-associated lipocalin (NGAL) and matrix metalloproteinase-9 (MMP-9) prognostic value in stage I colorectal carcinoma

The expression of neutrophil gelatinase-associated lipocalin (NGAL) has been suggested to behave like a negative prognostic marker in stage I colorectal carcinoma. In the aim of clarifying whether its association with adverse outcome may descend from NGAL's ability to regulate matrix metallo-proteinase-9 (MMP-9), we analyzed the correlation, prognostic value, and association with neo-angiogenesis of NGAL and MMP-9 immunohistochemical expression in a series of stage I colorectal carcinomas. A variable NGAL immunoexpression was demonstrated in 17 of the 48 analyzed cases with a significantly higher frequency of positive cases among patients showing disease progression. NGAL expression was also positively correlated with VEGF expression detected in the same cases. MMP-9 immunostaining was present in the cytoplasm of the neoplastic cells in 30 cases; no significant correlations were evidenced with NGAL expression, as well as with the various clinico-pathological parameters or with progression of the colorectal carcinomas. By contrast, NGAL expression was confirmed as a significant independent negative prognostic marker related to a shorter disease-free survival in stage I colorectal carcinoma. Our preliminary results suggest that the association of NGAL with poor outcome might be independent from MMP-9 regulation, thus highlighting its prognostic value in this neoplasia. If our findings are confirmed in further analyses, NGAL assessment might be used in order to select those patients with a higher progression risk and to submit them to adjuvant therapies useful to prevent adverse outcome.     

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.     

Up-regulated expression of SNHG6 predicts poor prognosis in colorectal cancer

Long non-coding RNAs (lncRNAs) have been shown to play important roles in tumor formation and development. Small nucleolar RNA host gene 6 (SNHG6) is a recently identified cancer-related lncRNA, and its role in colorectal cancer (CRC) remains to be explored. The aim of this study was to evaluate the expression and function of SNHG6 in CRC. The expression of SNHG6 was detected by real time quantitative RT-PCR (qRT-PCR) in 74 CRC tissues and matched noncancerous tissues (NCTs). Relationships between the expression levels of SNHG6 and various clinicopathological features were analyzed by Chi-square test. The Kaplan-Meier method and log-rank test were applied to compare the survival distribution between different groups. CCK8 assay and colony formation assay were used to measure the effect of SNGH6 on cell proliferation. Flow cytometric analysis was performed to measure the effect of SNHG6 on cell cycle and apoptosis. Our results showed that SNHG6 was up-regulated more than 1.5-fold in 50.0% (37/74) of CRC tissues compared with paired NCTs (P?<?0.0001). High level of SNHG6 expression was strongly associated with advanced tumor stage (P?=?0.026) and predicted poor prognosis of CRC (P?=?0.0215). The Cox proportional hazards model demonstrated that SNHG6 expression was an independent prognostic factor for CRC (HR, 2.568; 95% CI, 1.055–6.252; P?=?0.038). Furthermore, SNHG6 knockdown by siRNA could inhibit cell proliferation, cell cycle progression, and induce apoptosis. Taken together, SNHG6 functions as an oncogene in CRC and appears as a novel prognositic factor for CRC patients.     

胃腺癌IGFBP4的表达与患者预后的关系

目的探讨胃腺癌中胰岛素样生长因子结合蛋白4(IGFBP4)的表达情况及预后意义。方法免疫组织化学技术检测2000年1月至2006年12月间401例胃癌术后标本中IGFBP4的表达,并探讨IGFBP4表达与临床病理参数及预后相关性。结果结果显示401例患者中208例(51.9%)IGFBP4表达下调,且在低分化胃腺癌、T4a/b、及Ⅲ/Ⅳ期胃癌患者中表达下调明显。生存分析显示IGFBP4低表达与较差的预后相关(P<0.001)。多因素分析显示IGFBP4可作为一个独立预后风险因素(HR=2.175,P<0.001)。结论 IGFBP4在胃腺癌中表达下调,提示预后不良。