Dake Chu

Matrix Metalloproteinase-9 Is Associated with Relapse and Prognosis of Patients with Colorectal Cancer

BackgroundMatrix metalloproteinase-9 is a member of the MMP family, which is overexpressed in some solid tumors and is thought to enhance tumor invasion and metastasis ability. The present study aims to examine MMP-9 expression in human colorectal cancer and to determine its association with clinicopathological characteristics and prognosis.MethodsColorectal cancer and adjacent normal tissues from 192 patients were investigated by immunohistochemical assay. Staining evaluation results were analyzed statistically in relation to various clinicopathological characters, disease-free survival, and overall survival.ResultsHigh level of MMP-9 expression was detected in colorectal cancer, significantly more than in normal colorectal epithelial cells. In colorectal cancer, MMP-9 was significantly positively correlated with depth of invasion, lymph node metastasis, and distant metastasis. However, no correlations between MMP-9 expression and patient age, sex, tumor location or differentiation status were detected. Disease-free and overall survival were significantly poorer for patients with positive MMP-9 staining than for those with MMP-9-negative tumors.ConclusionsOur findings emphasize the important role of MMP-9 in the invasion and metastasis process in human colorectal cancer. It could also serve as a novel prognostic marker that is independent of, and additive to, the tumor–node–metastasis (TNM) staging system.

Notch2 Expression Is Decreased in Colorectal Cancer and Related to Tumor Differentiation Status

BackgroundThe significance of Notch2 expression in colorectal cancer (CRC) has not been clearly investigated. We investigated the expression of Notch2 and its relationship with differentiation status and tumor stage by studying clinical CRC specimens with matched adjacent normal tissues and normal control colorectal specimens.MethodsImmunohistochemistry, real-time polymerase chain reaction, and Western blot analysis were performed to assess the expression of Notch2 in clinical CRC specimens. Also, Notch2 levels in an induced differentiation model of CRC cell lines were investigated.ResultsIt was found that Notch2 expression was decreased in cancer tissues compared with adjacent normal tissue and normal control tissues. Also, a tendency for decreased expression was observed when going from well to poorly differentiated carcinomas, as well as going from tumor, node, metastasis system stage I to stage IV. With the differentiation of colon cancer cells, the expression of Notch2 increased. To support this observation, colon cancer cell lines HT29 and SW620 were induced to differentiate in culture, and expression of Notch2 was investigated. A clear increase expression of Notch2 was observed.ConclusionsNotch2 expression correlated closely with CRC and may play a role in tumor inhibition in colon carcinogenesis.

Increased MicroRNA-630 Expression in Gastric Cancer Is Associated with Poor Overall Survival

MicroRNAs are noncoding RNAs that regulate multiple cellular processes during cancer progression. Among various microRNAs, MiR-630 has recently been identified to be implicated in many critical processes in human malignancies. We aimed to investigate the significance and prognostic value of miR-630 in human gastric cancer. Gastric cancer and adjacent normal specimens from 236 patients from who had not received neoadjuvant chemotherapy were collected. The expression of miR-630 was investigated by quantitative real-time PCR assay and its association with overall survival of patients was analyzed by statistical analysis. MiR-630 expression level was significantly elevated in gastric cancer in comparison to adjacent normal specimens. It is also proved that miR-630 expression was to be associated with gastric cancer invasion, lymph node metastasis, distant metastasis and TNM stage. In addition, survival analysis proved that elevated miR-630 expression was associated with poor overall survival of patients. Multivariate survival analysis also proved that miR-630 was an independent prognostic marker after adjusted for known prognostic factors. The present study proved the over-expression of miR-630 and its association with tumor progression in human gastric cancer. It also provided the first evidence that miR-630 expression was an independent prognostic factor for patients with gastric cancer, which might be a potential valuable biomarker for gastric cancer.

Tumor suppressor NDRG2 inhibits glycolysis and glutaminolysis in colorectal cancer cells by repressing c-Myc expression

Cancer cells use glucose and glutamine as the major sources of energy and precursor intermediates, and enhanced glycolysis and glutamimolysis are the major hallmarks of metabolic reprogramming in cancer. Oncogene activation and tumor suppressor gene inactivation alter multiple intracellular signaling pathways that affect glycolysis and glutaminolysis. N-Myc downstream regulated gene 2 (NDRG2) is a tumor suppressor gene inhibiting cancer growth, metastasis and invasion. However, the role and molecular mechanism of NDRG2 in cancer metabolism remains unclear. In this study, we discovered the role of the tumor suppressor gene NDRG2 in aerobic glycolysis and glutaminolysis of cancer cells. NDRG2 inhibited glucose consumption and lactate production, glutamine consumption and glutamate production in colorectal cancer cells. Analysis of glucose transporters and the catalytic enzymes involved in glycolysis revealed that glucose transporter 1 (GLUT1), hexokinase 2 (HK2), pyruvate kinase M2 isoform (PKM2) and lactate dehydrogenase A (LDHA) was significantly suppressed by NDRG2. Analysis of glutamine transporter and the catalytic enzymes involved in glutaminolysis revealed that glutamine transporter ASC amino-acid transporter 2 (ASCT2) and glutaminase 1 (GLS1) was also significantly suppressed by NDRG2. Transcription factor c-Myc mediated inhibition of glycolysis and glutaminolysis by NDRG2. More importantly, NDRG2 inhibited the expression of c-Myc by suppressing the expression of β-catenin, which can transcriptionally activate C-MYC gene in nucleus. In addition, the growth and proliferation of colorectal cancer cells were suppressed significantly by NDRG2 through inhibition of glycolysis and glutaminolysis. Taken together, these findings indicate that NDRG2 functions as an essential regulator in glycolysis and glutaminolysis via repression of c-Myc, and acts as a suppressor of carcinogenesis through coordinately targeting glucose and glutamine transporter, multiple catalytic enzymes involved in glycolysis and glutaminolysis, which fuels the bioenergy and biomaterials needed for cancer proliferation and progress.

Notch1 Expression in Colorectal Carcinoma Determines Tumor Differentiation Status

IntroductionThe significance of Notch1 expression in colorectal cancer has not been clearly described. We investigated the expression of Notch1 and its relationship with differentiation status and tumor (Union Internationale Contre le Cancer, UICC) stage using a series of 237 colorectal cancer samples with matched adjacent normal tissues and a series of 46 normal colorectal specimens.Materials and MethodsImmunohistochemistry, real-time polymerase chain reaction, and Western blot analysis were performed to assess the expression of Notch1.ResultsIt was found that Notch1 was overexpressed in cancer tissues as compared with adjacent normal tissue and normal control tissues. Also, a tendency for increased expression was observed when going from well to poorly differentiated carcinomas, as well as going from UICC stage I to stage IV. With the differentiation of colon cancer cells, the expression of Notch1 decreased. To support this observation, colon cancer cell lines HT29 and SW620 were induced to differentiate in culture, and expression of Notch1 was investigated. A clear reduction of Notch1 expression was observed.ConclusionThese results suggest that Notch1 expression correlated closely with colorectal cancer and may play an oncogenic role during colonic carcinogenesis.

Matrix Metalloproteinase-14 Is a Negative Prognostic Marker for Patients with Gastric Cancer

BackgroundMatrix metalloproteinase-14 (MMP-14) has been considered to play an important role in invasion and metastasis of human solid tumor.AimThe present study aimed to investigate the association of MMP-14 with overall survival in human gastric cancer.MethodsGastric cancer and adjacent normal specimens were collected from 205 patients who had not received neoadjuvant chemotherapy. MMP-14 expression was investigated by immunohistochemistry assay and staining evaluation results were analyzed statistically in relation to overall survival of patients.ResultsMMP-14 expression proved to be increased in gastric cancer compared with that in normal tissues. It was also proved that MMP-14 expression was associated with tumor invasion, metastasis, and TNM stage while no correlations were detected between MMP-14 expression and age, sex, differentiation status, or Lauren’s classification. Moreover, patients with gastric cancer of MMP-14-positive expression tend to have worse overall survival compared with those with MMP-14 negative expression.ConclusionsThe present study confirmed the over-expression of MMP-14 in human gastric cancer and its association with tumor progression. It also provided the first evidence that MMP-14 expression in gastric cancer was an independent negative prognostic factor of patients.

Notch1 Expression, Which Is Related to p65 Status, Is an Independent Predictor of Prognosis in Colorectal Cancer

Purpose: Notch1 has been proven to be aberrantly expressed in colorectal cancer and related to tumor differentiation status. However, few previous studies concentrated on the predictive role of Notch1 expression on the overall survival of patients with colorectal cancer. This study explored expression of Notch1 and its relationship with p65 and prognosis in colorectal cancer. Experimental Design: Two independent study cohorts were involved in the present study. Clinical specimens from 941 eligible patients were constructed into tissue microarrays. The expression of Notch1 and p65 protein was investigated by immunohistochemistry. Results: Statistically significant positive correlations were found between protein expression of Notch1 and p65 in both retrospective and prospective study cohorts. Patients with higher Notch1 expression showed a trend of having shorter survival time, whereas patients with lower Notch1 expression had better survival in both study cohorts. In multivariate analysis, Notch1 expression was proven to be an independent predictor of prognosis. Moreover, the prognostic value of Notch1 might differ according to p65 status. Conclusions: Notch1 is an independent predictor of prognosis for patients with colorectal cancer. In addition, the predictive role of Notch1 on clinical outcome might be modified by p65 status, suggesting that targeting Notch1 and nuclear factor κB (NF-κB) might be a promising strategy for colorectal cancer treatment. Clin Cancer Res; 17(17); 5686–94. ©2011 AACR.

MicroRNA-630 is a prognostic marker for patients with colorectal cancer

MicroRNAs are noncoding RNAs that regulate multiple cellular processes during cancer progression. Among various microRNAs, miR-630 has recently been identified to be implicated in many critical processes in human malignancies. We investigated the expression pattern and prognostic value of miR-630 in human colorectal cancer by utilizing cancer and adjacent normal specimens from 206 patients. Quantitative real-time PCR assay was used to detect the expression of miR-630, and appropriate statistical analysis was used to evaluate the association of miR-630 with overall survival. It was found that miR-630 expression was significantly increased in colorectal cancer specimens compared with that in adjacent normal specimens. It was also proved that miR-630 expression in colorectal cancer was associated with tumor invasion, lymph node metastasis, distant metastasis, and tumor-node-metastasis (TNM) stage. The Kaplan-Meier survival analysis proved that increased miR-630 expression was associated with poor overall survival of patients with colorectal cancer. Multivariate analysis proved that miR-630 was an independent prognostic marker after adjusted for known prognostic factors. These results confirmed the overexpression of miR-630 in human colorectal cancer and its association with tumor progression. It also suggested that miR-630 expression might serve as a prognostic biomarker for patients with colorectal cancer.

Overexpression of Matrix Metalloproteinase-21 is Associated with Poor Overall Survival of Patients with Colorectal Cancer

IntroductionMatrix metalloproteinase-21 (MMP-21) is a member of the MMP family, which is overexpressed in some solid tumors and is thought to enhance the tumor invasion and metastasis ability. The aim of the present study is to examine the MMP-21 expression in human colorectal cancer and normal colorectal tissue using tissue microarray technique and to determine its association with clinicopathological characteristics and prognostic value.Materials and MethodsFour array blocks including 256 cases of colorectal cancer and adjacent normal tissues were investigated by immunohistochemistry assay. Staining evaluation results were analyzed statistically in relation to various clinicopathological characters and overall survival.ResultsHigh level of MMP-21 expression was detected in colorectal cancer, significantly more than in normal colorectal epithelial cells. In colorectal cancer, MMP-21 was significantly positively correlated with depth of invasion, lymph node metastasis, and distant metastasis. The overall survival rate was significantly lower for patients with MMP-21 positive than those with MMP-21 negative tumors. However, no correlations between MMP-21 expression and patients’ age, sex tumor location, or differentiation status were detected.ConclusionOur findings emphasize the important role of MMP-21 in the invasion and metastasis process in human colorectal cancer. It might also serve as a novel prognostic marker that is independent of, and additive to, the TNM staging system.

CD147 Expression in Human Gastric Cancer Is Associated with Tumor Recurrence and Prognosis

CD147 is correlated with tumor aggressiveness in various human malignancies. Here, we investigated CD147 protein expression in 223 patients with gastric cancer by immunohistochemistry and analyzed its association with disease-free and overall survival. CD147 was increased in gastric cancer compared to normal tissues. Additionally, CD147 expression was associated with gastric cancer invasion, metastasis and TNM stage, whereas it was not related to age, sex, differentiation status, tumor site or Lauren classification. Kaplan-Meier analysis confirmed that CD147 was associated with disease-free and overall survival in patients with gastric cancer; i.e., patients with positive CD147 staining tend to have worse disease-free and overall survival. Moreover, Coxs proportional hazards analysis demonstrated that CD147 was an independent marker of disease-free and overall survival for patients with gastric cancer. These results confirm the association of CD147 with gastric cancer invasion and metastasis and prove that CD147 might be an indicator of tumor recurrence and prognosis in gastric cancer.