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BACKGROUND: The Notch signaling regulates numerous cell growth, differentiation, and death. However, the expression pattern of its ligand Delta-like 4 (DLL4) in tumors is still uncertain. OBJECTIVE: In the present study, we examined DLL4 expression in colorectal cancer as well as assessed its role as a prognostic indicator in the present study. METHODS: DLL4 expression was examined by immunohistochemistry in 289 surgically resected specimens of colorectal cancer and adjacent normal tissues. The relationship between DLL4 expression and clinicopathological characteristics was analyzed. The association of DLL4 expression with the patients’ overall survival rate was assessed by Kaplan-Meier and Cox proportional-hazards regression. RESULTS: Increased DLL4 level was detected in colorectal cancer compared with that of normal tissues. Elevated DLL4 level in colorectal cancer was associated with increased body mass index of patients. Moreover, increased DLL4 level was also found to be correlated with tumor invasion, metastases and unfavorable clinical outcom of patients. CONCLUSIONS: DLL4 level is increased in colorectal cancer, especially in patients with increased body mass index, indicating potential involvement of obesity-related tumorigenesis and development. It might also serve as a novel molecular marker to predicate outcome of patients.

The aim of this study was to evaluate the feasibility, safety, and efficacy of magnetic anchoring and guidance-assisted endoscopic irreversible electroporation (MAG-IRE) for gastric mucosal ablation. A catheter-based, donut-like, and MAG-assisted electrode was developed. MAG-IRE for gastric mucosal ablation was performed in eight beagle canines. The parameters of one set of IRE was 500 V voltage, 100 μs pulse duration, and 99 pulses. The MAG time, operation time, success rate, and adverse events were measured. Endoscopic examination was performed from 30 min to 28 days post-IRE. Full-thickness gastric tissue was harvested by wedge biopsy for histopathological analysis. 30 (93.75%) of the 32 lesions were successfully ablated by MAG-IRE. The median MAG time was 300 s (IQR 120–422.5 s), and the median operation time was 491.5 s (IQR 358.3–632.5 s). No adverse events occurred. Ulceration was observed, starting from 3 days post-IRE. The mucosa healed 14 to 28 days post-IRE. Hematoxylin–Eosin (H&E) staining showed inflammatory infiltration, edema, and congestion in the ablated mucosa. Masson’s Trichrome staining showed that the gastric wall and blood vessels in the ablation area were intact. TUNEL assay showed diffuse positive cells in ablated mucosa as early as 30 min post-IRE. MAG-IRE for gastric mucosal ablation is feasible, safe, and effective. It can be a potential therapeutic option for minimally invasive treatment of gastric neoplasm.

Irreversible electroporation (IRE) is an emerging tissue ablation technique, which is safe for sites where thermal-basis techniques are not suitable. The aim of this study is to evaluate the safety and efficacy of magnetic anchoring electrode (MAE)-assisted IRE for normal gastric tissue ablation in a rabbit model. IRE (500 V, 100 μs, 99 pulses, 1 Hz) of the gastric wall was performed in 24 adult New Zealand rabbits with a novel catheter-mounted MAE with fluoroscopy and a surgical approach. Procedure time, procedure-related bleeding, perforation, and other complications were recorded. Animals were sacrificed at 30 min, 1 day, 3 days, 7 days, 14 days, and 28 days post-IRE. The stomach was removed en bloc, and the diameter of each lesion was measured. Histopathological analyses by Hematoxylin–Eosin (H&E), masson trichrome, alpha-smooth muscle action (α-SMA), and terminal-deoxynucleotidyl transferase mediated nick end labeling (TUNEL) were performed. Gastric tissue ablation with MAE-assisted IRE was successfully performed without any interruption. No perforation or bleeding was observed during IRE or throughout the follow-up period. A demarcated hemorrhage was found in the ablated area upon gross examination. H&E staining showed complete cell death with inflammatory infiltration, edema, and hemorrhaging. TUNEL presented diffuse positive cells in the ablated area. The tissue scaffold was well preserved without damage as indicated by Masson trichrome staining. Ulceration was observed starting from 3 days post-IRE. The mucosal layer was gradually recovered and regenerated within 14–28 days. No other complication was observed post-IRE. MAE-assisted IRE is safe and effective for normal gastric tissue ablation and the gastric wall recovered in 14–28 days post-IRE.

Aims. There are two treatment modalities for early gastric cancer (EGC)—surgery and endoscopic submucosal dissection (ESD). We aimed to compare the safety and efficacy of ESD with surgery. Method. The article was performed by searching PubMed databases. Data were extracted using predefined form and odds ratios (OR) with 95% confidence intervals (CI) calculated and P value. Results. 13 studies were identified. The incidence of perforation in two groups was different [OR = 6.18 (95% CI: 1.37–27.98), P=0.02]. The prevalences of synchronous and metachronous cancer in the ESD group were higher than those in the surgery group [OR = 8.52 (95% CI: 1.99–36.56), P = 0.004 and OR = 7.15 (95% CI: 2.95–17.32), P<0.0001]. The recurrence and complete resection rates were different [OR = 6.93 (95% CI: 2.83–16.96), P<0.0001 and OR = 0.32 (95% CI: 0.20–0.52), P<0.00001]. Compared with the surgery group, the hospital stay was shorter [IV = −7.15 (95% CI: −9.08–5.22), P<0.00001], the adverse event rate was lower, and the quality of life (QOL) was better in the ESD group. The difference of bleeding was not found. Conclusion. ESD appears to be preferable for EGC, due to a lower rate of adverse events, shorter hospital stay, cheaper cost, and higher QOL.

// Jianyong Zheng 1 , Yunming Li 2 , Shaojun Zhu 3 , Jipeng Li 1 , Qingchuan Zhao 1 , Gang Ji 1 , Weizhong Wang 1 , Dake Chu 1, 4 1 State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi’an, China 2 Department of Health Statistics, Fourth Military Medical University. Xi’an, China 3 Department of Pathology, Fourth Military Medical University. Xi’an, China 4 Department of Biochemistry and Molecular Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi’an, China Correspondence to: Dake Chu, e-mail: chudake@hotmail.com Keywords: NDRG4, colorectal cancer, obesity, disease-free survival, overall survival Received: May 12, 2015 Accepted: October 04, 2015 Published: October 20, 2015 ABSTRACT NDRG4 is a novel candidate tumor suppressor and can inhibit PI3K/AKT signal which is related with energy balance and related carcinogenesis. In the present study, we investigated whether NDRG4 status could modify the association of obesity with clinical outcome of colorectal cancer. For this purpose, a hospital-based prospective study cohort of 226 colorectal cancer patients was involved. NDRG4 mRNA levels were determined by real-time PCR. Association of NDRG4 mRNA expression with disease-free and overall survival was studied first. Then, the association of obesity with clinical outcome was determined according to NDRG4 level. Multivariate Cox proportional hazards model was used to compute hazard ratio, adjusting for covariates including microsatellite instability, KRAS, BRAF and PIK3CA mutation. Results showed that NDRG4 mRNA expression was decreased in tumor specimens and significantly correlated with tumor differentiation, invasion and metastasis. Patients with tumor of reduced NDRG4 mRNA level had unfavorable disease-free and overall survival. Obesity was found to be adversely associated with disease-free and overall survival in tumors with reduced NDRG4 level, not in preserved NDRG4 level group, in both univariate and multivariate analysis. These data provided the first evidence that NDRG4 level in colorectal cancer could effectively stratify the prognostic value of obesity, which would better the understanding of the prognostic role of obesity in colorectal cancer. Our results also support the notion that the host-tumor interactions in colorectal cancer might influence tumor aggressiveness.

The role of NDRG4 in human malignancies is largely unknown. We investigated the role of NDRG4 protein in colorectal cancer and its prognostic value in a hospital-based retrospective training cohort of 272 patients and a prospective validation cohort of 708 patients were. Cell line was transfected with an NDRG4 expression construct to confirm the suppression of PI3K-AKT activity by NDRG4. Appropriate statistical methods were utilized for analysis. Results showed that NDRG4 protein expression was significantly decreased from normal mucosa, chronic colitis, ulcerative colitis, atypical hyperplasia to colorectal cancer. Significant negative correlations were found between NDRG4 staining and p-AKT. Patients with positive NDRG4 staining had favorable survival in both study cohorts. In multivariate analysis, NDRG4 staining proved to be an independent predictor of overall survival. Moreover, the prognostic role of NDRG4 was stratified by p-AKT. Overexpression of NDRG4 in colorectal cancer cell can significantly suppress PI3K-AKT activity, even after EGF stimulation. These results indicated NDRG4 protein expression was decreased in colorectal cancer. It may play its tumor suppressive role in carcinogenesis and progression through attenuation of PI3K-AKT activity. Therefore, high risk colorectal cancer patients could be better identified based on the combination of NDRG4 and PI3K-AKT activity.

Notch signal has complex roles in human malignancies, which might be attributed to the diversity of Notch receptors. Here, we set out to identify the association of NOTCH4 with colorectal cancer (CRC). In the hospital-based study cohort, we investigated NOTCH4 mRNA levels in primary CRC, as well as its association with clinicopathologic characteristics. Besides, NOTCH4 cDNA and siRNA was transfected into colorectal cancer cell line to elucidate its impact on tumor cell proliferation and migration. Results revealed a statistically significant lower expression of NOTCH4 mRNA in tumor specimens compared with that in control. NOTCH4 level in CRC was found to be related to tumor differentiation, invasion, and node metastasis. Moreover, it was demonstrated that NOTCH4 mRNA level could be an independent prognostic factor for both disease-free and overall survival of CRC patients. Overexpression of NOTCH4 in CRC cell lines suppressed tumor cell proliferation, migration, and invasion, while induced apoptosis. In the opposite, the malignant behavior of CRC cells was enhanced by NOTCH4 knockdown. These results demonstrated for the first time that NOTCH4 expression was decreased in CRC, which could determine tumor proliferation, relapse, and prognosis.

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.

Background Recent studies revealed contrasting prognostic roles of body-mass index (BMI) and tumor location in colorectal cancer (CRC). Given that right-sided and left-sided CRC may exhibit inverse impact on outcome and body weight, the present study is to examine whether the prognostic value of BMI and tumor location could be stratified reciprocally. Methods This prospective, observational study recruited 4,086 patients with diagnosed stage III CRC from 5 independent clinical centers in China. verall survival (OS) and disease-specific survival (DSS) was included as the clinical endpoints. The association of patients’ outcome with BMI and tumor location was evaluated hierarchically by Kaplan-Meier and Cox proportional-hazards model. Results Although BMI was not associated with outcome within total patients, this association was significantly modified by tumor location. Among left-sided tumors, obesity and overweight was significantly associated with adverse OS and DSS. In contrast, among right-sided tumors, overweight was significantly associated with more favorable OS and DSS compared with normal-weight group. The association of survival with tumor location did not reach statistical significance either. However, hierarchical analysis by BMI revealed that left-sided tumors were associated with more favorable outcome in normal-weight group, while no statistically significant difference in overweight or obese group. Conclusions BMI and tumor location may have opposing prognostic impact on CRC, stratified by each other, after adjusting for known prognostic factors. These findings are the first to show the interactive prognostic impact of BMI and tumor location, which could be relevant to stratification of patients' management. Clinical trial identification NCT02215642. Legal entity responsible for the study The authors. Funding National Natural Science Foundation of China. Disclosure All authors have declared no conflicts of interest.

Background and Objectives Matrix metalloproteinase-12 (MMP-12) plays an important role in invasion and metastasis of human solid tumor cells. This study aimed to investigate the association of MMP-12 with overall survival in human gastric cancer. Methods Gastric cancer and adjacent normal tissue specimens were collected from 165 patients who had not received neoadjuvant chemotherapy. MMP-12 expression was determined by immunohistochemical staining, and the results were analyzed statistically in relation to the overall survival of the patients. Results MMP-12 expression was increased in gastric cancer compared with that observed in normal tissues. Increased MMP-12 expression was associated with tumor invasion, lymph node metastasis, distant metastasis, and TNM stage. No correlations were detected between MMP-12 expression and age, sex, differentiation status, tumor site, or Lauren classification. Moreover, patients with MMP-12 positive gastric cancer tended to have worse overall survival compared with those patients without MMP-12 expression. Conclusions The study results showed that increased expression of MMP-12 was associated with tumor progression in gastric cancer. It also provided the first evidence for MMP-12 expression in gastric cancer as an independent prognostic factor. J. Surg. Oncol. 2013;107:746–751. © 2012 Wiley Periodicals, Inc.

Members of the NDRG (N-Myc downstream-regulated) gene family have been shown to play a variety of roles in human malignancies. In the present study, we examined the expression of NDRG2 protein in glioma samples of WHO grades I-IV. We also investigated the association between NDRG2 expression and survival. Immunohistochemical analysis was used to measure NDRG2 protein expression in 316 specimens of human glioma and 41 normal control tissues. Survival analysis was performed using the Kaplan-Meier method and Cox's proportional hazards model. We found that NDRG2 expression was reduced in glioma relative to normal tissue, and that NDRG2 expression decreased with increasing glioma grade. Kaplan-Meier analysis showed that patients without NDRG2 expression had a lower survival rate than other patients. Multivariate analysis showed that NDRG2 expression was an independent prognostic factor for overall survival of patients with glioma. The present study provides the first evidence that NDRG2 expression is decreased in gliomas, indicating that NDRG2 may play an inhibitory role during the development of gliomas. NDRG2 expression may also be a significant and independent prognostic indicator for glioma.

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.

Matrix 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. Colorectal 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. High 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. Our 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.

NDRG2 (N-Myc downstream-regulated gene 2) is aberrantly expressed in colorectal cancer (CRC) and related to tumor differentiation status. In the present study, we investigated the association between NDRG2 mRNA levels in primary CRC to determine whether levels of NDRG2 mRNA could predict relapse and survival. A hospital-based study cohort of 226 CRC patients was involved in the study. NDRG2 mRNA levels were determined by real-time PCR. Correlations of NDRG2 mRNA expression with tumor clinicopathologic features, disease-free survival, and overall survival of the patients were studied. Significant decreased expression of NDRG2 mRNA was detected in tumor specimens. NDRG2 mRNA expression significantly correlated with differentiation status (P < 0.001), lymph node metastasis (P < 0.001), and tumor node metastasis stage (P < 0.001). Patients with reduced level of NDRG2 mRNA had a statistically significantly shorter disease-free survival and overall survival duration than patients with preserved expression of NDRG2 mRNA. In multivariate analysis, NDRG2 mRNA level was found to be an independent prognostic factor for both disease-free survival and overall survival of CRC patients. The present research provided the first evidence that decreased NDRG2 mRNA expression in primary human CRC might be a powerful, independent predictor of recurrence and outcome. Mol Cancer Ther; 10(1); 47–56. ©2011 AACR.

Intestinal transplantation using living-related donors could potentially reduce the severity of rejection responses against this highly immunogenic organ by better tissue matching and shorter cold ischemia duration, compensating for the shortage of donor grafts. The purpose of this study is to assess the safety of donors receiving living donor small bowel transplantation (LDSBT) in our hospital by reviewing the risk of operations and absorbing capability recovering retrospectively based on the parameters, such as body weight loss, blood loss, blood transfusion, operation time, duration of hospitalization, complications, and d-xylose tolerance test. After a follow-up period (mean 72 months, range: 48-96 months) of four cases of donors performed LDSBT in Xijing Hospital of digestive diseases dated from May 1999 to September 2003, no complication occurred. Therefore, pre-operation angiography, meticulous management of operation and accurate post-operation monitoring were particularly necessary to guarantee the safety of donors.

The 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.Immunohistochemistry, 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.It 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.Notch2 expression correlated closely with CRC and may play a role in tumor inhibition in colon carcinogenesis.

The 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.Immunohistochemistry, real-time polymerase chain reaction, and Western blot analysis were performed to assess the expression of Notch1.It 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.These results suggest that Notch1 expression correlated closely with colorectal cancer and may play an oncogenic role during colonic carcinogenesis.

Human leukocyte antigen G (HLA-G) is a non-classical HLA class I molecule thought to play a key role in maternal-fetal tolerance and cancer immune evasion. This study aimed to investigate the HLA-G expression in lesion sections and plasma sHLA-G levels of primary esophageal squamous cell carcinoma (ESCC) patients and its clinical significance in diagnosis and prognosis of ESCC. 60 ESCC patients and 28 healthy controls were recruited, and the positive expression of HLA-G in ESCC lesions and adjacent normal tissues were 70% (42/60) and 8.6% (5/60) (P

EMMPRIN/CD147 has been proved to be associated with tumor invasion and metastasis in various human malignancies. In the present study, we investigated the expression of CD147 and its association with disease-free survival of colorectal cancer patients. CD147 expression was investigated in 328 cases of colorectal cancer by immunohistochemistry assay. Statistical analysis was utilized to evaluate the association of CD147 expression with disease-free survival of colorectal cancer patients. CD147 expression was proved to be increased in colorectal cancer (P < 0.001) and related to tumor invasion (P < 0.001), metastasis (P < 0.001), and TNM stage (P < 0.001). Kaplan-Meier showed CD147 was associated with disease-free survival of patients with colorectal cancer for patients with higher CD147 expression tend to have shorter disease-free survival (P < 0.001). Multivariate analysis also proved CD147 to be an independent prognostic factor for disease-free survival of colorectal cancer patients (P < 0.05). These results suggested the potential role of CD147 in relapse of human colorectal cancer. It might be a novel molecular marker to predict relapse of patients with colorectal cancer.

MicroRNAs are known as non-coding RNAs that regulate the expression of target mRNA. Accumulating evidence has indicated that microRNA expression in human malignancies can be utilized as a prognostic marker for patients. However, the prognostic value of miR-650 in human glioma has not been investigated yet. In the present investigation, we have recruited 168 cases glioma specimens and 21 normal control brain specimens. Quantitative real-time PCR was carried out to investigate the expression of miR-650. Kaplan–Meier analysis and Cox’s proportional hazards model was used to evaluate the association of miR-650 with prognosis of glioma patients. Results showed that miR-650 expression was increased in glioma compared with normal control specimens (P < 0.001). It was also found that miR-650 expression was related to World Health Organization grade and Karnofsky performance score (KPS) for high expression was more frequently detected in glioma of high grade or low KPS score (P < 0.001). The prognosis of glioma with high miR-650 expression was significantly worse compared with that of glioma with low miR-650 expression. These results proved that miR-650 expression was a significant prognostic indicator in glioma, which may suggest new management of human glioma.

Matrix metalloproteinase-14 (MMP-14) has been considered to play an important role in invasion and metastasis of human solid tumor. The present study aimed to investigate the association of MMP-14 with overall survival in human gastric cancer. Gastric 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. MMP-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. The 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.

Background: Aberrantly activated Notch signaling has been shown to play a key role in carcinogenesis and progression of various human malignancies. In this study, we investigated the expression of Notch1 and Notch2 in colorectal cancer to determine whether they could serve as prognostic predictors. Patients and methods: The protein expression of Notch1 and Notch2 was examined by immunohistochemistry in 1003 clinical colorectal cancer specimens. Notch1 and Notch2 protein levels were investigated by immunohistochemistry. Statistical analysis was carried out to assess their prognostic value. Results: Significantly negative correlation between Notch1 and Notch2 was found in colorectal cancer (P < 0.001). Notch1 and Notch2 were proved to be inversely correlated with tumor differentiation, depth of invasion, lymph node metastases, distant metastasis, TNM (tumor‐node‐metastasis) stage and survival of patients, suggesting opposite function of the two receptors. Notch1 and Notch2 were proved to be adverse independent prognostic predictors (P < 0.001). Moreover, a synergistic effect of positive Notch1 and negative Notch2 coexpression on predicting poor overall survival was proved. Conclusions: Notch1 and Notch2 may be independent adverse prognostic predictors for patients with colorectal cancer. These results would contribute to identify more efficient prognostic predictors and therapeutic targets.

Matrix 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.Four 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.High 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.Our 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.

Matrix metalloproteinase-9 is a member of the Matrix metalloproteinases (MMP) family, which is overexpressed in some solid tumor and thought to enhance the tumor invasion and metastasis ability. Our study is to investigate the association of MMP-9 expression with disease-free survival and overall survival of patients with gastric cancer. Clinical gastric cancer specimens and adjacent normal tissues from 286 patients who had not received neoadjuvant chemotherapy were investigated by immunohistochemistry assay. Staining evaluation results were analyzed statistically in relation to various clinicopathological characters, disease-free survival and overall survival. High level of MMP-9 expression was detected in gastric cancer, significantly more than in adjacent normal epithelial cells. In gastric 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 patients' age, sex, tumor location or differentiation status were detected. The disease-free survival and overall survival were significantly shorter for patients with MMP-9 positive than those with MMP-9 negative tumors. Multivariate analysis identified MMP-9 was an independent prognostic factor for both disease-free survival and overall survival. Our findings provided convincing evidence for MMP-9 as an important role in human gastric cancer recurrence and prognosis. It might also serve as a novel target for both prognostic prediction and therapeutics.

Notch1 regulates cell proliferation, development, and apoptosis. Aberrant expression of Notch1 has been discovered in many types of tumors. We examined Notch1 expression in colorectal cancer to assess its role as a prognostic indicator. Notch1 protein expression was examined by immunohistochemistry in 223 surgically resected specimens of colorectal cancer and adjacent tissues. The relationship between various clinicopathological features and overall patient survival rate was analyzed. The association of Notch1 expression with the colorectal cancer survival rate was assessed by Kaplan–Meier and Cox proportional-hazards regression. Significantly high Notch1 expression was found in colorectal cancer cells compared with that of normal colorectal epithelial cells. Notch1 was positively correlated with depth of invasion (P = 0.005), lymph node metastases (P = 0.03), and tumor–node–metastasis (TNM) stage (P