Ying-Ying Xu

MicroRNA-148b suppresses cell growth by targeting cholecystokinin-2 receptor in colorectal cancer

MicroRNAs (miRNAs) play an important role in the regulation of a variety of cellular processes, including cell growth, differentiation, apoptosis and carcinogenesis. The purpose of this study was to elucidate the molecular mechanisms by which miR‐148b acts as a tumor suppressor in colorectal cancer. The expression of miR‐148b was significantly downregulated in 96 pairs of human colorectal cancer tissues (p < 0.0001) and three cell lines (p < 0.01) compared with non‐tumor adjacent tissues by quantitative real‐time PCR. The results of in situ hybridization highlighted that miR‐148b was important in the cancer transformation process. Using statistical analysis, we found that the expression level of miR‐148b was associated with tumor size (p = 0.033) in colorectal cancer patients. Moreover, overexpression of miR‐148b in HCT‐116 and HT‐29 cells could inhibit cell proliferation in vitro and suppress tumorigenicity in vivo. Importantly, the result of luciferase activity assay and western blot showed that the cholecystokinin‐2 receptor gene (CCK2R) was a target of miR‐148b and was downregulated by miR‐148b at the translational level. Then, we used siRNA, radioimmunoassay and ELISA to demonstrate that miR‐148b might have an effect on cell proliferation by regulating the expression of CCK2R which functioned depending on the gastrin in colorectal cancer. Taken together, our data provides the first evidences that miR‐148b acts as a tumor suppressor in colorectal cancer and should be further evaluated as a biomarker and therapeutic tool against colorectal cancer.

Evaluation of the seventh edition of American Joint Committee on Cancer TNM staging system for gastric cancer: results from a Chinese monoinstitutional study.

BackgroundTo investigate the validity of the 7th edition of American Joint Committee on Cancer (AJCC) TNM staging system for gastric cancer with special attention paid to pT2/pT3, pN1/pN2, and pN3a/pN3b category.Materials and MethodsClinicopathologic data of 1998 patients underwent R0 surgery for histologically proven gastric cancers with >15 lymph nodes retrieved were retrospectively reviewed.ResultsPrognoses were significantly different between pT2 and pT3 categories, between pN1 and pN2 categories, or between pN3a and pN3b categories. Each stage in the 6th edition was divided into the 7th edition stage with different survival rates. Moreover, stage IIIA, IIIB, and IIIC in the 7th edition system was divided into the 6th edition stage with different survival rates. Prognoses for patients in 7th edition T4aN1M0/T3N2M0/T2N3aM0, T4bN0-1M0/T4aN2M0/T3N3aM0, and T4aN3aM0/T4bN2M0 were similar to that of patients in T1N3bM0, T2N3bM0, and T3N3bM0, respectively, but significantly better than that of patients in T2N3bM0, T3N3bM0, and T4aN3bM0, respectively. However, no significant difference could be observed among patients in T4bN3aM0, T4aN3bM0, T4bN3bM0, and stage IV. A revised TNM system was proposed, in which T1N3bM0 was incorporated into stage IIIA, T2N3bM0 into stage IIIB, T3N3bM0 into stage IIIC, T4bN3aM0/T4aN3bM0/T4bN3bM0 into stage IV. Further analyses revealed the revised TNM system had better homogeneity, discriminatory ability, and monotonicity of gradients than the 6th and the 7th edition system.ConclusionsIt is reasonable to subclassify the 6th edition pT2 category and pN1 category into the 7th edition pT2/pT3 category and pN1/pN2 category, respectively. However, for better prognostic stratification, it might be more suitable for pN3a and pN3b categories to be considered individual determinants of the 7th edition TNM staging system.

Clinical significance of palliative gastrectomy on the survival of patients with incurable advanced gastric cancer: a systematic review and meta-analysis

BackgroundPalliative gastrectomy for patients with advanced gastric cancer remains controversial. The objective of the present meta-analysis was to analyze survival outcomes and establish a consensus on whether palliative gastrectomy is suitable for patients with incurable advanced gastric cancer and which type of patients should be selected to receive palliative gastrectomy.MethodsA literature search was conducted in PubMed, EMBASE and the Cochrane Library. The results for overall survival in the meta-analysis are expressed as hazard ratios (HRs) with 95% confidence intervals (CIs).ResultsOf 1647 articles and abstracts reviewed, 14 studies with 3003 patients were eligible for the final analysis. The meta-analysis revealed that palliative gastrectomy is associated with a significantly improvement in overall survival (HR 0.56; 95%CI 0.39–0.80; p < 0.002) compared that of patients treated without palliative gastrectomy. An improvement in survival was also observed in patients with stage M1 gastric cancer who received palliative gastrectomy (HR 0.62; 95%CI 0.49–0.78; p < 0.0001), especially those with peritoneal dissemination (HR = 0.76, 95%CI 0.63–0.92), liver metastasis (HR = 0.41, 95%CI 0.30–0.55), or distant lymph-node metastasis (HR = 0.36, 95%CI 0.23–0.59). Combined hepatic resection may be beneficial for patients who under palliative gastrectomy (HR 0.30; 95%CI 0.15–0.61; p = 0.0008). The overall survival of patients who underwent palliative gastrectomy combined with chemotherapy was significantly improved (HR 0.63; 95%CI 0.47–0.84; p = 0.002).ConclusionsFrom the results of the meta-analysis, palliative gastrectomy for patients with incurable advanced gastric cancer may be associated with longer survival, especially for patients with stage M1 gastric cancer. Combined hepatic resection for patients with liver metastasis and chemotherapy may be beneficial factors compared to simple palliative gastrectomy.

Benefits of hyperthermic intraperitoneal chemotherapy for patients with serosal invasion in gastric cancer: a meta-analysis of the randomized controlled trials

BackgroundIn this meta-analysis we aimed to determine the effectiveness and safety of hyperthermic intraperitoneal chemotherapy (HIPC) for patients with advanced gastric cancer who underwent gastrectomy.MethodsIn accordance with standard meta-analysis procedures, our study included patients who underwent resection for advanced gastric cancer and were randomly allocated to receive either hyperthermic intraperitoneal chemotherapy or control. We searched PubMed (up to November 2011), EMBASE (up to November 2011), Cochrane Database of Systematic Reviews (CDSR), and Cochrane Central Register of Controlled Trials (CCTR) (up to November 2011). Both published and unpublished trials were included in the analysis, and no search restrictions were imposed. There was no language restriction. The results were analyzed using RevMan 5.1 software, which was provided by Cochrane Collaboration.ResultsThere were ten randomized controlled trials included in the analysis. A total of 1062 patients with gastric cancer in these studies were divided into the HIPC group (n = 518) and control group (n = 544). A significant improvement in survival was observed in the HIPC groups compared to the control group in the mitomycin C (MMC) subgroup (RR = 0.75, 95%CI 0.65-0.86; P < 0.00001) and the 5-FU group (RR = 0.69, 95%CI 0.52-0.90; P < 0.00001); the total RR was 0.73 (95%CI 0.64-0.83; P < 0.00001). Our findings indicated that HIPC potentially exhibited a lower peritoneal recurrence rate in the HIPC group compared to the control group (RR = 0.45, 95%CI 0.28-0.72; P = 0.001).ConclusionsOur meta-analysis demonstrated that HIPC may improve the overall survival rate for patients who receive resection for advance gastric cancer potentially, and help to prevent peritoneal local recurrence among patients with serosal invasion in gastric cancer.

Is the prediction of prognosis not improved by the seventh edition of the TNM classification for colorectal cancer? Analysis of the surveilla006Ece, epidemiology, and end results (SEER) database

BackgroundWhether the 7th edition of American Joint Committee on Cancer (AJCC) TNM staging system (AJCC-7) is a successful revision remains debatable. We aimed to compare the predictive capacity of the AJCC-7 for colorectal cancer with the 6th edition of the AJCC TNM staging system (AJCC-6).MethodsThe National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) dataset consisting of 158,483 records was used in this study. We evaluated the predictive capacity of the two editions of the staging system using Harrell’s C index and Bayesian Information Criterion (BIC).ResultsThere was a significant prognostic difference between patients at stage IIB and IIC (P < 0.001). Stage III patients with similar prognoses were adequately sub-grouped in the same stage according to AJCC-7. The Harrell’s C index revealed a value of 0.7692 for AJCC-7, which was significantly better than 0.7663 for AJCC-6 (P < 0.001). BIC analysis provided consistent results (P < 0.001).ConclusionsThis study demonstrates that AJCC-7 is superior to the AJCC-6 staging system in predictive capacity.

Which Is the Most Suitable Classification for Colorectal Cancer, Log Odds, the Number or the Ratio of Positive Lymph Nodes?

Objective The aim of the current study was to investigate which is the most suitable classification for colorectal cancer, log odds of positive lymph nodes (LODDS) classification or the classifications based on the number of positive lymph nodes (pN) and positive lymph node ratio(LNR) in a Chinese single institutional population. Design Clinicopathologic and prognostic data of 1297 patients with colorectal cancer were retrospectively studied. The log-rank statistics, Coxs proportional hazards model, the Nagelkerke R2 index and a Harrells C statistic were used. Results Univariate and three-step multivariate analyses identified that LNR was a significant prognostic factor and LNR classification was superior to both the pN and LODDS classifications. Moreover, the results of the Nagelkerke R2 index (0.130) and a Harrells C statistic (0.707) of LNR showed that LNR and LODDS classifications were similar and LNR was a little better than the other two classifications. Furthermore, for patients in each LNR classification, prognosis was homologous between those in different pN or LODDS classifications. However, for patients in pN1a, pN1b, LODDS2 and LODDS3 classifications, significant differences in survival were observed among patients in different LNR classifications. Conclusions For patients with colorectal cancer, the LNR classification is more suitable than pN and LODDS classifications for prognostic assessment in a Chinese single institutional population.

Comparison Different Methods of Intraoperative and Intraperitoneal Chemotherapy for Patients with Gastric Cancer: A Meta-analysis

PURPOSE To investigate the efficacy and safety of intraperitoneal chemotherapy (IPC) for patients with gastric cancer and to compare effects between different regimens of IPC. METHOD Randomized controlled trials comparing the effects of surgery plus intraperitoneal chemotherapy with surgery alone or comparing the efficacy between different regimens of intraperitoneal chemotherapy were searched for in Medline, Embase, Pubmed, the Cochrane Library and the Chinese BioMedical Disc and so on by two independent reviewers. After quality assessment and data extraction, data were pooled for meta-analysis using RevMan5.16 software. Tests of interaction were used to test for differences of effects among subgroups grouped according to different IPC regimens. RESULTS Fifteen RCTs with a total of 1713 patients with gastric cancer were included for quality assessment and data extraction. Ten studies were judged to be of fair quality and entered into meta-analysis. Hyperthermic intraoperative intraperitoneal chemotherapy (HR=0.60, P<0.01), hyperthermic intraoperative intraperitoneal chemotherapy plus postoperative intraperitoneal chemotherapy (HR=0.47, P<0.01) and normothermic intraoperative intraperitoneal chemotherapy (HR=0.70, P=0.01) were associated with a significant improvement in overall survival. Tests of interaction showed that hyperthermia and additional postoperative intraperitoneal chemotherapy did not impact on its effect. Further analysis revealed that intraperitoneal chemotherapy remarkably decrease the rate of postoperative hepatic metastasis by 73% (OR=0.27, 95% CI=0.12 to 0.67, P<0.01). However, intraperitoneal chemotherapy increased risks of marrow depression (OR=5.74, P<0.01), fever (OR=3.67, P=0.02) and intra-abdominal abscess (OR=3.57, P<0.01). CONCLUSION The present meta-analysis demonstrates that hyperthermic intraoperative intraperitoneal chemotherapy and normothermic intraoperative intraperitoneal chemotherapy should be recommended to treat patients with gastric cancer because of improvement in overall survival. However, it is noteworthy that intraperitoneal chemotherapy can increase the risks of marrow depression, intra-abdominal abscesses, and fever.

Macroscopic Serosal Classification Predicts Peritoneal Recurrence for Patients with Gastric Cancer Underwent Potentially Curative Surgery

BackgroundPrevious studies revealed serosal invasion as one of the most important predictors of peritoneal micrometastasis. However, even for cancers with serosal invasion, the macroscopic serosal appearance is highly heterogeneous. The aim of the present study was to propose a macroscopic serosal classification (MSC) and to investigate the validity of this classification as a predictor of peritoneal recurrence.Materials and MethodsClinicopathologic features including MSC of 1528 patients with pT3/pT4a stage gastric cancers who underwent potentially radical surgery were retrospectively reviewed. MSC was classified as reactive type, nodular type, tendonoid type, and color-diffused type according to the macroscopic serosal appearance.ResultsThere were significant differences in tumor size, location, Bormann type, Lauren grade, lymphatic and/or blood vessels invasion (LBVI), width of serosa changes, depth of invasion, number of nodes metastasis, lymph node metastasis ratio, pN stage, and peritoneal cytology between patients with different types of serosa. Multivariate analysis revealed MSC, as well as depth of invasion, Lauren grade, and pN stage, significantly predicted the presence of peritoneal-free cancer cells. Both MSC and peritoneal cytology significantly correlated with patient survival. However, only MSC significantly predicted peritoneal recurrence on multivariate analysis, but peritoneal cytology did not, indicating MSC was more sensitive than cytologic examination. Further investigation suggested MSC and pN stage were also independent predictors of peritoneal recurrence for patients with negative peritoneal cytology.ConclusionsThe MSC sensitively predicts the presence of peritoneal micrometastasis for pT3/pT4a-stage gastric cancer patients who underwent potentially radical surgery. Consequently, it might be considered a good indicator to guide perioperative adjuvant therapy for patients with high risk of peritoneal recurrence.

Midkine positively regulates the proliferation of human gastric cancer cells.

Midkine (MDK), a heparin-binding growth factor, modulates the proliferation and migration of various cells, is often highly expressed in many malignant tumors, and may act as an oncoprotein. We found that MDK is overexpressed in clinical human gastric cancer tissues relative to its expression in adjacent noncancerous tissues. To further investigate the biological activities of MDK in gastric cancer, we introduced the MDK gene into human SGC7901 gastric cancer cells, where it contributed to the proliferation of SGC7901 cells in vitro and in vivo. Conversely, the knockdown of MDK expression by siRNA resulted in significantly reduced proliferation of BGC823 cells. Our study also shows that MDK activates both the Akt and ERK1/2 pathways and upregulates the expression of several cell-cycle-related proteins, including cyclin A, cyclin D1, Cdk2, Cdk4, and Cdk6, which in part explains the contribution of MDK to gastric cancer cell survival and growth. These results demonstrate that MDK contributes to gastric cancer cell proliferation and suggest that it plays an important role in the development of human gastric cancer.

CARMA3 is overexpressed in colon cancer and regulates NF-κB activity and cyclin D1 expression.

CARMA3 was recently reported to be overexpressed in cancers and associated with the malignant behavior of cancer cells. However, the expression of CARMA3 and its biological roles in colon cancer have not been reported. In the present study, we analyzed the expression pattern of CARMA3 in colon cancer tissues and found that CARMA3 was overexpressed in 30.8% of colon cancer specimens. There was a significant association between CARMA3 overexpression and TNM stage (p=0.0383), lymph node metastasis (p=0.0091) and Ki67 proliferation index (p=0.0035). Furthermore, knockdown of CARMA3 expression in HT29 and HCT116 cells with high endogenous expression decreased cell proliferation and cell cycle progression while overexpression of CARMA3 in LoVo cell line promoted cell proliferation and facilitated cell cycle transition. Further analysis showed that CARMA3 knockdown downregulated and its overexpression upregulated cyclin D1 expression and phospho-Rb levels. In addition, we found that CARMA3 depletion inhibited p-IκB levels and NF-κB activity and its overexpression increased p-IκB expression and NF-κB activity. NF-κB inhibitor BAY 11-7082 reversed the role of CARMA3 on cyclin D1 upregulation. In conclusion, our study found that CARMA3 is overexpressed in colon cancers and contributes to malignant cell growth by facilitating cell cycle progression through NF-κB mediated upregulation of cyclin D1.