Miao Zhen Qiu

Overexpression of paxillin induced by miR-137 suppression promotes tumor progression and metastasis in colorectal cancer

The deregulation of paxillin (PXN) has been involved in the progression and metastasis of different malignancies including colorectal cancer (CRC). miR-137 is frequently suppressed in CRC. PXN is predicted to be a direct target of miR-137 in CRC cells. On this basis, we hypothesized that overexpression of PXN induced by suppression of miR-137 may promote tumor progression and metastasis and predicts poor prognosis. We detected the expression of PXN and miR-137 in clinical tumor tissues by immunohistochemical analysis and real-time PCR, positive PXN staining was observed in 198 of the 247 (80.1%) cases, whereas no or weak PXN staining was observed in the adjacent non-cancerous area. Higher level of PXN messenger RNA (mRNA) and lower level of miR-137 was observed in cancer tissues than adjacent non-cancerous tissues. High expression of PXN and low expression of miR-137 was associated with aggressive tumor phenotype and adverse prognosis. Moreover, the expression of PXN was negatively correlated with miR-137 expression. A dual-luciferase reporter gene assay validated that PXN was a direct target of miR-137. The use of miR-137 mimics or inhibitor could decrease or increase PXN mRNA and protein levels in CRC cell lines. Knockdown of PXN or ectopic expression of miR-137 could markedly inhibit cell proliferation, migration and invasion in vitro and repress tumor growth and metastasis in vivo. Taken together, these results demonstrated that overexpression of PXN induced by suppression of miR-137 promotes tumor progression and metastasis and could serve as an independent prognostic indicator in CRC patients.

ABO blood group, hepatitis B viral infection and risk of pancreatic cancer

Little is known about the role of association between ABO blood type and risk of pancreatic cancer develops through effects on hepatitis B viral (HBV) infection. Our study aimed to determine whether joint ABO blood type and HBV infection could increase the risk for pancreatic cancer. A total of 645 patients with pancreatic adenocarcinoma and 711 age‐ and sex‐matched individuals who had nonmalignant diseases treated at the Sun Yat‐sen University Cancer Center in China were retrospectively analyzed. Blood samples were tested for ABO blood type and hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti‐HBs), hepatitis B e antigen (HBeAg), hepatitis B e antibody (anti‐HBe) and hepatitis B core antibody (anti‐HBc). Multivariable unconditional logistic regression analysis was used to estimate adjusted odds ratios [AORs] and 95% confidence interval [CI]. Multivariable analysis with adjustment for risk factors showed that A blood type, HBsAg‐positive/anti‐HBc‐positive, anti‐HBs‐positive/anti‐HBc‐positive were significantly associated with pancreatic cancer. The estimated AORs (95% CI) were as follows: A blood type, 1.425 (1.071–1.894), HBsAg‐positive/anti‐HBc‐positive, 1.610 (1.125–2.304), anti‐HBs‐positive/anti‐HBc‐positive, 1.526 (1.159–2.011). The effect of A blood type significantly modified the risk of pancreatic cancer among subjects with anti‐HBc‐positive (AORs = 1.882, 95% CI, 1.284–2.760). In our study, we reported an association between A blood type, infection with HBV and pancreatic cancer risk. Moreover, we found a synergism between A blood type and HBV infection in the development of pancreatic cancer.

Identification of MicroRNA-214 as a negative regulator of colorectal cancer liver metastasis by way of regulation of fibroblast growth factor receptor 1 expression

The purpose of this study was to identify microRNAs (miRNAs) involved in the pathology of colorectal cancer (CRC) liver metastasis and investigate their underlying mechanisms. A total of 39 miRNAs were identified to be differentially expressed between 16 primary CRC tissues with liver metastases and 16 CRC tissues without liver metastases from 32 patients by Affymetric miRNA microarrays. A panel of eight miRNAs were confirmed to be significantly and differentially expressed between CRC tissues with and without liver metastases through quantitative reverse‐transcription polymerase chain reaction (RT‐PCR) analysis in the 32 patients. In a validated cohort of 99 CRC patients (44 with and 55 without liver metastases), only miR‐214 was validated to be significantly down‐regulated in CRC with liver metastases, which was associated with an unfavorable prognosis. Ectopic expression of miR‐214 suppressed proliferation, migration, and invasion in vitro, tumor growth and liver metastasis in an in vivo xenograft mouse model, whereas miR‐214 knockdown promoted proliferation, migration, and invasion in CRC cell lines. Further studies indicated that fibroblast growth factor receptor 1 (FGFR1) was a potential target of miR‐214. Restoring miR‐214 expression in CRC cells decreased endogenous FGFR1 messenger RNA (mRNA) and protein levels. FGFR1 knockdown mimicked the tumor suppressive effect of miR‐214 on CRC cells, while reintroduction of FGFR1 abolished the tumor suppressive effect of miR‐214 on CRC cells. Moreover, miR‐214 expression levels were inversely correlated with FGFR1 in CRC patients. Conclusion: Down‐regulation of miR‐214 expression was correlated with increased FGFR1 expression levels, which may contribute to increased CRC liver metastasis. miR‐214 may serve as a potential marker to predict survival, and the miR‐214‐FGFR1 axis may be a therapeutic target in CRC patients. (Hepatology 2014;60:598–609)

Long non-coding RNA XIST regulates gastric cancer progression by acting as a molecular sponge of miR-101 to modulate EZH2 expression

BackgroundLong non-coding RNAs (lncRNAs) have emerged as critical regulators of tumor progression. However, the role and molecular mechanism of lncRNA XIST in gastric cancer is still unknown.MethodsReal-time PCR analysis was performed to measure the expression levels of lncRNA XIST in gastric cancer tissues and cell lines, the correlation between lncRNA XIST expression and clinicopathological characteristics and prognosis was analyzed in gastric cancer patients. The biological function of lncRNA XIST on gastric cancer cells were determined both in vitro and in vivo. The regulating relationship between lncRNA XIST and miR-101 was investigated in gastric cancer cells.ResultslncRNA XIST was significantly up-regulated in gastric cancer tissues and cell lines. Overexpression of lncRNA XIST was markedly associated with larger tumor size, lymph node invasion, distant metastasis and TNM stage in gastric cancer patients. Functionally, knockdown of lncRNA XIST exerted tumor-suppressive effects by inhibiting cell proliferation, migration and invasion in vitro and tumor growth and metastasis in vivo. Furthermore, an inverse relationship between lncRNA XIST and miR-101 was found. Polycomb group protein enhancer of zeste homolog 2 (EZH2), a direct target of miR-101, could mediated the biological effects that lncRNA XIST exerted.ConclusionslncRNA XIST is up-regulated and is associated with aggressive tumor phenotypes and patient survival in gastric cancer, and the newly identified lncRNA XIST/miR-101/EZH2 axis could be a potential biomarkers or therapeutic targets for gastric cancer patients.

Comparison of 6th and 7th AJCC TNM Staging Classification for Carcinoma of the Stomach in China

BackgroundThe 7th edition of American Joint Committee on Cancer tumor-node-metastasis (AJCC TNM) staging system was put into use recently. The study aimed to evaluate its predictive ability on survival and compare the difference between the 6th and 7th editions of AJCC TNM system in gastric carcinoma.Materials and MethodsA total of 1000 gastric carcinoma patients receiving treatment in our center were selected for the analysis. Patients were staged using both the 6th and 7th editions AJCC TNM staging system. Survival analysis was performed with a Cox regression model.ResultsOf previous stage IV patients, 39.9% (112 of 281) migrated to a lower tier in the 7th edition. By setting the cutoff of positive lymph nodes as 0, 2, 6, and 15, the 7th edition strengthens the role of positive lymph nodes. Multivariable regression analysis showed that both 6th and 7th TNM stage systems were independent factors for overall survival. For lymph nodes negative patients, the 5-year overall survival for patients with fewer than 15 resected lymph nodes was significantly lower than those with more than 15.ConclusionsAJCC 7th is not superior to AJCC 6th in predicting the 5-year overall survival rates of gastric adenocarcinoma patients. The definition of stage IV and the selection of cutoffs for MLNC in the AJCC 7th system is much more reasonable compared with the AJCC 6th system.

Impact of pretreatment hematologic profile on survival of colorectal cancer patients

Pretreatment hematologic abnormalities have been reported to have prognostic value in patients with solid tumors. The aim of our study was to determine the prevalence of abnormalities in the hematologic profile in patients with colorectal cancer before treatment and to evaluate if such a profile could be used for prognostic evaluations. We identified all patients in Cancer Center of Sun Yat-Sen University who were diagnosed as colorectal cancers between May 2005 and August 2009. All subjects were investigated regarding levels of white blood cells, platelets, and hemoglobin concentration. Survival was compared by using the log-rank test on the Kaplan–Meier life table. Multivariate Cox regression analysis was used to evaluate if the pretreatment hematologic profile was independent prognostic factor. We identified 363 patients with colorectal cancer and 315 patients with benign diseases for the final analysis. The percentages of leukocytosis, anemia, and thrombocytosis were significantly higher in colorectal cancer patients than in patients with benign diseases. Univariate analysis showed that advanced tumor stages, leukocytosis, anemia, thrombocytosis, and low histological grade were all significantly associated with shorter survival. The multivariate Cox analysis revealed that low histological grade, tumor stage, pretreatment anemia, and thrombocytosis remained independent prognostic variables for survival. The cumulative effect of anemia and thrombocytosis yielded shorter survival. Anemia and thrombocytosis can be considered as useful prognostic markers in patients with colorectal cancer.

Prognostic effects of 25-hydroxyvitamin D levels in gastric cancer

BackgroundResults from large epidemiologic studies on the association between vitamin D and gastric cancer are controversial. Vitamin D significantly promotes apoptosis in the undifferentiated gastric cancer cell, but the prognostic effects of its levels are unknown.Methods197 gastric carcinoma patients who received treatment in the cancer centre of Sun Yat-sen University from January 2002 to January 2006 were involved in the study. The stored blood drawn before any treatment was assayed for 25-hydroxyvitamin D levels. The clinicopathologic data were collected to examine the prognostic effects of vitamin D.ResultsThe mean vitamin D levels of the 197 gastric patients was 49.85 ± 23.68 nmol/L, among whom 114(57.9%) were deficient in Vitamin D(< 50 nmol/L), 67(34%) were insufficient (50-75 nmol/L) and 16(8.1%) were sufficient (> 75 nmol/L). Clinical stage (P = 0.004) and lymph node metastasis classification (P = 0.009) were inversely associated with vitamin D levels. The patients with high vitamin D levels group (≥ 50 nmol/L) had a higher overall survival compared with the low vitamin D levels group (< 50 nmol/L)(P = 0.018). Multivariate analysis indicated that vitamin D levels were an independent prognostic factor of gastric cancer (P = 0.019).ConclusionsVitamin D deficiency may be associated with poor prognosis in gastric cancer.

Clinicopathological characteristics and prognostic analysis of Lauren classification in gastric adenocarcinoma in China

BackgroundAccording to the Lauren classification, gastric adenocarcinomas are divided into diffuse and intestinal types. The causative attribution explaining the dismal prognosis of diffuse-type remains unknown.MethodsWe examined the archive of 1000 patients with gastric adenocarcinomas who received radical gastrectomy in our center and assessed the effect of the Lauren classification on survival in a multivariate approach. Moreover we compared the variation of clinical features between the diffuse-type and intestinal-type and explored the contributing factors for the prognostic difference.ResultsThere were 805 resectable patients for the final analysis. Diffuse-type comprised of 48.7% in the gastric carcinoma in our group and showed poorer prognosis than intestinal-type (P=0.013). Multivariate analysis revealed that independent prognostic factors for gastric carcinoma patients were T stage (P<0.001), N stage (P<0.001) tumor size (P<0.001) and Lauren classification (P=0.003). For the clinical features, diffuse-type was significantly associated with younger age (p<0.001), female preponderance (p <0.001), distal location (P<0.001), advanced pT (p < 0.001), advanced pN (p < 0.001) and advanced TNM stage (p = 0.027).ConclusionsDiffuse type adenocarcinoma carries a worse prognosis that may be partially explained by the tendency of this subtype to present at more advanced T and N stage. However, Lauren classification has prognostic significance that is independent of T and N stage as well as other prognostic variables based on the multivariate cox analysis.

Expressions of hypoxia-inducible factor-1α and hexokinase-II in gastric adenocarcinoma: the impact on prognosis and correlation to clinicopathologic features

The impact of hypoxia-inducible factor (HIF)-1α and hexokinase-II (HK-II) expression on prognosis of gastric adenocarcinoma patients has not been clearly established. We identified all patients in Cancer Center of Sun Yat-Sen University who were diagnosed as gastric adenocarcinoma and underwent radical gastrectomy between January 1999 and December 2001. We used immunohistochemistry to determine the expressions of HIF-1α protein and HK-II in the surgical sections. We identified 188 patients with gastric adenocarcinoma for the final analysis. The positive rate of HIF-1α and HK-II were 110/188 (54.6%) and 40/188 (21.3%), respectively. Both HIF-1α and HK-II were all positively correlated with tumor size, lower differentiation, and tumor stage. Univariate analysis showed that advanced tumor stages (P < 0.001), tumor size (P = 0.003), HIF-1α expression (P < 0.001), and HK-II expression (P < 0.001) were all significantly associated with shorter survival. The multivariate Cox analysis revealed that tumor stage (P < 0.001), HIF-1α expression (P < 0.001), and HK-II expression (P = 0.002) remained independent prognostic variables for survival. In addition, there was a positive correlation of HIF-1α protein expression and HK-II (P = 0.022). Both HIF-1α and HK-II were overexpressed in gastric adenocarcinoma. The multivariate Cox analysis revealed that both of them were independent factors on survival of gastric adenocarcinoma patients.

Incidence of anemia, leukocytosis, and thrombocytosis in patients with solid tumors in China

Despite the fact that malignancies are associated with hematological abnormalities, some clinical studies have been unable to detect such a relation. The aim of our study was to detect the prevalence of pretreatment hematologic abnormalities in patients with common solid tumors and to determine if such a profile could be used for prognostic evaluations. We identified all patients in Cancer Center of Sun Yat-sen University who were diagnosed as solid tumors (breast carcinoma, hepatocellular carcinoma, nasopharyngeal carcinoma, esophageal carcinoma, gastric cancer, cervical carcinoma, endometrial cancer, renal cell carcinoma, and non-small cell lung cancer) between January 2000 and August 2009. All subjects were investigated regarding levels of white blood cells, platelets, and hemoglobin concentration. We identified 3,180 patients with solid tumors and 285 patients with benign diseases for the final analysis. The percentages of leukocytosis, anemia, and thrombocytosis in patients with solid tumors ranged from 4.0% to 25.6%, 3.3% to 29.2%, and 2.1% to 9.7%, respectively. The multivariate Cox analysis revealed that anemia was an independent prognostic factor in patients with breast cancer (P = 0.006), hepatocellular carcinoma (P = 0.002), nasopharyngeal carcinoma (P = 0.008), and esophageal carcinoma (P = 0.001). Leukocytosis was an independent prognostic factor in patients with cervical cancer (P = 0.007). The incidence of hematological abnormalities in Chinese patients with solid tumors was relatively lower than that of the counterparts in the Western countries. A pretreatment anemia or leukocytosis can serve as a useful marker to predict outcome of patients in some of the solid tumors.