Zuli Yang

NFκB1 and NFκBIA polymorphisms are associated with increased risk for sporadic colorectal cancer in a southern Chinese population.

Background Nuclear factor κB (NFκB) plays a key role in the regulation of apoptosis. The function of NFκB is inhibited by binding to NFκB inhibitor (IκB), and disruption of the balance of NFκB and IκB is related to the development of many diseases, including tumors. Therefore, we hypothesized that the NFκB1 (-94del/insATTG) and NFκBIA (2758 A>G) polymorphisms were associated with colorectal cancer (CRC) susceptibility. Methods In a hospital-based case–control study of 1001 CRC patients and 1005 cancer-free controls frequency matched by age and sex, we genotyped polymorphisms using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method and performed luciferase assays and Western blotting analysis to identify whether genetic variants in NFκBIA alter its gene expressions and functions and thus cancer risk. Results We found that both NFκB1-94 ins/delATTG and NFκBIA 2758 A>G polymorphisms were correlated with CRC risk (OR = 1.47; 95%CI = 1.14–1.86, and OR = 1.38; 95% CI = 1.14–1.66, respectively). Furthermore, when evaluated these two polymorphisms together, the combined genotypes with 2 variant (risk) alleles (2758GG and -94ins/ins+del/ins) were associated with an increased risk of CRC (OR = 1.71; 95% CI = 1.23–2.38) compared to 0 variant, and the significant trend for 2 variant (risk) alleles were more pronounced among subgroups of aged <60 years, women, never drinkers, never smokers, persons with a normal BMI and those with a family history of cancer(Ptrend<0.01). Moreover, luciferase assays showed that the G allele in the 3′UTR significantly decreased NFκBIA mRNA stability and the A allele regulation by miRNA449a in vitro and that the NFκBIA protein expression levels of the AA+AG variant carriers were significantly higher in peritumoral tissues than those of the 2758GG genotype. Conclusion NFκB1 and NFκBIA polymorphisms appear to jointly contribute to risk of CRC. These two variants may be a genetic modifier for CRC susceptibility in this southern Chinese population.

Neoadjuvant chemotherapy for gastric cancer: A meta‐analysis of randomized, controlled trials

Although the effect of neoadjuvant chemotherapy in gastric cancer has been extensively studied, the data of survival benefit are still controversial. The purpose of this work was to assess the effectiveness of neoadjuvant chemotherapy followed by surgery in patients with gastric cancer.

Clinicopathologic Characteristics and Outcomes of Patients with Obstructive Colorectal Cancer

PurposeThe aim of this retrospective study was to analyze the clinicopathologic characteristics and short-term and long-term outcomes of colorectal cancer patients with obstruction compared to those of non-obstructive colorectal cancer patients.MethodsBetween January 1998 and December 2005, 1,672 colorectal cancer patients undergoing operation were enrolled in this study. Patients were classified into two groups according to the presentation: patients with complete obstructive colorectal cancer (COC, n = 215) receiving emergency procedures and patients with non-obstructive colorectal cancer (NOC, n = 1,457) receiving elective procedures. The data on the clinicopathologic characteristics and short-term and long-term outcomes of patients were analyzed retrospectively.ResultsAmong 1,672 colorectal cancer patients, 215 cases presented with complete obstruction. The distribution of tumor location and size, macroscopic type, depth of invasion, liver metastasis, peritoneal carcinomatosis, and TNM stage were found to be different between the COC and NOC groups. Logistic regression analysis showed that tumor location, depth of invasion, and peritoneal carcinomatosis were independent factors associated with obstruction. Patients with obstruction had an increased risk of death by a factor of 2.251 compared to patients without obstruction. Peritoneal carcinomatosis and TNM stage were independent factors for the survival of the COC group. Obstruction, peritoneal carcinomatosis, tumor macroscopic type, and TNM stage were independent indicators for postoperative recurrence. Postoperative mortality was significantly higher in the COC group than the NOC group. The overall 5- and 10-year survival rates in the COC group were 47.8% and 42.8%, respectively, compared to 67.2% and 59.8% in the NOC group, respectively (p < 0.05). The postoperative recurrence rates were 43.1% in the COC group and 32.8% in the NOC group (p < 0.05).ConclusionsObstruction is an independent indicator for the survival and postoperative recurrence for patients with colorectal cancer. Patients in the COC group have worse overall survival with high postoperative recurrence rate compared to those in the NOC group.

High expression of Beclin-1 predicts favorable prognosis for patients with colorectal cancer

PURPOSE Beclin-1 is an autophagy gene. It promotes the formation of the autophagic vesicle as well as plays an essential role in guarding the cells against chromosomal instability. Overexpression of Beclin-1 has been reported to predict a favorable survival in various cancers. However, little is known about its prognostic significance in colorectal cancer. METHODS AND MATERIALS A total of three hundred and sixty-three (363) colorectal tissues from colorectal cancer (CRC) patients were collected. Tissue micro-arrays and immunohistochemistry were used to investigate the expression and prognostic significance of Beclin-1 in CRC. The associations among Beclin-1 expression, clinicopathological parameters and prognosis were evaluated. RESULTS Beclin-1 had a higher expression in CRC tissues than in normal tissues. A high expression of Beclin-1 was positively correlated with gender (P=0.027), histological grade (P=0.003), pM status (P=0.003) and clinical stage (P=0.024). Patients with a high Beclin-1 expression, when compared to those with a lower expression had both a better overall survival (OS, P=0.006) and disease-free survival (DFS, P=0.008). In the pT3 subgroup, Beclin-1 was also found to be a good prognostic indicator (P<0.05). Multivariate analysis showed a high expression of Beclin-1 was indeed a positive independent prognostic factor of OS and DFS for CRC patients (P<0.05). CONCLUSION Our results demonstrated that a high expression of Beclin-1 correlated with a better overall survival and disease-free survival, thus serving as a favorable independent prognostic marker in CRC.

Epithelial–mesenchymal transition biomarkers and support vector machine guided model in preoperatively predicting regional lymph node metastasis for rectal cancer

Background:Current imaging modalities are inadequate in preoperatively predicting regional lymph node metastasis (RLNM) status in rectal cancer (RC). Here, we designed support vector machine (SVM) model to address this issue by integrating epithelial–mesenchymal-transition (EMT)-related biomarkers along with clinicopathological variables.Methods:Using tissue microarrays and immunohistochemistry, the EMT-related biomarkers expression was measured in 193 RC patients. Of which, 74 patients were assigned to the training set to select the robust variables for designing SVM model. The SVM model predictive value was validated in the testing set (119 patients).Results:In training set, eight variables, including six EMT-related biomarkers and two clinicopathological variables, were selected to devise SVM model. In testing set, we identified 63 patients with high risk to RLNM and 56 patients with low risk. The sensitivity, specificity and overall accuracy of SVM in predicting RLNM were 68.3%, 81.1% and 72.3%, respectively. Importantly, multivariate logistic regression analysis showed that SVM model was indeed an independent predictor of RLNM status (odds ratio, 11.536; 95% confidence interval, 4.113–32.361; P<0.0001).Conclusion:Our SVM-based model displayed moderately strong predictive power in defining the RLNM status in RC patients, providing an important approach to select RLNM high-risk subgroup for neoadjuvant chemoradiotherapy.

Epigenetic Inactivation and Tumor-Suppressor Behavior of NGFR in Human Colorectal Cancer

The nerve growth factor receptor (NGFR/p75) is a potential tumor suppressor, but its role in colorectal cancer is unknown. Here, the hypermethylation status, biologic function, and clinical relevance were determined for p75NGFR in colorectal cancer. The methylation status and expression of p75NGFR were assessed in colorectal cancer cell lines and clinical tissues by bisulfite genomic sequencing (BGS), qRT-PCR, and immunoblot assay. Methylation of p75NGFR was frequently found in colorectal cancer, leading to its silencing or downregulation, and it was effectively restored by a demethylation agent. The overexpression of p75NGFR in multiple colorectal cancer cell model systems significantly inhibited cell proliferation (concomitant with G1-phase arrest), invasion, and colony formation and induced cell apoptosis. In contrast, p75NGFR knockdown significantly promoted proliferative and invasive phenotypes. Importantly, p75NGFR methylation was observed in the majority of primary colorectal cancer specimens and was associated with histologic grade and preoperative serum CA19-9 levels. Multivariate analysis indicated that patients who lack p75NGFR have reduced overall survival (64% vs. 75%, P = 0.028) and disease-free survival (61% vs. 72%, P = 0.034) compared with p75NGFR-positive patients. In conclusion, p75NGFR is predominantly silenced or downregulated in colorectal cancer, and its biologic activities are consistent with it being a relevant tumor suppressor. Implications: p75NGFR is a candidate tumor suppressor and has independent prognostic potential in colorectal cancer. Mol Cancer Res; 13(1); 107–19. ©2014 AACR.

Functional variants of -1318T > G and -673C > T in c-Jun promoter region associated with increased colorectal cancer risk by elevating promoter activity

C-Jun plays important roles in the development of multiple cancers, but no well-designed association studies have been conducted to assess the roles of its genetic polymorphisms in cancer risk. In a cohort of 1016 pairs of colorectal cancer (CRC) patients and matched cancer-free controls, we investigated two genetic polymorphisms in the promoter regions of the c-Jun (rs4646999, -673C > T and rs2760501, -1318T > G) via the Taqman assay and evaluated the association between two polymorphisms and risk of CRC. We found that both the -1318G and -673C variant genotypes were associated with an increased risk of CRC [-1318TG: odds ratio (OR) = 1.26, 95% confidence interval (CI) = 1.04-1.54; -1318GG: OR = 1.63, 95% CI = 1.03-2.60; -673CT: OR = 1.60, 95% CI = 1.23-2.07; -673CC: OR = 1.80, 95% CI = 1.36-2.37]. Haplotype association analysis showed that compared with the carriers of -1318T-673T haplotype, carriers of the -1318T-673C, -1318G-673T, and -1318G-673C haplotypes all had a significantly increased risk of CRC (P < 0.05 for all). The combined genotypes incorporating both polymorphisms obtained a more significantly additive risk of CRC (one variant genotype: OR = 1.81, 95% CI = 1.30-2.51; two variant genotype: OR = 2.42, 95% CI = 1.70-3.44). Moreover, we found that the change of the -1318T to G allele interact with the -673T to C allele elevated the transcription activity of the c-Jun, and we confirmed the same trends by analyzing c-Jun protein expression in the CRC tissues from patients carrying different number of variant genotypes. This study suggests that -673C > T and -1318T > G genetic variants in c-Jun promoter regions contribute to an increased risk of CRC, possibly by elevating the transcription activity and protein expression levels that appeared to upregulate activity of c-Jun thus tumorigenesis.

Levels of human replication factor C4, a clamp loader, correlate with tumor progression and predict the prognosis for colorectal cancer

BackgroundHuman replication factor C4 (RFC4) is involved in DNA replication as a clamp loader and is aberrantly regulated across a range of cancers. The current study aimed to investigate the function of RFC4 in colorectal cancer (CRC).MethodsThe mRNA levels of RFC4 were assessed in 30 paired primary CRC tissues and matched normal colonic tissues by quantitative PCR. The protein expression levels of RFC4 were evaluated by western blotting (n = 16) and immunohistochemistry (IHC; n = 49), respectively. Clinicopathological features and survival data were correlated with the expression of RFC4 by IHC analysis in a tissue microarray comprising 331 surgically resected CRC. The impact of RFC4 on cell proliferation and the cell cycle was assessed using CRC cell lines.ResultsRFC4 expression was significantly increased in CRC specimens as compared to adjacent normal colonic tissues (P <0.05). High levels of RFC4, determined on a tissue microarray, were significantly associated with differentiation, an advanced stage by the Tumor-Node-Metastasis (TNM) staging system, and a poor prognosis, as compared to low levels of expression (P <0.05). However, in multivariate analysis, RFC4 was not an independent predictor of poor survival for CRC. In vitro studies, the loss of RFC4 suppressed CRC cell proliferation and induced S-phase cell cycle arrest.ConclusionRFC4 is frequently overexpressed in CRC, and is associated with tumor progression and worse survival outcome. This might be attributed to the regulation of CRC cell proliferation and cell cycle arrest by RFC4.

Upregulation of a disintegrin and metalloprotease 8 is associated with progression and prognosis of patients with gastric cancer.

A disintegrin and metalloprotease 8 (ADAM8) is involved in the tumorigenesis of several types of solid tumors. However, its exact role in gastric cancer (GC) remains unclear. The aim of this study was to evaluate the clinical significance of ADAM8 in GC and to explore its biological effects on gastric carcinogenesis. In this study, quantitative reverse transcription-polymerase chain reaction, Western blotting, and immunohistochemical staining analysis revealed that ADAM8 messenger RNA expression was significantly upregulated in GC tissues compared with noncancerous tissues (P = 0.004), and that positive ADAM8 expression is much more common in tumor tissues compared with normal tissues (P < 0.001) and is correlated with T stage (P = 0.036), N stage (P = 0.048), vessel invasion (P = 0.002), and a shorter patient overall survival (P = 0.024). In vitro assay indicated that ADAM8 overexpression promoted cell growth and increased migration and invasion abilities by decreasing the p-p38/p-extracellular regulated protein kinases (p-ERK) ratio. In conclusion, ADAM8 promotes GC cell proliferation and invasion, and its expression is positively correlated with poor survival, indicating that it might be a promising target in GC therapy.

Tumor Volume Reduction Rate Predicts Pathologic Tumor Response of Locally Advanced Rectal Cancer Treated with Neoadjuvant Chemotherapy alone: Results from a Prospective Trial.

Purpose: To evaluate tumor volume reduction rate (TVRR) measured by three-dimensional region-of-interest (3D-ROI) magnetic resonance (MR) volumetry in predicting pathological tumor response of preoperative chemotherapy alone for locally advanced rectal cancer (LARC). Methods: LARC patients who received neoadjuvant chemotherapy only from a prospective and randomized trial were recruited. Tumor volumes were measured with 3D-ROI MR volumetry. TVRR was determined using the equation TVRR = (VPre-Therapy - VPost-Therapy) / VPre-Therapy ×100%. Correlation between TVRR and clinical or pathological characteristics and predictive value of TVRR for pathological tumor response in terms of Tumor Regression Grade (TRG), T downstage, N downstage and overall downstage were analyzed. Results: 80 eligible cases of LARC were included in our study with TVRR of (51.7±25.1) %. TVRR was higher in well-differentiated tumors compared with poor-differentiated tumors (P=0.040). TVRR was found to be related with TRG (P<0.001), T downstage (P<0.001) and overall downstage (P<0.001). Risk of achieving TRG 2/3 decreased to 57.5% (P=0.002) and odds of achieving overall downstage increase to 179.3% (P<0.001) when TVRR increased by every 10%. A sensitivity of 0.704 and specificity of 0.804 were calculated when ROC curve was constructed to predict TRG using TVRR with a cutoff of 65%. Conclusion: TVRR is correlated with TRG and overall downstage significantly in LARC patients treated with preoperative chemotherapy alone and shows great value in predicting favorable TRG and overall downstage with good sensitivity and specificity. It could be considered as a promising parameter candidate for efficacy evaluation.