Haiming Sun

Colorectal cancer progression correlates with upregulation of S100A11 expression in tumor tissues

Background and aimsEarly detection and treatment of human colorectal cancers remain a challenge. Identification of new potential markers may help in the diagnosis of colorectal cancer.Materials and methodsBy comparative two-dimensional gel electrophoresis using extracts from colorectal tumor and adjacent normal tissues, we identified a calcium-binding protein, S100A11, which was highly expressed in colorectal cancer compared with adjacent normal tissues. We expanded our study in 89 clinical colorectal tumor samples to validate this finding and correlates S100A11 expression in human colorectal cancer tissues with various stages of the tumor by Western blotting and immunohistochemical staining.ResultsWe identified a calcium-binding protein, S100A11, which was highly expressed in colorectal cancer compared with adjacent normal tissues. S100A protein was expressed predominantly in the cytoplasm of normal tissue; however, it was expressed in both the nuclei and cytoplasm of colorectal cancer. S100A11 level in colorectal cancer tissue was increased following stage progression of the disease.ConclusionThese findings suggest S100A11 could be helpful in the pathological study of colorectal cancer, especially for the classification of different stages in colorectal cancer.

XRCC3 Thr241Met polymorphism with lung cancer and bladder cancer: A meta‐analysis

Several studies have investigated the associations between X‐ray repair cross‐complementing group 3 (XRCC3) Thr241Met polymorphism and the susceptibility to lung cancer and bladder cancer, but results have been inconclusive. In order to derive a more precise estimation of the relationship, a meta‐analysis was performed. A total of 22 case control studies, including 2976 cases and 4495 controls for lung cancer, and 3445 cases and 4599 controls for bladder cancer, met the inclusion criteria and were selected. Overall, there was no evidence showing a significant association between XRCC3 Thr241Met polymorphism and lung cancer risk. Furthermore, the results for bladder cancer showed that significant decreased risk was found for the additive model (odds ratio [OR] = 0.959, 95% confidence interval [CI], 0.924–0.996) and dominant model (OR = 0.982, 95% CI, 0.963–1.000) but not for the recessive model (OR = 0.958, 95% CI, 0.905–1.014). In summary, our meta‐analysis indicates that XRCC3 Thr241Met polymorphism may be weakly associated with the risk of bladder cancer. (Cancer Sci 2010)

Genetic variants of TCF7L2 are associated with type 2 diabetes in a northeastern Chinese population

Variants in the gene encoding transcription factor 7-like 2 (TCF7L2) are associated with type 2 diabetes mellitus (T2D) in several ethnic groups. Two intronic variants, rs290487 and rs11196218, were originally identified as T2D modifiers in Hong Kong Chinese and Taiwan Chinese populations, respectively. However, discrepancies were noted in subsequent replicated studies. In this study, an association of these two loci with T2D was investigated in a Harbin Chinese population. Whereas the two populations in the initial studies were southern Han Chinese, Harbin Chinese are from northeastern China. The SNPs rs290487 and rs11196218 were genotyped by ligase detection reactions in 700 T2D patients and 570 unrelated non-diabetic controls. Association analyses, which were carried out using the case-control sample set, yielded a significant association between rs290487 and T2D, with a trend opposite to that described in a previous report. Specifically, rs290487T was found to be significantly associated with disease susceptibility (p=0.039), and the allelic OR of rs290487T carriers was 1.184 (95% CI 1.008-1.391). There was no significant association between rs11196218 and T2D. Taken together, TCF7L2 may be an important susceptibility gene for T2D in some Chinese populations. The discrepancies in the allelic associations determined for northern vs. southern Chinese allude to the presence of genetic variation among the Han Chinese.

The -22018A allele matches the lactase persistence phenotype in northern Chinese populations.

Abstract Objective. It has been reported that some single-nucleotide polymorphisms (-13910C/T, -22018G/A, -13907C/G, -13915T/G, and -14010G/C) within the lactase gene are associated with lactase persistence. In our previous study, we found that -13910C/T is not a good predictor of lactase persistence in Chinese populations. To obtain a better understanding of the mechanism of lactase persistence, we examined the frequencies in Northern China of the four other alleles that are associated with lactase persistence. Material and methods. We evaluated the allele frequencies of -22018G/A, -13907C/G, -13915T/G, and -14010G/C in six northern Chinese populations (Manchu, Mongol, Hezhen, Oroqen, Kazak, and northern Han) using the methods of polymerase chain reaction–restriction fragment length polymorphism and resequencing. Results. By genotyping 1092 chromosomes, we found that the frequency of the -22018A allele was highest in the Kazak population and extremely low in the northern Han population. Although there are little available data about the frequency of lactase persistence in northern Chinese populations, we compared the allele frequencies with the phenotype frequencies that have been published previously. We found that the frequency of the -22018A allele was basically consistent with the reported frequencies of lactase persistence in Northern China. With respect to the -13907C/G, -13915T/G, and -14010G/C polymorphisms, we found no individuals with the derived allele. Conclusions. The frequency of the -22018A allele differed significantly among the six populations and the frequency reflected the frequency of lactase persistence. Taking into consideration the results of previous studies, we believe that the origins of lactase persistence-associated alleles are different in different pastoral populations.

Differential expression of PAI-RBP1, C1orf142, and COTL1 in non-small cell lung cancer cell lines with different tumor metastatic potential.

Human non–small cell lung cancer (NSCLC) is one of the most common malignancies in the modern world. Its recurrence is mainly due to its ability to invade and metastasize. However, the precise mechanism for tumor development and metastasis is still not fully understood. To shed light on the development of lung cancer, the human giant cell lung carcinoma cell lines 95D with high metastatic potential and 95C with low metastatic potential were selected in this study. The 2 cell lines originated from the same parental cell and share a similar genetic background. In the current study, we identified 3 differentially expressed proteins in 95C and 95D cell lines, namely, PAI-RBP1, C1orf142, and COTL1, by using 2-dimensional electrophoresis proteomics analysis. We found that PAI-RBP1 and C1orf142 expression levels were higher in 95D than in 95C cells, whereas COTL1 expression level was lower in 95D when compared to 95C cells. We also confirmed these results by reverse transcription–polymerase chain reaction and immunoblotting analyses. The messenger RNA and protein levels of PAI-RBP1 and C1orf142 were much higher in 95D than in 95C cells, and COTL1 expression level was lower in 95D than in 95C cells. The PAI-RBP1 expression was assessed by immunohistochemistry in 70 NSCLC and 7 normal lung tissue samples from patients. PAI-RBP1 expression level was higher in tumor tissues (positive staining in 87.1% of cases [61/70]) than in normal tissues (positive staining in 14.3% of cases [1/7]). In conclusion, by studying protein expression in NSCLC cell lines with high and low metastasis as well as in human lung cancer tissues, we have identified 3 proteins, namely, PAI-RBP1, C1orf142, and COTL1, which were differentially expressed in NSCLC cell lines with different metastatic potential. In addition, we also found that PAI-RBP1 might contribute to NSCLC development.

The polymorphisms of the TNF-α gene in multiple sclerosis?—a meta-analysis

The association between multiple sclerosis (MS) and tumor necrosis factor-alpha gene (TNF-α) polymorphisms has been analyzed in several studies, but conflicting results have been reported. The main purpose of this study was to integrate previous findings and explore whether the three single nucleotide polymorphisms (SNPs; -238G/A, -308G/A, and -376G/A) of TNF-α are associated with susceptibility to MS. A total of 2,639 patients and 3,303 controls from 21 studies, which were identified by searching the ISI Web of Knowledge database and the PubMed database up to December 2009, were collected for this meta-analysis. The association between MS and TNF-α -238G/A, -308G/A, and -376G/A was previously analyzed in 4, 18, and 4 studies, respectively. Overall, no associations were identified for the TNF-α -238G/A polymorphism and MS in any of genetic model. Similarly, no associations were found for the TNF-α -308G/A polymorphism and MS or between the TNF-α -376G/A polymorphism and MS. Furthermore, no significant association between the three SNPs and MS was identified using subgroup analyses examining ethnicity and clinical manifestation. The results of the present study indicated that TNF-α -238G/A, -308G/A, or -376G/A may not be the main risk factor for MS, which should be interpret with caution for the limited study numbers.

Association of single nucleotide polymorphisms in TCF2 with type 2 diabetes susceptibility in a Han Chinese population.

Hepatocyte nuclear factor 1β (HNF1β), a transcription factor encoded by the transcription factor 2 gene (TCF2), plays a critical role in pancreatic cell formation and glucose homeostasis. It has been suggested that single nucleotide polymorphisms (SNPs) of TCF2 are associated with susceptibility to type 2 diabetes (T2D). However, published results are inconsistent and inclusive. To further investigate the role of these common variants, we examined the association of TCF2 polymorphisms with the risk of T2D in a Han population in northeastern China. We genotyped five SNPs in 624 T2D patients and 630 healthy controls by using a SNaPshot method, and evaluated the T2D risk conferred by individual SNPs and haplotypes. In the single-locus analysis, we found that rs752010, rs4430796 and rs7501939 showed allelic differences between T2D patients and healthy controls, with an OR of 1.26 (95% CI 1.08–1.51, P = 0.003), an OR of 1.23 (95% CI 1.06–1.55, P = 0.001) and an OR of 1.28 (95% CI 1.10–1.61, P = 0.001), respectively. Genotype association analysis of each locus also revealed that the homozygous carriers of the at-risk allele had a significant increased T2D risk compared to homozygous carriers of the other allele (OR 1.78, 95% CI 1.20–2.64 for rs752010; OR 1.82, 95% CI 1.24–2.67 for rs4430796; OR 1.95, 95% CI 1.31–2.90 for rs7501939), even after Bonferroni correction for multiple comparisons. Besides, the haplotype-based analysis demonstrated that AGT in block rs752010-rs4430796-rs7501939 was associated with about 30% increase in T2D risk (OR 1.31, 95% CI 1.09–1.57, P = 0.01). Our findings suggested that TCF2 variants may be involved in T2D risk in a Han population of northeastern China. Larger studies with ethnically diverse populations are warranted to confirm the results reported in this investigation.

Y Chromosomal STR Polymorphism in Northern Chinese Populations

Y chromosomal STRs show sufficient variability among individduals in a population and a high degree of geographical differentiation, such that their polymorphic character makes them especially suited for population genetic studies. To investígate the polymorphism of a set of 17 Y-STR loci in northern China, we genotyped the 17 Y chromosomal STR loci in a population sample of 377 unrelated males from eight ethnic populations in northern China. We calculated the haplotype frequencies, Rst value and carried out the analysis of molecular variance (AMOVA). We then drew the multidimensional scaling analysis (MDS) plot and phylogenetic tree based on the Rst value. All populations showed a high level of haplotype diversity, with low inter-population variance as measured by an analysis of molecular variance. However, the genetic distances were significant when the eight populations were compared to other populations. By MDS and the phylogenetic tree, we found that the eight populations had a close relationship and Xibo had a northeast origination.

Combinational analysis of linkage and exome sequencing identifies the causative mutation in a Chinese family with congenital cataract

BackgroundCongenital cataract is a Mendelian disorder that frequently causes blindness in infants. To date, various cataract-associated loci have been mapped; more than 30 genes have been identified by linkage analysis. However, the pathogenic loci in some affected families are still unknown, and new research strategies are needed. In this study, we used linkage-exome combinational analysis to further investigate the pedigree of a four-generation Chinese family with autosomal dominant coralliform cataract.MethodsWe combined whole exome sequencing and linkage analysis to identify the causative mutation. The exome capture and next-generation sequencing were used to sequence the protein-coding regions in the genome of the proband to identify rare mutations, which were further screened for candidate mutations in linkage regions. Candidate mutations were independently verified for co-segregation in the whole pedigree using Sanger sequencing.ResultsWe identified a C to A transversion at nucleotide position c.70 in exon 2 of CRYGD, a cataract-associated gene. This mutation resulted in a threonine substitution for proline at amino acid residue 24.ConclusionsWe identified a missense P24T mutation in CRYGD that was responsible for coralliform cataract in our studied family. Our findings suggest that the combination of exome sequencing and linkage analysis is a powerful tool for identifying Mendelian disease mutations that might be missed by the classic linkage analysis strategy.

Overexpression of RCC2 Enhances Cell Motility and Promotes Tumor Metastasis in Lung Adenocarcinoma by Inducing Epithelial–Mesenchymal Transition

Purpose: Investigate the role of regulator of chromosome condensation 2 (RCC2) on lung adenocarcinoma (LUAD) metastasis. Experimental Design: Clinical specimens were used to assess the impact of RCC2 on LUAD metastasis. Mouse models, cytobiology, and molecular biology assays were performed to elucidate the function and underlying mechanisms of RCC2 in LUAD. Results: RCC2 expression was frequently increased in LUADs (88/122, 72.13%). It was confirmed by analysis of a larger cohort of TCGA RNA-seq data containing 488 LUADs and 58 normal lung tissues (P < 0.001). Importantly, increased level of RCC2 was significantly associated with T status of tumor (P = 0.002), lymph node metastasis (P = 0.004), and advanced clinical stage (P = 0.001). Patients with LUAD with higher expression of RCC2 had shorter overall survival. Cox regression analysis demonstrated that RCC2 was an independent poorer prognostic factor for patients with LUAD. Moreover, forced expression of RCC2 promoted intrapulmonary metastasis in vivo and significantly enhanced LUAD cell migration, invasion, and proliferation in vitro. Further study found that RCC2 induced epithelial–mesenchymal transition (EMT) and also stimulated the expression of MMP-2 and MMP-9. In addition, RCC2 was able to activate JNK, while inhibition of JNK suppressed the effect of RCC2 on LUAD cell migration, invasion, EMT, and the expression of MMP-2 and MMP-9. Conclusions: RCC2 plays a pivotal role in LUAD metastasis by inducing EMT via activation of MAPK–JNK signaling. Clin Cancer Res; 23(18); 5598–610. ©2017 AACR.