Zhenlin Nie

Effects of genetic variations in the Adiponectin pathway genes on the risk of colorectal cancer in the Chinese population

BackgroundDecreased expression of adiponectin (ADIPOQ) is associated with an increased risk for developing colorectal cancer (CRC) in humans. This study was designed to determine whether polymorphisms present in the ADIPOQ and its type 1 receptor (ADIPOR1) could affect the risk of CRC.MethodsWe measured five polymorphisms in the ADIPOQ and two polymorphisms in ADIPOR1, and analyzed their associations with CRC risk in 420 CRC patients and 555 age- and gender-matched healthy individuals.ResultsMultivariate logistic regression analyses revealed that the CRC risks (adjusted odds ratio and 95% confidence interval) associated with the ADIPOR1 genotypes were 0.53 (95% CI, 0.35-0.81) for rs12733285C/T, 0.59 (95% CI, 0.45-0.78) for rs1342387A/G, and 0.59 (95% CI, 0.39-0.89) for rs1342387A/A, respectively. Furthermore, the risks were more significant in carriers of the allele A of rs1342387A/G (adjusted OR, 0.59; 95% CI, 0.46-0.77) than noncarriers (G/G). In a further subgroup analysis, we observed that rs266729G/C was associated with an increased risk for colon cancer (adjusted OR, 1.50; 95% CI, 1.05-2.14) but not for rectal cancer (adjusted OR, 0.88; 95% CI, 0.63-1.22), and that carriers of the G allele had an increased risk for developing colon cancer (adjusted OR, 1.45; 95% CI, 1.03-2.05).ConclusionsWe conclude that the rs12733285C/T genotype and the carriage of the A allele of rs1342387 (A/G or A/A) in ADIPOR1 are the protective factors for CRC, while that rs266729G/C and G allele of ADIPOQ are the risk factors for colon cancer after excluding rectal cancer cases.

Different Effects of Three Polymorphisms in MicroRNAs on Cancer Risk in Asian Population: Evidence from Published Literatures

MicroRNAs (miRNAs) are a class of small non-protein-coding RNAs, which have emerged as integrated and important post-transcriptional regulators of gene expression. It has been demonstrated that single nucleotide polymorphisms (SNPs) exist in protein-coding genes. Accumulated studies have evaluated the association of miRNA SNPs with cancer risk, especially in Asian population, which included a series of related studies. However, the results remain controversial for the different genetic backgrounds, living habits and environment exposed. To evaluate the relationship between SNPs in miRNAs and cancer risk, 21 studies focused on Asian population were enrolled for the pooled analysis for three polymorphisms rs2910164, rs11614913, rs3746444 in three miRNAs miR-146aG>C, miR-196a2C>T, miR-499A>G using odds ratios (ORs) with 95% confidence intervals (CIs). For rs2910164 polymorphism, C allele was observed association with decreased overall cancer risk. In addition, subgroup analysis revealed of rs2910164 C allele decreased hepatocellular carcinoma (HCC), cervical cancer and prostate cancer risk among Chinese population. For rs11614913 polymorphism, TT genotype was observed to be associated with decreased cancer risk, especially for cancer type of colorectal cancer (CRC), lung cancer and country of Korea, North India. Whereas, rs3746444 G allele was an increased cancer risk factor in Chinese population, especially for breast cancer. In conclusion, this meta-analysis indicated that rs2910164 C allele was associated with decreased cancer risk in Chinese population. However, the association varied from different cancer types. Furthermore, TT genotype of rs11614913 was associated with decreased cancer risk. While different cancer types and countries contributed to different effects. Whereas, rs3746444 G allele was a risk factor in Chinese population, and the association varied from different cancer types.

Inhibition of miR-21 Induces Biological and Behavioral Alterations in Diffuse Large B-Cell Lymphoma

MicroRNA-21 (miR-21) has been ascribed a key role in many cellular processes, e.g. tumorigenesis via inhibition of target gene expression. However, its role in diffuse large B-cell lymphoma (DLBCL) is still unclear, and there are no in-depth studies on the relationship between miR-21 and the cellular phenotype of DLBCL. In this study, we investigated the expression and role of miR-21 in the regulation of cell biological processes in DLBCL. Firstly, miR-21 expression was evaluated in three DLBCL cell lines by real-time quantitative reverse-transcription (qRT) polymerase chain reaction (PCR). Then, to determine the possible role of miR-21 in the biological and behavioral characteristics of DLBCL, we performed miR-21 knockdown by transfection with anti-miR-21. In addition, PDCD4 and PTEN were assessed by luciferase reporter assay, qRT-PCR, and Western blot. Our study revealed that miR-21 was significantly upregulated in activated B-cell-like DLBCL cells compared to germinal center-like DLBCL cells. We demonstrated that inhibition of miR-21 induced suppression of proliferation and invasion, as well as increased apoptosis in DLBCL. Moreover, knockdown of miR-21 increased PDCD4 and PTEN expression at the protein level but not at the mRNA level. In conclusion, miR-21 can regulate proliferation, invasion, and apoptosis, and thus it has a potential therapeutic application in DLBCL.

Prognostic significance of long noncoding RNA Z38 as a candidate biomarker in breast cancer

Long noncoding RNA (lncRNA) Z38 has been shown to promote cell proliferation and tumorigenesis in breast cancer. However, expression pattern and prognostic value of lncRNA Z38 in breast cancer patients remain elusive.

ERK1/2 signalling pathway is involved in CD147-mediated gastric cancer cell line SGC7901 proliferation and invasion

This study aimed to investigate the role of CD147 in the progression of gastric cancer and the signalling pathway involved in CD147-mediated gastric cancer cell line SGC7901 proliferation and invasion. Short hairpin RNA (shRNA) expression vectors targeting CD147 were constructed to silence CD147, and the expression of CD147 was monitored by quantitative realtime reverse transcriptase polymerase chain reaction and Western blot and further confirmed by immunohistochemistry in vivo. Cell proliferation was determined by Cell Counting Kit-8 assay, the activities of matrix metalloproteinase (MMP)-2 and MMP-9 were determined by gelatin zymography, and the invasion of SGC7901 was determined by invasion assay. The phosphorylation and non-phosphorylation of the mitogen-activated protein kinases, extracellular signal-regulated kinase1/2 (ERK1/2), P38 and c-Jun NH2-terminal kinase were examined by Western blot. Additionally, the ERK1/2 inhibitor U0126 were used to confirm the signalling pathway involved in CD147-mediated SGC7901 progression. The BALB/c nude mice were used to study tumour progression in vivo. The results revealed that CD147 silencing inhibited the proliferation and invasion of SGC7901 cells, and down-regulated the activities of MMP-2 and MMP-9 and the phosphorylation of the ERK1/2 in SGC7901 cells. ERK1/2 inhibitor U0126 decreased the proliferation, and invasion of SGC7901 cells, and down-regulated the MMP-2 and MMP-9 activities. In a nude mouse model of subcutaneous xenografts, the tumour volume was significantly smaller in the SGC7901/shRNA group compared to the SGC7901 and SGC7901/snc-RNA group. Immunohistochemistry analysis showed that CD147 and p-ERK1/2 protein expressions were down-regulated in the SGC7901/shRNA2 group compared to the SGC7901 and SGC7901/snc-RNA group. These results suggest that ERK1/2 pathway involves in CD147-mediated gastric cancer growth and invasion. These findings further highlight the importance of CD147 in cancer progression, indicating that CD147 would be an attractive therapeutic target for gastric cancer.

Gene therapy for colorectal cancer by an oncolytic adenovirus that targets loss of the insulin-like growth factor 2 imprinting system

BackgroundColorectal cancer is one of the most common malignant tumors worldwide. Loss of imprinting (LOI) of the insulin-like growth factor 2 (IGF2) gene is an epigenetic abnormality observed in human colorectal neoplasms. Our aim was to investigate the feasibility of using the IGF2 imprinting system for targeted gene therapy of colorectal cancer.ResultsWe constructed a novel oncolytic adenovirus, Ad315-E1A, and a replication-deficient recombinant adenovirus, Ad315-EGFP, driven by the IGF2 imprinting system by inserting the H19 promoter, CCCTC binding factor, enhancer, human adenovirus early region 1A (E1A) and enhanced green fluorescent protein (EGFP) reporter gene into a pDC-315 shuttle plasmid. Cell lines with IGF2 LOI (HCT-8 and HT-29), which were infected with Ad315-EGFP, produced EGFP. However, no EGFP was produced in cell lines with maintenance of imprinting (HCT116 and GES-1). We found that Ad315-E1A significantly decreased cell viability and induced apoptosis only in LOI cell lines in vitro. In addition, mice bearing HCT-8-xenografted tumors, which received intratumoral administration of the oncolytic adenovirus, showed significantly reduced tumor growth and enhanced survival.ConclusionsOur recombinant oncolytic virus targeting the IGF2 LOI system inhibits LOI cell growth in vitro and in vivo, and provides a novel approach for targeted gene therapy.

Increased risk for gastric cancer in carriers of the lymphotoxin-α+252G variant infected by Helicobacter pylori.

The objective of this study is to determine whether polymorphisms in the lymphotoxin-α (LTA) and interleukin-10 (IL-10) genes were associated with gastric cancer (GC) in a Chinese population. One hundred ninety-six patients with GC and 248 healthy individuals were enrolled in this case-control study. The LTA 252G was associated with an increased risk of GC, with an adjusted odds ratio (OR) of 1.74 (95% confidence interval [CI]: 1.12-2.69) for the LTA 252G heterozygotes and 2.42 (95% CI: 1.28-4.58) for the LTA 252G homozygotes as compared with noncarriers. In contrast, such association is not found in polymorphisms in IL-10; however, a potential interaction between LTA +252 G allele and IL-10-1082 G/A was found to be associated with the occurrence of GC (adjusted OR: 1.91; 95% CI: 1.01-3.64). This study indicates that the LTA +252G allele is associated with increased risk for the presence of GC in a Helicobacter pylori infection positive subgroup and potential interaction between IL-10 and LTA may contribute to the risk of GC.

Gene therapy for cancer through adenovirus vector‑mediated expression of the Ad5 early region gene 1A based on loss of IGF2 imprinting.

Loss of (genomic) imprinting (LOI) of the insulin-like growth factor 2 gene (IGF2) is a common epigenetic abnormality in many human cancers. IGF2 imprinting is regulated by differentially methylated domains (DMD) in the imprinting control region that is located between IGF2 and H19 on human chromosome 11. In the present study, combined expression of adenoviral vectors (Ad-EGFP and Ad-E1A) driven by H19 enhancer-DMD-H19 promoter complex was investigated and their effects on the tumor growth were assessed in vitro and in vivo. When infected with Ad-EGFP, the cancer cell lines with the LOI, such as HRT-18 and HT-29 cells, had the expression of the EGFP protein, whereas three cancer cell lines with the maintenance of imprinting (MOI) (HCT-116, MCF-7 and GES-1) had weak expression of EGFP. Furthermore, the expressed Ad-E1A significantly decreased cell viability and induced cell apoptosis only in HRT-18 and HT-29 cells in vitro, and effectively suppressed tumor development in HRT-18 and HT-29 xenograft in nude mice. It is concluded that this gene therapy vector is effective in the suppression of the growth of human colon cancer cells in vitro and in vivo, and that cancer gene therapy based on loss of IGF2 imprinting may prove to be a novel therapeutic option.

Differential effects of insulin-like growth factor-1 CA repeat polymorphism on breast cancer risk along with race: a meta-analysis.

BACKGROUND Insulin-like growth factor (IGF)-I has been implicated in processes leading to breast cancer initiation and progression. A CA repeat polymorphism in the promoter region of IGF-I may suppress transcriptional activity and be associated with risk of breast cancer. A variety of case-control studies have been published evaluating the association between IGF1 CA repeat polymorphism and breast cancer. However, those published studies yielded contradictory conclusions. RESULTS This meta-analysis enrolled eleven studies to estimate the overall breast cancer risk of IGF1 CA repeat polymorphism. There was no significantly breast cancer risk found for pooled ORs among all the models. In the sub-stratified analysis by ethnicity, significantly decreased risks were found among Caucasian (19/19 versus non19/non19: OR=0.81, 95% CI: 0.70-0.94, P=0.922; 19/non19 versus non19/non19: OR=0.86, 95% CI: 0.74-0.99, P=0.005; dominant model: OR=0.84, 95% CI: 0.73-0.96, P=0.871). However, no significantly breast cancer risk was found among Asian and other ethnicities for all the genetic models. Furthermore, in the menopausal status stratified analysis, a significant decreased risk for postmenopausal woman was observed in the comparison of genotype 19/19 versus 19/non19+non19/non19: OR=0.89, 95% CI: 0.81-0.99, P=0.603. In addition, in the stratified analysis by case size, significantly decreased risk was observed in studies whose case size was more than 500 (19/19 versus 19/non19+non19/non19: OR=0.92, 95% CI: 0.86-1.00, P=0.457). CONCLUSIONS This study suggested that genotype 19/19 of IGF1 CA repeat polymorphism is a decreased risk for developing breast cancer in Caucasian but not in Asian, indicating that the association might be adjusted by race.

The association of Phosphatase and tensin homolog (PTEN) deletion and prostate cancer risk: A meta-analysis

OBJECTIVE Phosphatase and tensin homolog (PTEN) deleted on chromosome 10, a tumor suppressor that negatively regulates the phosphoinositide-3-kinase(PI3K) which has been implicated in a number of human malignancies including prostate cancer. However the prognostic value of PTEN deletion in prostate cancer patients diagnosis and the mechanism of PTEN deletion in prostate cancer development still remain unclear. METHOD A meta-analysis of 26 published studies including 8097 prostate cancer patients was performed. RESULTS Compared to PTEN normal patients, PTEN deletion patients showed a higher aggressive Gleason score(OR: 1.284, 95%CI=1.145-1.439) and pathological stage(OR: 1.628, 95%CI=1.270-2.087) which generally had a higher risk in prostate replace(HR: 1.738, 95%CI=1.264-2.390). Significant association between PTEN deletion and ERG rearrangements in prostate cancer development was also proved that compared to PTEN normal patients, patients with PTEN deletion showed a higher risk in ERG rearrangements(OR: 1.345, 95%CI=1.102-1.788). CONCLUSION This study indicated that patients with PTEN deletion were associated with higher pathological stage or Gleason score and a higher risk in prostate cancer replace potentially represent a novel clinically relevant event to identify individuals at increased risk for the occurrence, progression and prognosis of prostate cancer. Prostate cancer patients with PTEN deletion usually had a higher risk in ERG rearrangements than other patients may be a potential new area for identifying poor prognosis patients and selecting patients for targeted therapies which required confirmation through adequately designed prospective studies.