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Haplogroups and single-nucleotide polymorphisms (SNP) of mitochondrial DNA (mtDNA) were associated with the prognosis of many types of cancer patients. However, whether mtDNA haplogroups contribute to clinical outcomes of colorectal cancer (CRC) in Chinese population remains to be determined. In this study, mtDNA of tissue samples from 445 CRC patients from Northwestern China was sequenced to evaluate the association between haplogroup and prognosis. The mtDNA sequencing data of 1015 CRC patients from Southern China were collected for validation. We found patients with mtDNA haplogroup M7 had a significantly higher death risk when compared with patients with other haplogroups in both Northwestern (Hazard ratio [HR] = 3.093, 95% CI = 1.768-5.411, p 0.001) and Southern (HR = 1.607, 95% CI = 1.050-2.459, p = 0.029) China. Then, a haplogroup M7-based mtSNP classifier was selected by using LASSO Cox regression analysis. A nomogram comprising the mtSNP classifier and clinicopathological variables was developed to predict the prognosis of CRC patients (area under the curve [AUC] 0.735, 95% CI = 0.679-0.791). Furthermore, patients with high- and low-risk scores calculated by the haplogroup M7-based mtSNP classifier exhibited significantly different overall survival (OS) and recurrence-free survival (RFS) (all p 0.001). Finally, RNA-seq and immunohistochemical analyses indicated the poor prognosis of patients with haplogroup M7 may be related to mitochondrial dysfunction and immune abnormalities in CRC tissues. In conclusion, the haplogroup M7 and haplogroup M7-based mtSNP classifier seems to be a practical and reliable prognostic predictor for CRC patients, which provides a potential tool of clinical decision-making for patients with haplogroup M7 in Chinese population.

Background Mitochondria are key regulators in cell proliferation and apoptosis. Alterations in mitochondrial function are closely associated with inflammation and tumorigenesis. This study aimed to investigate whether mitochondrial transcription factor A (TFAM), a key regulator of mitochondrial DNA transcription and replication, is involved in the initiation and progression of colitis‐associated cancer (CAC). Methods TFAM expression was examined in tissue samples of inflammatory bowel diseases (IBD) and CAC by immunohistochemistry. Intestinal epithelial cell (IEC)‐specific TFAM‐knockout mice (TFAM △IEC) and colorectal cancer (CRC) cells with TFAM knockdown or overexpression were used to evaluate the role of TFAM in colitis and the initiation and progression of CAC. The underlying mechanisms of TFAM were also explored by analyzing mitochondrial respiration function and biogenesis. Results The expression of TFAM was downregulated in active IBD and negatively associated with the disease activity. The downregulation of TFAM in IECs was induced by interleukin‐6 in a signal transducer and activator of transcription 3 (STAT3)/miR‐23b‐dependent manner. In addition, TFAM knockout impaired IEC turnover to promote dextran sulfate sodium (DSS)‐induced colitis in mice. Of note, TFAM knockout increased the susceptibility of mice to azoxymethane/DSS‐induced CAC and TFAM overexpression protected mice from intestinal inflammation and colitis‐associated tumorigenesis. By contrast, TFAM expression was upregulated in CAC tissues and contributed to cell growth. Furthermore, it was demonstrated that β‐catenin induced the upregulation of TFAM through c‐Myc in CRC cells. Mechanistically, TFAM promoted the proliferation of both IECs and CRC cells by increasing mitochondrial biogenesis and activity. Conclusions TFAM plays a dual role in the initiation and progression of CAC, providing a novel understanding of CAC pathogenesis., Our study uncover the opposite roles of TFAM in the initiation and progression of CAC, indicating that TFAM switches from tumor suppressor in the premalignant stages of tumorigenesis to oncogene at later stages of disease. Our data suggest that measuring TFAM status may serve as a clinically useful tool to identify patients at risk for colon dysplasia or cancer. In contrast, TFAM might also be a prognostic biomarker and pharmacological target for advanced CAC.

Hepatocellular carcinoma (HCC) is the leading cause of cancer-related death worldwide. Enhanced mitochondrial fragmentation (MF) is associated with poor prognosis in HCC patients. However, its molecular mechanism in HCC remains elusive. Although enhanced MF activates effector T cells and dendritic cells, it induces immunoescape by decreasing the number and cytotoxicity of natural killer cells in the HCC immune microenvironment. Therefore, the influence of MF on the activity of different immune cells is a great challenge. Enhanced MF contributes to maintaining stemness by promoting the asymmetric division of liver cancer stem cells (LCSCs), suggesting that MF may become a potential target for HCC recurrence, metastasis, and chemotherapy resistance. Moreover, mechanistic studies suggest that MF may promote tumour progression through autophagy, oxidative stress, and metabolic reprogramming. Human-induced hepatocyte organoids are a recently developed system that can be genetically manipulated to mimic cancer initiation and identify potential preventive treatments. We can use it to screen MF-related candidate inhibitors of HCC progression and further explore the role of MF in hepatocarcinogenesis. We herein describe the mechanisms by which MF contributes to HCC development, discuss potential therapeutic approaches, and highlight the possibility that MF modulation has a synergistic effect with immunotherapy.

As emerging tumor components, intratumoral bacteria have been found in many solid tumors. Several studies have demonstrated that different cancer subtypes have distinct microbial compositions, and mechanistic studies have shown that intratumoral bacteria may promote cancer initiation and progression through DNA damage, epigenetic modification, inflammatory responses, modulation of host immunity and activation of oncogenes or oncogenic pathways. Moreover, intratumoral bacteria have been shown to modulate tumor metastasis and chemotherapy response. A better understanding of the tumor microenvironment and its associated microbiota will facilitate the design of new metabolically engineered species, opening up a new era of intratumoral bacteria-based cancer therapy. However, many questions remain to be resolved, such as where intratumoral bacteria originate and whether there is a direct causal relationship between intratumoral bacteria and tumor susceptibility. In addition, suitable preclinical models and more advanced detection techniques are crucial for studying the biological functions of intratumoral bacteria. In this review, we summarize the complicated role of intratumoral bacteria in the regulation of cancer development and metastasis and discuss their carcinogenic mechanisms and potential therapeutic aspects.

Influence of folate metabolism has long been studied in cancer and copies evidences have suggested that the key genes involved were correlated with GC risk and prognosis. However, their genetically association and contribution for GC prognosis are still elusive. To evaluate the effect of folate metabolism related genes polymorphisms on the prognosis of gastric cancer (GC), the genotype of seven single nucleotide polymorphisms (SNPs) of three genes were selected and genotyped in a cohort of 664 GC patients, including genes of Methylenetetrahydrofolate reductase (MTHFR), Methionine synthase reductase (MTRR), and Methionine synthase (MTR). Kaplan-Meier Curve, long-rank tests and multivariate Cox proportional hazard model were used for prognosis analysis. The results demonstrated that TT or CT/TT genotypes of SNP rs1532268 in MTRR gene coding region are significantly associated with a poorer overall survival (OS) when compared with CC genotype (HR=2.340, 95% CI: 1.240-4.414, p=0.009; or HR=1.502, 95% CI: 1.083-2.085, p=0.015, respectively). Furthermore, comparing to that of the CC genotype, the detrimental effect of rs1532268 TT genotype was also evident in the special subgroups of GC patients, especially in patients with BMI

Growing evidence indicates that the dysregulation of mitochondrial calcium (Ca2+) plays a critical role in the growth of tumor cells, including colorectal cancer (CRC). However, the underling mechanism is not fully elucidated. In this study, the regulatory effects of mitochondrial Ca2+ on phosphodiesterase 2 (PDE2)/cAMP/PKA axis and the phosphorylation of mitochondrial transcription factor A (TFAM) as well as the growth of CRC cells were systematically investigated both in vitro and in vivo. Our findings demonstrated that MCU-induced mitochondrial Ca2+ uptake activated mitochondrial PDE2 in CRC cells. Moreover, overexpression MCU in CRC led to a 1.9-fold increase in Ca2+ uptake compared to control cells. However, knockdown of MCU resulted in 1.5-fould decrease in Ca2+ uptake in mitochondria compared to the controls. Activation of mitochondrial PDE2 significantly inhibited the activity of mitochondrial protein kinase A (PKA), which subsequently leads to decreased phosphorylation of TFAM. Our data further revealed that PKA regulates the phosphorylation of TFAM and promotes the degradation of phosphorylated TFAM. Thus, TFAM protein levels accumulated in mitochondria when the activity of PKA was inhibited. Overall, this study showed that the overexpression of MCU enhanced CRC growth through promoting the accumulation of TFAM proteins in mitochondria. Conversely, knockdown of MCU in CRC cells resulted in decreased CRC growth. Collectively, these data suggest that the mitochondrial Ca2+-activated PDE2/cAMP/PKA axis plays a key role in regulating TFAM stability and the growth of CRC cells.

BACKGROUND Although combination of cyclin-dependent kinase 4 and 6(CDK4/6) inhibitors with endocrine therapy for advanced breast cancer (ABC) prolongs PFS in patients, but also has associated toxic side effects. However, few previous studies have summarized the toxic and side effects of CDK4/6 inhibitors. Therefore, this study summarized the corresponding toxic and side effects of CDK/6 inhibitors, which is of great importance for doctors and patients to understand how to balance the high survival rate brought by drugs with the decreased quality of life and improve the management of BC. METHODS PubMed, Embase, The Cochrane Library, and VIP databases were systematically searched to collect randomized controlled trials (RCTs) of CDK4/6 inhibitors combined with endocrine therapy for advanced breast cancer from January 2010 to December 2019.Two investigators independently reviewed the literatures. Before using the RevMan 5.3 software for a meta-analysis, date were extracted and the risk of bias with the include studies were assessed. RESULTS A total of 64 RCTs involving 3685 patients were included. Compared with placebo combined with endocrine therapy, CDK4/6 inhibitors combined with endocrine therapy could improve the median progression free survival rate (hazard ratio 0.54, 95% confidence interval (CI):0.50-0.60, P

BACKGROUND: This study aimed to assess the safety and efficacy of laparoscopic distal gastrectomy (LDG) with intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) for advanced gastric cancer (AGC). METHODS: In this case-matched study, we retrospectively reviewed the database of 223 patients with AGC who underwent LDG in Tangdu Hospital from April 2016 to February 2019. Among all participants, 177 patients underwent LDG alone and 46 underwent LDG with HIPEC. We matched total of 138 (1:2) patients from the LDG + HIPEC group (n 46) and the LDG group (n 92) for gender, age, date of operation, and tumor-node-metastasis (TNM) stage of tumor. RESULTS: There was no significant difference in the Clavien-Dindo classification of complications between LDG alone and LDG + HIPEC patients. Further analysis showed the morbidity of gastroparesis to be significantly increased in LDG + HIPEC patients. At the same time, we found that the operation time, the time to 1st flatus, and hospital stay were longer in LDG + HIPEC patients and the incidence of abdominal recurrence 2 years after operation was significantly higher in the LDG group than the LDG + HIPEC group. CONCLUSIONS: The combination of LDG with intraoperative HIPEC is a safe and feasible method for AGC and HIPEC will limit the recovery of gastrointestinal functions. In addition, during the follow-up of our study, although there was no statistical difference between the two groups in abdominal recurrence at 2 years after surgery, a decreasing trend of abdominal recurrence in LDG + HIPEC patients could be seen in comparison to LDG patients.

Background: Gastric cancer (GC) is one of the most common malignancies and its incidence rates vary widely between men and women. Previous studies have suggested that Cx43 and SCAMP1 are key functional proteins in tumors. Herein, the association between GJA1 and SCAMP1 polymorphisms and GC susceptibility and prognosis was evaluated.Methods: A total of three SNPs among 681 GC patients and 756 controls were tested using the Agena Mass ARRAY RS1000 system including GJA1 rs2071165, SCAMP1 rs4530741, and rs6874309. The strength of the association with cancer risk was assessed by the odds ratios and 95% confidence intervals generated from the logistic regression model. Kaplan-Meier Curve, long-rank tests, and a multivariate Cox proportional hazard model were used for prognosis analysis. The expression of GJA1 was assessed by immunohistochemistry.Results: The GJA1 rs2071165 AA/AG genotype significantly increased the risk of GC in the female Chinese population (odds ratio [OR] =1.55, 95% confidence interval, 95%CI] = 1.03–2.32, p = 0.034). Furthermore, the risk effect of rs2071165 was more evident in the subgroups of female patients with GC, stratified by age, clinical stage, tumor size, and recurrence/metastasis. However, no obvious differences in Cx43 expression in GC tissues were observed between males and females. Furthermore, no significant association between rs4530741 and rs6874309 polymorphisms in SCAMP1 and GC risk or prognosis was observed. Conclusion: In conclusion, this study suggests that GJA1 rs2071165 polymorphisms are associated with increased GC risk in females for the first time, which showed a potential new clinical marker for assessing GC risk in females.

Recently, increasing literature has been reported on optimal therapies in patients with advanced hepatocellular carcinoma (HCC) and many therapeutic modalities have been proposed to improve the survival rate. However, the results are not consistent due to different research protocols, small sample sizes and different study endpoints and there is no standard treatment protocol has been defined. Therefore, it is very important to explore the optimal bonding mode and to evaluate the efficacy and safety of the optimal sequential therapy for those patients.We searched available databases through January 2020 for relevant studies. The main outcome measure was 1-year overall survival (OS) and overall response rate (ORR); the secondary outcome measure was a composite of toxic effects retrieved grade 3 or 4 adverse events (AEs) from all included studies. Statistical analyses were conducted using STATA version 15 and GeMTC package in the R statistical software.After a detailed review, 8 randomized controlled trials (RCTs) and 20 retrospective studies involving 3,675 advanced HCC patients were included for network meta-analysis. Indirect comparisons showed that hepatic arterial infusion chemotherapy (HAIC) plus radiofrequency ablation (RFA) was highest probability of obtaining the best OS rate of 1 year [surface under the cumulative ranking (SUCRA), 0.95] and ORR (SUCRA, 0.86) when compared with other potential optimal therapies and which had ranked the first in all treatment regimens, followed by HAIC (SUCRA, 0.75). Direct and indirect comparison of 1-year OS and ORR with all treatment regimens each other showed that for all treatment regimens, patients showed significant clinical benefit when compared with transcatheter arterial chemoembolization (TACE) or sorafenib alone. However, the incidence of treatment-related AEs of grade 3 or 4 occurred in patients who have received targeted drug sorafenib therapy (SUCRA, 0.51) compared with other interesting regimens.HAIC may be a valuable therapeutic strategy for advanced HCC patients to prevent recurrence and metastasis after RFA, as well as in improving patient prognosis and quality of life. Meanwhile, HAIC combined with RFA is a safe and effective treatment in patients with advanced HCC, and this combination therapy can significantly prolong 1-year survival rate when compared with other optimal sequential therapies.This study is registered with PROSPERO, number CRD42020176149.

It is now widely accepted that mitochondrial biogenesis is inhibited in most cancer cells. Interestingly, one of the possible exceptions is colorectal cancer (CRC), in which the content of mitochondria has been found to be higher than in normal colon mucosa. However, to date, the causes and effects of this phenomenon are still unclear. In the present study, we systematically investigated the functional role of mitochondrial single-strand DNA binding protein (mtSSB), a key molecule in the regulation of mitochondrial DNA (mtDNA) replication, in the mitochondrial biogenesis and CRC cell growth. Our results demonstrated that mtSSB was frequently upregulated in CRC tissues and that upregulated mtSSB was associated with poor prognosis in CRC patients. Furthermore, overexpression of mtSSB promoted CRC cell growth in vitro by regulating cell proliferation. The in vivo assay confirmed these results, indicating that the forced expression of mtSSB significantly increases the growth capacity of xenograft tumors. Mechanistically, the survival advantage conferred by mtSSB was primarily caused by increased mitochondrial biogenesis and subsequent ROS production, which induced telomerase reverse transcriptase (TERT) expression and telomere elongation via Akt/mTOR pathway in CRC cells. In addition, FOXP1, a member of the forkhead box family, was identified as a new transcription factor for mtSSB. Moreover, our results also demonstrate that proinflammatory IL-6/STAT3 signaling facilitates mtSSB expression and CRC cell proliferation via inducing FOXP1 expression. Collectively, our findings demonstrate that mtSSB induced by inflammation plays a critical role in the regulation of mitochondrial biogenesis, telomerase activation, and subsequent CRC proliferation, providing a strong evidence for mtSSB as drug target in CRC treatment.

CpG island methylator phenotype (CIMP), characterized by multiple genes are concurrently methylated, has been reported to be associated with the prognosis of colorectal cancer. However, current studies have not explored the relationship between CIMP status with hepatocellular carcinoma (HCC) clinicopathological features.To assess these associations, we performed a comprehensive search of PubMed, EMBASE, and the Web of Science to identify all eligible studies. Publication bias was tested using Begg's and Egger's test.Seven studies that involved 568 HCC patients (379 CIMP+ and 189 CIMP-) were eligible for inclusion in our study. CIMP+ in HCC was significantly associated with distant metastasis (OR = 4.28, 95% CI = 2.57-7.10, P 0.00001, heterogeneity = 0.888), TNM tumor stage IIII + IV (OR = 5.73, 95% CI = 3.70-8.88, P 0.0001, heterogeneity = 0.449), cirrhosis (OR = 2.54, 95% CI = 1.33,4.83, P = 0.005, heterogeneity = 0.121) and a higher level of AFP (300 ng/ml) than those with CIMP- (OR = 2.63, 95% CI = 1.79,3.89, P0.00001, heterogeneity = 0.432). Moreover, CIMP+ was associated with an unfavorable overall survival (OS) (HR = 3.02, 95% CI = 1.60-5.70, P 0.001, heterogeneity = 0.251) and a disease-free survival (DFS) (HR = 2.80, 95% CI = 1.79-4.37, P 0.001, heterogeneity = 0.603).CIMP is independently associated with significantly worse prognosis in HCC patients. Examination of CIMP status may be useful for identifying patients who are at higher risk for disease progression.

Nan Wang,1 Xianli He,1 Ru Zhou,2 Guozhan Jia,1 Qing Qiao1 1Department of General Surgery, Tangdu Hospital, Fourth Military Medical University, Xi’an, Shanxi, 710038, China; 2Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shanxi, 710032, China Purpose: Colorectal carcinoma (CRC) is among the most common causes of death. Recent studies have shown that both STAT3 and miR-572 contribute to CRC progression. STAT3 plays an important role in miRNA expression. Moreover, MOAP-1, which is a pro-apoptotic protein that induces cell death or apoptosis, has a direct correlation with miRNA. Therefore, the current study is designed to explore whether miR-572 and STAT3 are involved in a common pathway and the role of MOAP-1 in this process. Patients and methods: The expressions of STAT3, miR-572, and MOAP-1 in human CRC tissues and multiple cell lines were estimated by qRT-PCR or Western blot. MTT, transwell migration, and invasion assays were used to assess cell growth, migration, and invasion, respectively. Dual-luciferase reporter assay was applied to examine the association between miR-572 and MOAP-1. Results: Elevated STAT3 levels were accompanied by increased miR-572 and decreased MOAP-1 levels in primary CRC specimens and cell lines. STAT3 promoted CRC cell growth, migration, and invasion via the upregulated expression of miR-572. Subsequently, miR-572 inhibited MOAP-1 protein expression through an interaction with its 3'UTR. Conclusion: Our study proposes a novel STAT3-miR-572-MOAP-1 pathway involved in the process of CRC progression, which might be a potential target for the development of new preventive and therapeutic approaches against human colorectal cancer. Keywords: colorectal neoplasm, STAT3, MOAP-1, miR-572, tumor progression

Xenopus kinesin-like protein 2 (TPX2) is a microtubule-associated protein that plays an important role in spindle assembly and dynamics. However, the clinical and prognostic value of TPX2 in the digestive system cancers remains unclear. The objective of this review was to evaluate the association of TPX2 expression with disease-free survival (DFS), overall survival (OS), and clinicopathological features of digestive system cancers. The software Stata 12.0 was used to analyze the outcomes, including OS, disease-free survival (DFS), and clinicopathological characteristics. A total of 10 eligible studies with 906 patients were included. Elevated TPX2 expression was significantly associated with poor DFS (pooled hazard ratio [HR] =2.48, 95% confidence interval [CI]: 1.96–3.13) and OS (pooled HR =2.66, 95% CI: 2.04–3.48) of digestive system malignancies. Subgroup analyses showed that cancer type, sample size, study quality, and laboratory detection methods did not alter the significant prognostic value of TPX2. Additionally, TPX2 expression was found to be an independent predictive factor for DFS (HR =2.31, 95% CI: 1.78–3.01). TPX2 expression might be associated with TNM stage and pathological grade in digestive system cancer. In conclusion, TPX2 is an independent prognostic factor for survival of patients with digestive system cancer. Furthermore, its overexpression is associated with TNM stage and pathological grade in digestive system cancer.

// Qiuchen Li 1, * , Falin Qu 2, * , Renli Li 3 , Xianli He 2 , Yulong Zhai 2 , Weigang Chen 1 and Yong Zheng 1 1 Department of Gastroenterology, First Affiliated Hospital of the Medical College, Shihezi University, Shihezi, Xinjiang, 832008, China 2 Department of General Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi’an, Shaanxi, 710038, China 3 Department of General Surgery, The Fourth Hospital of Chinese PLA, Xining, Qinhai, 810007, China * These authors contributed equally to this work Correspondence to: Yong Zheng, email: zhengyongshz@163.com Weigang Chen, email: cwg_sh@126.com Keywords: single nucleotide polymorphism; gastric cancer; prognosis; single-strand DNA-binding protein 1; chemotherapy Received: July 27, 2017 Accepted: November 03, 2017 Published: December 02, 2017 ABSTRACT Growing evidence has indicated that single-stranded DNA-binding proteins 1 ( SSBP1 ) is involved in tumor initiation and progression. However, effects of single nucleotide polymorphisms (SNPs) in SSBP1 gene on gastric cancer (GC) prognosis are still unknown. In present study, two functional SNPs from SSBP1 were selected and genotyped in a large cohorts of 1030 resected GC patients (326 in the training set, 704 in the validation set) to explore the association of SNPs with patients’ survival. The rs6976500 G allele (CG/GG) genotypes were found significantly associated with both worse overall survival (OS) and recurrence-free survival (RFS) in the training and the independent validation set when compared to C allele genotype, which reaching a more robust statistical significance in the pooled analysis. Furthermore, integration of rs6976500 genotypes and TNM stage significantly improved the prognosis prediction models based on TNM stage alone. In addition, only carriers with at least one G allele of rs6976500 gained significant survival benefit from FOLFOX-based ACT. Mechanistically, SNP rs6976500 G allele genotype could significantly decrease promoter transcriptional activity and markedly reduce expression level of SSBP1 compared with the C allele genotype in GC cells. This was further substantiated by immunohistochemical assay in 70 GC tissue samples. Our study presents the first evidence that SNP rs6976500 G allele genotypes might contribute to GC prognosis by attenuating SSBP1 promoter activity and gene expression, and provides the guidance in refining therapeutic decisions of GC patients. Further exploration on its function is needed to clarify the exact biological mechanism behind.

// Nan Wang 1, * , Qing Qiao 1, * , Guoqiang Bao 1 , Tao Wu 1 , Yizhou Li 2 , Jingjie Li 3 , Jianguo Lu 1 , Xianli He 1 1 Department of General Surgery, Tangdu Hospital, Fourth Military Medical University, Xi’an, Shaanxi, 710038, China 2 Inner Mongolia Medical University, Hohhot, Inner Mongolia, 010050, China 3 Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, Xi’an, Shaanxi, 710069, China * These authors have contributed equally to this work Correspondence to: Jianguo Lu, email: lujianguoLJG123@163.com Xianli He, email: wanghe@fmmu.edu.cn Keywords: gastric cancer, colorectal cancer, single-nucleotide polymorphism, susceptibility, case-control Received: September 26, 2016 Accepted: January 10, 2017 Published: February 26, 2017 ABSTRACT Here, we genotyped eleven single-nucleotide polymorphisms (SNPs) and evaluated their association with the risk of developing gastric cancer (GC) or colorectal cancer (CRC) in 1,790 Han Chinese participants (588 GC patients, 499 CRC patients, and 703 healthy controls). Statistically analysis showed that the “C” allele of rs2689154 in MIPEPP2 was associated with a decreased risk of GC (odds ratio [OR] = 0.81, 95 % confidence interval [CI]: 0.66-0.99, P = 0.041), whereas the “T” allele of rs12615966 in LOC284998 was associated with a 1.29-fold increase in the risk of GC (OR = 1.29, 95% CI: 1.03-1.63, P = 0.029). Additionally, genetic model analyses showed that rs2689154 was associated with a reduced risk of GC under the recessive model (adjusted OR = 0.46, 95% CI: 0.22-0.98, P = 0.037), and rs12615966 in FOXF1 was associated with an increased risk of GC in both the dominant and log-additive models after adjusted for age and gender (adjusted OR = 1.36, 95% CI: 1.02-1.81, P = 0.033; adjusted OR = 1.36, 95% CI: 1.05-1.75, P = 0.018, respectively). We also observed that rs2178146 in FOXF1 was associated with an increased risk of CRC in the recessive model (adjusted OR = 1.90, 95% CI: 1.05-3.45, P = 0.034). Our results confirmed that rs2689154 in MIPEPP2 was significantly decreased GC risk, but rs12615966 in LOC284998 was significantly increased GC risk, and rs2178146 in FOXF1 was associated with increased CRC risk in the Han Chinese population.

Succinate dehydrogenase is a heterotetrameric complex comprising four nuclear-encoded subunits, catalyzes the oxidation of succinate to fumarate in the tricarboxylic acid cycle. A subset of cancers have been found to be associated with mutations in the four SDH genes. However, the functional roles of the SDH complex in tumorigenesis remain largely unclear, especially in hepatocellular carcinoma (HCC). Here, we investigated the expression levels of the four SDH subunits and their clinical significance in HCC, followed by systematic exploration of the effects of SDH dysfunction on HCC cell survival and metastasis both in vitro and in vivo, as well as the underlying molecular mechanisms. Our results showed that the expression of the SDHA/B/C/D subunits was significantly downregulated in HCC, associated with poor patient prognosis, and contributed to SDH inactivation. Additionally, attenuated SDH activity following SDHC knockdown promoted HCC-cell growth and metastasis both in vitro and in vivo via elevated reactive oxygen species levels and subsequent activation of nuclear factor-κB signaling. These findings suggest a critical tumor-suppressive role for SDH and provide strong evidence supporting this enzyme as a potential drug target in the treatment of HCC.

Compelling epidemiological evidences indicate a significant association between leukocyte mitochondrial DNA (mtDNA) content and incidence risk of several malignancies, including hepatocellular carcinoma (HCC). However, whether leukocyte mtDNA content affect prognosis of HCC patients and underlying mechanism has never been explored. In our study, leukocyte mtDNA content was measured in 618 HCC patients and its prognostic value was analyzed. Moreover, we detected the immunophenotypes of peripheral blood mononuclear cells (PBMCs) and plasma concentrations of several cytokines in 40 HCC patients and assessed the modulating effects of mtDNA content on immunosuppression in cell models. Our results showed that HCC patients with high leukocyte mtDNA content exhibited a significantly worse recurrence-free survival (RFS) and overall survival (OS) than those with low leukocyte mtDNA content. Leukocyte mtDNA content and TNM stage exhibited a notable joint effect in prognosis prediction. Furthermore, we found that patients with high leukocyte mtDNA content exhibited a higher frequency of CD4+CD25+FOXP3+ regulatory T (Treg) cells and lower frequency of NK cells in PBMCs and had higher TGF-β1 and lower TNF-α and IFN-γ plasma concentration when compared with those with low leukocyte mtDNA content, which suggests an immunosuppressive status. High leukocyte mtDNA content significantly enhanced the ROS-mediated secretion of TGF-β1, which accounted for higher Treg and lower NK frequency in PBMCs. In a conclusion, our study for the first time demonstrates that leukocyte mtDNA content is an independent prognostic marker complementing TNM stage and associated with an ROS-mediated immunosuppressive phenotype in HCC patients.

Gastric cancer (GC) is the second most common cancer in China and the second leading cause of cancer-related death in the world. Identifying circulating biomarkers is helpful to improve theranostics of gastric cancer. Herein, we are for the first time to report miR-16-5p and miR-19b-3p were identified to be the novel potential plasma biomarkers to detect gastric cancer. Differentially expressed miRNAs were initially screened out by genome-wide miRNA profiling microarrays between 16 plasma samples of gastric cancer and 18 matched normal controls, and then were quantified and validated by quantitative reverse transcription-PCR method between 155 gastric cancer cases and 111 normal controls. Additionally, 30 plasma samples from precancerous lesions and 18 paired samples from gastric cancer patients with gastrectomy were further detected. Results showed that based on two normalization methods, miR-16-5p and miR-19b-3p in plasma were found to be capable of distinguishing normal population from GC cases with different TNM stages and differentiation grades, particularly including the early cancer cases (P

The goal of this study is to evaluate the association between MMP-2, 3, TIMP-2, 3 polymorphisms and risk of colorectal cancer (CRC) in a Chinese Han population.Eight single nucleotide polymorphisms (SNP) were genotyped in 505 CRC patients and 510 controls. The association between candidate SNPs and risk of CRC were evaluated using odds ratio (OR), 95% confidence interval (95% CI).The minor allele frequency of rs1053605 in cases was significantly lower than controls (p = 0.005). The CT genotype frequency of rs1053605 in cases was significantly lower than those in controls, while the frequencies of rs4789936-CT and rs715572-AG genotype of in cases were significantly higher than those in controls (p 0.05). Genetic model analysis showed that rs522616 was associated with decreased risk of CRC under recessive model (p = 0.041); rs1053605 was correlated with decreased risk of CRC under dominant (p = 0.012) and additive (p = 0.009) models; rs4789936 also has association with decreased risk of CRC under recessive model (p = 0.021); while rs715572 was associated with increased risk of CRC under dominant (p = 0.007) and additive (p = 0.011) models.Our results shed new light on association between MMP and TIMP polymorphisms and CRC risk.

Compelling evidences indicate that relative telomere length (RTL) in peripheral blood leukocytes (PBLs) can predict the clinical outcome of several cancers. However, to date, the prognostic value of leukocyte RTL in gastric cancer (GC) patients has not been explored. In this study, relative telomere length (RTL) in peripheral blood leukocytes (PBLs) was measured using a real-time PCR-based method in a total of 693 GC patients receiving surgical resection. The prognostic value of leukocyte RTL was first explored in the training set (112 patients) using Kaplan–Meier and Cox proportional hazards regression analyses. Then an independent cohort of 581 patients was used as a validation set. To explore potential mechanism, we detected the immunophenotypes of peripheral blood mononuclear cells and plasma concentrations of several cytokines in GC patients. Patients with short RTL showed significantly worse overall survival (OS) and relapse-free survival (RFS) than those with long RTL in all patient sets. Furthermore, leukocyte RTL and TNM stage exhibited a notable joint effect in prognosis prediction. Integration of TNM stage and leukocyte RTL significantly improved the prognosis prediction efficacy for GC. In addition, we found that patients with short RTL had a higher CD4 + T cell percentage in PBMCs, CD19 + IL-10 + Breg percentage in B cells and plasma IL-10 concentration, indicating an enhanced immunosuppressive status with short leukocyte RTL. In conclusion, our study for the first time demonstrates that leukocyte RTL is an independent prognostic marker complementing TNM stage and associated with an immunosuppressive phenotype in the peripheral blood lymphocytes in GC patients.

Growth factor receptor bound protein 2 (Grb2) is a key adaptor performing a principal role in the oncogenic Ras signaling pathway. In the present study, we generated two fusion proteins. One contained an Src homology 2 (SH2) domain of Grb2, a signal peptide sequence, FLAG-tag sequence, PTD region and we named it FPTD-Grb2-SH2, while the other contained one mutant SH2 domain, added to a signal peptide sequence, FLAG-tag sequence, PTD region and we named it FPTD-Grb2-SH2M. Western blot analysis and immunofluorescence assay were used to investigate the expression and location of the fusion proteins in breast cancer cells. The proliferation and migration of the cells were estimated by MTT and Transwell cell migration assays, respectively. Flow cytometric analysis was performed to evaluate the apoptosis of the breast cancer cells. The recombinant proteins FPTD-Grb2-SH2 and FPTD-Grb2-SH2M were successfully expressed in the breast cancer cell lines regardless of HER2-phenotype, and they suppressed breast cancer cell growth and migration as expected from the lack of SH3 domain. Both FPTD-Grb2-SH2 and FPTD-Grb2-SH2M exhibited significant toxicity to breast cancer cells. The present study demonstrated that the recombinant proteins FPTD-Grb2-SH2 and FPTD-Grb2-SH2M may be used for anticancer drug development.

Background Numerous studies indicate that the leukocyte telomere length is associated with the risk of cancers, including colorectal cancer (CRC). However, the prognostic value of leukocyte telomere length in CRC patients has not been investigated. Patients and methods Relative telomere length (RTL) of peripheral blood leukocytes (PBLs) from 571 CRC patients receiving surgical resection was measured using a polymerase chain reaction-based method. The Cox proportional hazards ratio model and the Kaplan–Meier curve were used to estimate the association between RTL and the clinical outcome of CRC patients in the training set (90 patients) and the testing set (86 patients). Finally, an independent cohort of 395 patients was used as an external validation set. The immunophenotype of PBLs and the plasma concentration of several immune-related cytokines were determined by flow cytometry and enzyme-linked immunosorbent assay, respectively. Results Patients with shorter RTL had significantly poorer overall survival and relapse-free survival than those with longer RTL in the training, testing and validation sets. Furthermore, leukocyte RTL and Tumor-Node-Metastasis (TNM) stage exhibited a significant joint effect in the prognosis prediction of combined CRC patients, indicating that patients with both short RTL and advanced stages had the worst prognosis, when compared with other subgroups. In addition, patients with short RTL showed the higher percentage of CD4+ T cell and the lower percentage of B cell in peripheral blood mononuclear cells, as well as the lower concentration of plasma transforming growth factor-β1, suggesting a possibility that the immune functions changed with RTL alteration. Conclusions Our study for the first time demonstrates that leukocyte RTL is an independent prognostic marker complementing TNM stage and associated with the immune functions in CRC patients.

The growth factor receptor bound protein 2 (Grb2) is one of the affirmative targets for cancer therapy, especially for breast cancer. In this study, we hypothesized the Src-homology 2 (SH2) domain in Grb2 may serve as a competitive protein-binding agent to interfere with the proliferation of breast cancer cells in vitro. We designed, constructed, expressed and purified a novel fusion protein containing the protein transduction domain (PTD) and Grb2-SH2 domain (we named it after PTD-Grb2-SH2). An immunofluorescence assay was used to investigate the location of PTD-Grb2-SH2 in cells. MTT assay and EdU experiments were applied to detect the proliferation of breast cancer cells. The ultra-structure was observed using transmission electron microscopy. Flow cytometry was used to determine the cytotoxicity of PTD-Grb2-SH2 on cell proliferation. We successfully obtained the PTD-Grb2-SH2 fusion protein in soluble form using a prokaryotic expression system. The new fusion protein successfully passed through both the cellular and nuclear membranes of breast cancer cells. The MTT assay showed that PTD-Grb2-SH2 exhibited significant toxicity to breast cancer cells in a dose- and time-dependent manner in vitro. EdU identified the decreased proliferation rates in treated MDA-MB-231 and SK-BR-3 cells. Observation by transmission electron microscopy and flow cytometry further confirmed the cytotoxicity as apoptosis. Our results show that the HIV1-TAT domain is a useful tool for transporting a low molecular weight protein across the cell membrane in vitro. The PTD-Grb2-SH2 may be a novel agent for breast cancer therapy.

Background: Cumulative data have shown that microRNAs (miRNA) are involved in the etiology and prognosis of colorectal cancer (CRC). Genetic polymorphisms in pre-miRNA genes may influence the biogenesis and functions of their host miRNAs. However, whether these polymorphisms are associated with CRC prognosis remains unknown. Methods: We analyzed the effects of seven single-nucleotide polymorphisms (SNP) in pre-miRNA genes on the prognosis of a Chinese population with 408 CRC patients with surgically-resected adenocarcinoma. Results: Two SNPs were identified to be significantly associated with recurrence-free survival and overall survival of the patients. The most significant SNP was rs6505162 in pre-miR-423. Compared with the homozygous wild-type genotype, the variant-containing genotypes of this SNP were significantly associated with both the overall survival (HR = 2.12, 95% CI = 1.34–3.34, P = 0.001) and the recurrence-free survival (HR = 1.59, 95% CI = 1.08–2.36, P = 0.019). Another SNP, rs4919510 in pre-miR-608, was also associated with altered recurrence-free survival (HR = 0.61, 95% CI = 0.41–0.92, P = 0.017). These effects were evident only in patients receiving chemotherapy but not in those without chemotherapy. In addition, the combined analysis of the two SNPs conferred a 2.84-fold (95% CI = 1.50–5.37, P = 0.001) increased risk of recurrence and/or death. Similarly, this effect was only prominent in those receiving chemotherapy (P < 0.001) but not in those without chemotherapy (P = 0.999). Conclusions: Our data suggest that genetic polymorphisms in pre-miRNA genes may impact CRC prognosis especially in patients receiving chemotherapy, a finding that warrants further independent validation. Impact: This is one of the first studies showing a prognostic role of pre-miRNA gene SNPs in CRC. Cancer Epidemiol Biomarkers Prev; 21(1); 217–27. ©2011 AACR.

BACKGROUND: Previous studies have demonstrated that circadian genes play a role in the development and progression of many cancers. This study aims to assess the effects of single nucleotide polymorphisms (SNPs) in circadian genes on recurrence and survival of colorectal cancer (CRC) patients. METHODS: Nine functional SNPs in 3 genes (CLOCK, NPAS2, and BMAL1) on the circadian positive feedback loop were selected and genotyped using the Sequenom iPLEX genotyping system in a cohort of 411 resected Chinese CRC patients. Multivariate Cox proportional hazards model and Kaplan-Meier curve were used for the prognosis analysis. RESULTS: The authors identified 2 SNPs in the CLOCK gene to be significantly associated with CRC overall survival. SNP rs3749474 exhibited a significant association with survival of CRC patients in the additive model (hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.37-0.81; P = .003). In addition, patients carrying the heterozygous variant of rs1801260 had significantly increased overall survival compared with those carrying homozygous wild-type genotype (HR, 0.31; 95% CI, 0.11-0.88; P = .03). Findings from functional assay provided further biological support for these significant associations. Stratified analysis found no modifying effect of chemotherapy on the prognostic significance of both SNPs. Moreover, we observed cumulative effects of these 2 SNPs on CRC overall survival (P for trend = .01). Compared with patients carrying no unfavorable genotypes, those carrying 2 unfavorable genotypes had a 2.92-fold increased risk of death (P = .03). CONCLUSIONS: The results suggest for the first time that CLOCK gene polymorphisms may serve as an independent prognostic marker for CRC patients. Cancer 2012;. © 2011 American Cancer Society.

Background The expression of matrix metalloproteinase-21 (MMP-21) has been shown to be elevated in some solid tumor and thought to enhance tumor invasion and metastasis ability. In the present study, we investigated the expression of MMP-21 and its association with prognosis in stage II and III colorectal cancer. Methods MMP-21 expression was investigated in 286 cases of colorectal cancer by immunohistochemistry assay. Statistical analysis was utilized to evaluate the association of MMP-21 expression with clinicopathological characters and overall survival of patients with stage II and III colorectal cancer. Results MMP-21 expression was significantly higher in colorectal cancer, compared with that in normal epithelial tissue. And it also correlated with tumor invasion, lymph node metastasis, and distant metastasis of colorectal cancer. MMP-21 was also proved to be an independent prognostic factor in patients with stage II as well as stage III colorectal cancer. However, no correlations between MMP-21 expression and patients' age, sex, tumor location, or differentiation status were detected. Conclusion These results suggested the potential role of MMP-21 in the invasion and metastasis process of human colorectal cancer. It could also be a novel molecular marker to predict prognosis of patients with stage II and stage III colorectal cancer. J. Surg. Oncol. 2011; 104:787–791. © 2011 Wiley Periodicals, Inc.

BACKGROUND: Compelling epidemiological evidence indicated that alterations of mitochondrial DNA (mtDNA), including mutations and abnormal content of mtDNA, were implicated in the tumorigenesis of several malignancies in a tumor-specific manner, such as lung cancer, breast cancer, and non-Hodgkin lymphoma. This study was undertaken to investigate whether mtDNA content in peripheral blood lymphocytes (PBLs) could be used as a risk predictor for colorectal cancer (CRC). METHODS: The mtDNA content was measured by using quantitative real-time polymerase chain reaction in PBLs from 320 CRC patients and 320 matched controls. RESULTS: The authors found that CRC patients exhibited statistically significantly higher mtDNA content than matched controls (median, 1.03 vs .86; P < .001). They further assessed the association between mtDNA content and CRC risk using multivariate logistic regression. By using the median value in controls as the cutoff point, they found that, compared with low mtDNA content, high mtDNA content was associated with a significantly increased CRC risk (adjusted odds ratio, 2.03; 95% confidence interval, 1.41-2.81). In a trend analysis, they found a statistically significant dose-response relationship between higher mtDNA content and increased CRC risk (P for trend

4058Background: Laparoscopic distal gastrectomy for early gastric cancer is widely accepted with superiority to conventional open surgery. However, oncologic validation for advanced gastric cancer ...

Background Genetic alterations in tricarboxylic acid (TCA) cycle metabolic enzymes were recently linked to various cancers. However, the associations of single nucleotide polymorphisms (SNPs) in genes of these enzymes have not been well studied. Methods We genotyped 16 SNPs from 7 genes encoding TCA cycle metabolic enzymes in 697 colorectal carcinoma (CRC) patients receiving surgical resection and analyzed their associations with clinical outcomes by multivariate Cox proportional hazard model. Then, the significant results were validated in another cohort of 256 CRC patients. Results We identified 4 SNPs in 2 genes had significant associations with CRC death risk and 5 SNPs in 3 genes had significant associations with CRC recurrence risk. Similar significant results were confirmed for rs4131826 in SDHC gene, rs544184 in SDHD gene and rs12071124 in FH gene in a validation cohort. Further analysis indicated that unfavorable genotypes exhibited a significant cumulative effect on overall and recurrence-free survival in a dose-dependent manner. Moreover, survival tree analysis indicated that SNP rs4131826 in SDHC gene and SNP rs12071124 in FH gene were the primary factors contributing to the different overall survival time and recurrence-free survival time of CRC patients, respectively. Immunohistochemical analysis further validated the effect of rs4131826 and rs544184 on expression of SDHC and SDHD in tissue samples. Conclusions Our study suggests that SNPs in TCA cycle metabolic enzymes might be significantly associated with clinical outcomes in Chinese population diagnosed with CRC. Further functional and validated studies are warranted to expend our results to clinical utility. Electronic supplementary material The online version of this article (doi:10.1186/s12943-015-0442-x) contains supplementary material, which is available to authorized users.

Compelling evidence has indicated a significant association between leukocyte mitochondrial DNA (mtDNA) content and incidence risks of several malignancies in a cancer-specific manner. However, to date, whether leukocyte mtDNA content can predict clinical outcome of cancer patients has never been investigated. In the present study, we measured leukocyte mtDNA content using real-time PCR-based method in a total of 598 colorectal cancer (CRC) patients and explored its prognostic values. To explore potential mechanism, we detected the immunophenotypes of peripheral blood mononuclear cells and plasma concentrations of several cytokines in CRC patients. We found that patients with high mtDNA content showed significantly worse overall survival (OS) and relapse-free survival (RFS) than those with low mtDNA content in all patient sets. Furthermore, mtDNA content and tumor node metastasis (TNM) stage exhibited a notable joint effect in prognosis prediction. Integration of TNM stage and leukocyte mtDNA content significantly improved the prognosis prediction efficacy for CRC. Importantly, patients with high mtDNA content showed OS and RFS benefits from adjuvant chemotherapy. In addition, we found that patients with high mtDNA content had a higher frequency of CD4(+)CD25(+)FOXP3(+) regulatory T cells, higher plasma interleukin-2 and transforming growth factor-β1 and lower tumor necrosis factor-α concentration than those with low mtDNA content, suggesting a stronger immunosuppressive phenotype. In conclusion, our study for the first time demonstrates that leukocyte mtDNA content is an independent prognostic marker complementing TNM stage and associated with immunosuppression in CRC patients. Additionally, leukocyte mtDNA content might serve as a potential biomarker to select CRC patients who will benefit from adjuvant chemotherapy.

Integrin β1 (ITGB1) has been recognized to play a major role in tumor growth, invasion and metastasis. However, effects of single-nucleotide polymorphisms (SNPs) in ITGB1 gene on the prognosis of patients with colorectal cancer (CRC) have not been reported. A total of 372 patients with resected colorectal adenocarcinoma were enrolled in our study. Three functional SNPs (rs2230395, rs1187075 and rs1187076) in ITGB1 were selected and genotyped using the Sequenom iPLEX genotyping system. We identified two SNPs (rs2230395 and rs1187075) in ITGB1 gene to be significantly associated with CRC overall survival (OS). Compared with the homozygous wild-type (AA) and heterozygous variant (AC), rs2230395 homozygous variant (CC) conferred a 1.55-fold (95 % CI 1.00–2.41, P = 0.049) increased risk of death. Similar result was obtained for homozygous variant (AA) in rs1187075 with a 1.62-fold (95 % CI 1.08–2.42, P = 0.020). In stratified analysis, this association in rs2230395 remained to be significant in patients receiving chemotherapy, but not in those without chemotherapy. We further evaluated the effects of chemotherapy on CRC survival in subgroups stratified by rs2230395 and rs1187075 genotypes. We found that chemotherapy resulted in a significantly better OS in patients with the homozygous wild-type (WW) or heterozygous variant (WV) genotype in both rs2230395 and rs1187075 when compared with patients with homozygous variant (VV) genotype. Our data suggest that ITGB1 SNPs might be a prognostic biomarker for CRC patients, especially in those receiving chemotherapy. Our findings warrant validation in larger independent populations.

Background Previous studies have demonstrated that ATP citrate lyase (ACLY) plays an important role in the development of many cancers. Our current study aims to assess the effects of functional single nucleotide polymorphisms (SNPs) in ACLY gene on recurrence and survival of colorectal cancer (CRC) patients. Methods A total of 697 resected Chinese CRC patients were included in this study. Two functional single nucleotide polymorphisms in ACLY gene were examined using the Sequenom iPLEX genotyping system. Multivariate Cox proportional hazards model and Kaplan-Meier curve were used for the prognosis analysis. Results Multivariate Cox regression analysis showed that there was no significant association between SNPs in ACLY gene and the prognosis of total patient cohort. However, in patients with stage III + IV diseases, the two functional SNPs (rs2304497 and rs9912300) exhibited a significant association with the risks of death (HR = 0.47, 95% CI = 0.24–0.90 and HR = 0.59, 95% CI = 0.37–0.92, respectively) and recurrence (HR = 0.46, 95% CI = 0.24–0.86 and HR = 0.54, CI = 0.35–0.83, respectively). Kaplan-Meier analysis indicated that those CRC patients carrying heterozygous (WV) or homozygous variant (VV) genotypes in rs2304497 and rs9912300 had significantly better overall survival (OS) and recurrence-free survival (RFS). Moreover, we observed remarkable cumulative effects of these two SNPs on overall survival and recurrence-free survival (P for trend = 0.012 and 0.003, respectively). Compared with patients carrying zero unfavorable genotype, those carrying two unfavorable genotypes had a 2.24-fold and 2.33-fold increase of death and recurrence risks, respectively. Conclusions The SNPs in ACLY gene may serve as independent prognostic markers for patients with advanced stage CRC. Electronic supplementary material The online version of this article (doi:10.1186/s12957-015-0440-x) contains supplementary material, which is available to authorized users.

Previous studies have demonstrated that monocarboxylate transporters (MCTs) play important roles in the development and progression of many cancers. The purpose of this study was to assess the effects of single-nucleotide polymorphisms (SNPs) of MCT genes on prognosis of colorectal cancer (CRC) patients. Nine functional SNPs in three MCT genes (MCT1, MCT2 and MCT4) were selected and genotyped using Sequenom iPLEX genotyping system in 697 Chinese CRC patients receiving surgery. Multivariate Cox proportional hazards model and Kaplan–Meier curve were used for the prognostic analysis. One SNP (MCT1: rs1049434/exon) was significantly associated with overall survival of CRC patients (HR 0.74; P = 0.046). Two other SNPs (MCT1: rs60844753/5′ near gene and MCT2: rs995343/intron) exhibited associations with recurrence-free survival of CRC patients (HR 0.67; P = 0.078 and HR 0.74; P = 0.036, respectively). Our study also showed that MCT1 rs1049434, rs60844753 and MCT2 rs995343 SNPs had a cumulative effect on CRC recurrence-free survival (P for trend 0.011). Those who carrying three unfavorable genotypes (WW for all SNPs) had a 2.06-fold increased risk of recurrence compared with patients carrying no unfavorable genotypes (P = 0.016). Moreover, we found that patients carrying no

Compelling evidences have suggested that high mobility group box-1 (HMGB1) gene plays a crucial role in cancer development and progression. This study aimed to evaluate the effects of single nucleotide polymorphisms (SNPs) in HMGB1 gene on the survival of gastric cancer (GC) patients. Three tag SNPs from HMGB1 gene were selected and genotyped using Sequenom iPEX genotyping system in a cohort of 1030 GC patients (704 in training set, 326 in validation set). Multivariate Cox proportional hazard model and Kaplan-Meier Curve were used for prognosis analysis. AG/AA genotypes of SNP rs1045411 in HMGB1 gene were significantly associated with better overall survival (OS) in a set of 704 GC patients when compared with GG genotypes (HR = 0.77, 95% CI: 0.60–0.97, P = 0.032). This prognostic effect was verified in an independent validation set and pooled analysis (HR = 0.80, 95% CI: 0.62–0.99, P = 0.046; HR = 0.78, 95% CI: 0.55–0.98, P = 0.043, respectively). In stratified analysis, the protective effect of rs1045411 AG/AA genotypes was more prominent in patients with adverse strata, compared with patients with favorable strata. Furthermore, strong joint predictive effects on OS of GC patients were noted between rs1045411 genotypes and Lauren classification, differentiation, stage or adjuvant chemotherapy. Additionally, functional assay indicated a significant effect of rs1045411 on HMGB1 expression. Our results suggest that rs1045411 in HMGB1 is significantly associated with clinical outcomes of Chinese GC patients after surgery, especially in those with aggressive status, which warrants further validation in other ethnic populations.

Matrix metalloproteinase-21 (MMP-21) has been shown to enhance tumor invasion and metastasis ability in some solid tumors. In the present study, we investigated the expression of MMP-21 as well as its association with overall survival of gastric cancer patients. MMP-21 expression was investigated in 296 cases of gastric cancer by immunohistochemistry assay. Statistical analysis was utilized to evaluate the association of MMP-21 expression with overall survival of patients. MMP-21 expression was proved to be increased in gastric cancer compared with that in normal tissues (P < 0.05). It was also proved MMP-21 expression was associated with tumor invasion, metastasis and TNM stage (P < 0.001). MMP-21 expression was showed to be associated with overall survival of gastric cancer patients for patients with tumor of higher MMP-21 expression tend to have worse overall survival (P < 0.001). Multivariate analysis proved MMP-21 to be an independent prognostic factor for overall survival of gastric cancer patients (P < 0.001). These results suggested the potential role of MMP-21 in progression of human gastric cancer. It might also be a novel molecular marker to predict overall survival of patients with gastric cancer.

Hypersensitivity to radiation exposure has been suggested to be a risk factor for the development of several malignancies, but not including gastric cancer. In this case-control study, radiation sensitivity as measured by chromatid breaks per cell (b/ c) was examined in cultured peripheral blood lymphocytes (PBLs) from 517 patients with gastric cancer and 525 healthy controls. Our results showed that b/c values were significantly higher in cases than in controls (Mean [SD], 0.47 [0.20] vs. 0.34 [0.17]; P,0.001). Using the 50 th percentile value for controls (0.34 b/c) as the cutoff point, unconditional logistic regression analysis revealed that c–radiation-sensitive individuals were at significantly higher risk for gastric cancer (adjusted odds ratio [OR] 2.01, 95% confidence interval [CI] 1.49–3.13). Quartile stratification analysis indicated a dose-response relationship between c-radiation sensitivity and gastric cancer risk (P for trend ,0.001). When using the subjects in first quartile of b/c values as reference, the adjusted ORs and corresponding CIs for the subjects in second, third, and fourth quartiles were 1.48 (0.91–2.17), 2.42 (1.76–3.64), and 3.40 (2.11–5.29), respectively. The c-radiation sensitivity was related to age and smoking status. In addition, a clear joint effect on cancer risk was found between c-Radiation sensitivity and smoking status. The risk for ever smokers with high sensitivity was higher than those for never smokers with high sensitivity and ever smokers with low sensitivity (OR [CI], 4.67 [2.31–6.07] vs. 2.14 [1.40–3.06] vs. 2.42 [1.57–3.95], respectively). No significant interaction was found between both factors (P for interaction =0.42). We conclude that chromatid radiosensitivity is associated with gastric cancer susceptibility in a Chinese population.

In the female population in Asia, systematic investigation concerning alterations in cancer-related genes in breast carcinoma is rare, and the correlation among oncogene or suppressor gene expression with tumor cell apoptosis, cell cycle regulation and tumor cell autophagy remains to be clarified. In this study, a tissue microarray consisting of 360 individual samples from three different breast tissues was generated. By comparing the expression of the tumor-suppressor genes (BRCA1, BECN1, CCND1, PTEN and UVRAG) in ductal breast cancer and normal breast tissues, respectively, we were able to assign changes in the expression of these mRNAs to specific stages and allocate them to define the roles in the multi‑step process of breast carcinogenesis. Tumor-suppressor genes, such as BRCA1 and BECN1, usually had lower signals in the carcinomatous tissues (10.2 and 6.6%) compared to the normal tissues (31 and 32.6%), while stronger positive dots (positive cells >30%) usually existed in the normal tissues. The patients in the oldest age group had the lowest expression rate. Only BECN1 and CCND1 expression showed a significant association with patient age (p=0.030 and p=0.003). A significant association was observed between BRCA1 and BECN1 expression and tumor size (p=0.028 and p=0.021). BECN1 gene expression was positively correlated with UVRAG and PTEN expression (p=0.006 and p=0.000). CCND1 was negatively correlated with PTEN, BECN1 and BRCA1 expression (p=0.011, p=0.000 and p=0.000). Abnormal expression of BRCA1, BECN1, CCND1, PTEN and UVRAG may play a role in human breast carcinogenesis through dysregulated mRNA expression. Overexpressed CCND1 may shorten the G1 phase of the cell cycle, suppress cell apoptosis and contribute to the formation of invasive ductal carcinoma (IDC).

Purpose Extensive evidence has suggested that risk factors of cancer development may also modulate cancer clinical outcome. Recent genome-wide association (GWA) studies identified several single nucleotide polymorphisms (SNPs) predisposing to colorectal cancer (CRC). Given the pivotal importance of these variants in CRC, we sought to evaluate their associations with clinical outcomes of the disease. Experimental Design In a well-characterised cohort including 380 Chinese CRC patients, we genotyped seven SNPs identified in previous multi-stage GWA studies and analysed their associations with patient recurrence and survival. Results One SNP on chromosome 15q13, rs4779584 was associated with reduced risk of death with a hazard ratio (HR) of 0.33 (95% confidence interval [CI] 0.15–0.72, P = 0.007). Another SNP in a gene-desert region on chromosome 10p14, rs10795668, was associated with a reduced risk of recurrence with an HR of 0.55 (95% CI 0.30–1.00, P = 0.05). In a stratified analysis, this association was only evident in patients receiving chemotherapy (HR = 0.32, 95% CI 0.14–0.78, P = 0.01, log rank P = 0.004), but not in those without chemotherapy (HR = 1.08, 95% CI 0.43–2.73, P = 0.87, log rank P = 0.66). Moreover, we found that the effects of chemotherapy on CRC recurrence was only evident in patients with the variant-containing genotypes (HR = 0.35, 95% CI 0.13–0.94, P = 0.04) but not in those with the wild-type genotype of rs10795668. Further analyses indicated a borderline significant interaction effect ( P interaction = 0.05) between rs10795668 and chemotherapy on patient recurrence. Conclusions Our data suggested that rs10795668, a CRC susceptibility variant identified by GWA studies, might be used as a biomarker to identify CRC patients with high risk of recurrence after chemotherapy.

Introduction HMGB1(High mobility group box 1), originally described as a nuclear protein, is now regarded as a multifunctional protein with a paradoxical dual effect in tumors. In the present study, HMGB1 overexpression and its correlation with the clinicopathologic characteristics and recurrence-free survival were evaluated in gastric adenocarcinomas. Methods 76 gastric adenocarcinomas surgically removed entered the study. The immunohistochemical staining was used to assess HMGB1 expression through tissue microarray procedure. The clinicopathologic characteristics of all patients were recorded, and the regular follow-up was made for all patients. Results Almost all the gastric adenocarcinomas showed HMGB1 positive staining mainly in the nucleus, and the overexpression of HMGB1 was found in cancerous tissues with higher strong reactivity rate, compared with non-cancerous tissues (total expression score ≥ 9, 42.0% vs. 9.0%, P < 0.001). Survival analysis revealed that tumor stage negatively correlated with cancer-free survival (P = 0.022). Furthermore, HMGB1 overexpression positively associated with cancer-free survival of resectable gastric adenocarcinomas (P = 0.023). Conclusions The overexpression of HMGB1 protein indicates that HMGB1 may play a role in the tumorigenesis of gastric adenocarcinomas. And the overexpression of HMGB1 may be a marker of good prognosis of gastric adenocarcinoma given curative resection combined with adjuvant chemotherapy.

122 Background: The efficacy of laparoscopic D2 gastrectomy for the treatment of advanced gastric cancer (AGC) with curative intent is still controversial. Thus, the Chinese Laparoscopic Gastrointestinal Surgery Study (CLASS) group conducted a multicenter prospective randomized controlled trial, aiming to evaluate the surgical safety and long-term outcomes of laparoscopic D2 gastrectomy compared with conventional open surgery for AGC. (NCT01609309) Methods: The patients with tumor located at distal stomach at clinical T2-4a, N0-3, M0 stage were eligible for enrollment, treated by either laparoscopic D2 distal subtotal gastrectomy (LG) or open D2 gastrectomy (OG) after randomization. Seventeen institutions currently participated in the study. The morbidity and mortality within postoperative 30 days were compared between the two groups. Results: A total of 607 consecutive eligible patients were randomly assigned to either LG group (n=308) or OG group (n=299) between September 2012 and January 2014. The compliance rates of D2 lymphadenectomy in the LG group and OG group were similar (97.4% vs. 98.3%; P=0.591). Open conversion rate was 4.5%. There was no significant differences between the LG group and OG group in the incidence of intraoperative complication (5.8% vs. 4.3%; P=0.402), postoperative morbidity (18.8% vs. 14.7%; P=0.175), and mortality (0.6% vs. 0; P=0.499). The severity grade pattern was also similar according to the Clavien-Dindo classification (P=0.372). Conclusions: Laparoscopic D2 distal subtotal gastrectomy for AGC could be safely performed by experienced surgeons. Thus, our multicenter prospective study on long-term outcomes can be ongoing. Clinical trial information: NCT01609309.

Background Telomerase expression is one of the characteristics of gastric cancer (GC) cells and telomerase activity is frequently up-regulated by a variety of mechanisms during GC development. Therefore, we hypothesized that elevated levels of activated telomerase might enhance GC risk due to increased propagation of cells with DNA damage, such as induced by γ-radiation. Methods To explore this hypothesis, 246 GC cases and 246 matched controls were recruited in our case-control study. TRAP-ELISA was used to assess the levels of telomerase activity at baseline and after γ-radiation and the γ-radiation-induced telomerase activity (defined as after γ-irradiation/baseline) in cultured peripheral blood lymphocytes (PBLs). Results Our data showed that there was no significant difference for the baseline telomerase activity between GC cases and controls (10.17 ± 7.21 vs. 11.02 ± 8.03, p = 0.168). However, after γ-radiation treatment, γ-radiation-induced telomerase activity was significantly higher in the cases than in the controls (1.51 ± 0.93 vs. 1.22 ± 0.66, p < 0.001). Using the median value of γ-radiation-induced telomerase activity in the controls as a cutoff point, we observed that high γ-radiation-induced telomerase activity was associated with a significantly increased GC risk (adjusted odds ratio, 2.45; 95% confidence interval, 1.83-3.18). Moreover, a dose response association was noted between γ-radiation-induced telomerase activity and GC risk. Age, but not sex, smoking and drinking status seem to have a modulating effect on the γ-radiation-induced telomerase activities in both cases and controls. Conclusion Overall, our findings for the first time suggest that the increased γ-radiation-induced telomerase activity in PBLs might be associated with elevated GC risk. Further confirmation of this association using a prospective study design is warranted.

Background NDRG2 (N-Myc downstream-regulated gene 2) was initially cloned in our laboratory. Previous results have shown that NDRG2 expressed differentially in normal and cancer tissues. Specifically, NDRG2 mRNA was down-regulated or undetectable in several human cancers, and over-expression of NDRG2 inhibited the proliferation of cancer cells. NDRG2 also exerts important functions in cell differentiation and tumor suppression. However, it remains unclear whether NDRG2 participates in carcinogenesis of the thyroid. Methods In this study, we investigated the expression profile of human NDRG2 in thyroid adenomas and carcinomas, by examining tissues from individuals with thyroid adenomas (n = 40) and carcinomas (n = 35), along with corresponding normal tissues. Immunohistochemistry, quantitative RT-PCR and western blot methods were utilized to determine both the protein and mRNA expression status of Ndrg2 and c-Myc. Results The immunostaining analysis revealed a decrease of Ndrg2 expression in thyroid carcinomas. When comparing adenomas or carcinomas with adjacent normal tissue from the same individual, the mRNA expression level of NDRG2 was significantly decreased in thyroid carcinoma tissues, while there was little difference in adenoma tissues. This differential expression was confirmed at the protein level by western blotting. However, there were no significant correlations of NDRG2 expression with gender, age, different histotypes of thyroid cancers or distant metastases. Conclusion Our data indicates that NDRG2 may participate in thyroid carcinogenesis. This finding provides novel insight into the important role of NDRG2 in the development of thyroid carcinomas. Future studies are needed to address whether the down-regulation of NDRG2 is a cause or a consequence of the progression from a normal thyroid to a carcinoma.

Background c-FLIP can be considered as a tumor-progression factor in regard to its anti-apoptotic functions. In the present study, we intended to investigate the expression of c-FLIP in human HCC tissues, and its relation with drug-induced cell apoptosis through the specific inhibition of c-FLIP expression by siRNA in 7721 cells. Methods c-FLIP expression was quantified immunohistochemically in HCC tissues(eighty-six cases), and corresponding noncancerous tissues (fifty-seven cases). Patients with HCC were followed up for cancer recurrence. Then, the c-FLIP gene was silenced with specific siRNA in 7721 HCC cells. c-FLIP expression was detected by RT-PCR, Western Blot and immunocytochemical staining. The cellular viability and cell apoptosis were assayed in vitro with cells treated with doxorubicin. Results Positive immunostaining was detected for c-FLIP in 83.72% (72/86) human HCC tissues, 14.81% (4/27) hepatic cirrhosis, 11.11% (2/18) hepatic hemangioma tissues, and absent in normal hepatic tissues. The overexpression(more than 50%) of c-FLIP in HCC adversely affected the recurrence-free survival. Through c-FLIP gene silencing with siRNA, the expressions of c-FLIP mRNA and protein were remarkably down-regulated in 7721 HCC cells. And doxorubicin showed apparent inhibition on cell proliferations, and induced more apoptosis. Conclusion These results indicate that c-FLIP is frequently expressed in human HCCs, and its overexpression implied a lesser probability of recurrence-free survival. The specific silencing of c-FLIP gene can apparently up-regulate drug-induced HCC cell apoptosis, and may have therapeutic potential for the treatment of human HCC.