Synthesis of Unsymmetrical Trisulfides from S-Substituted Sulphenylthiosulphates.

Trisulfide unit is widely found in natural products and has garnered attention due to the unique pharmacological and physiochemical properties. However, despite limited progress, widely applicable approaches for constructing unsymmetrical trisulfides have so far remain scarce. In this work, an easy-to-prepare, solid-state and scalable reagent, S-substituted sulphenylthiosulphate, has been developed for the divergent synthesis of unsymmetrical trisulfides. Alkyl electrophile substrates, including bromides, chlorides, iodides and tosylates, with diverse substituents are smoothly converted to the corresponding trisulfides with S-substituted sulphenylthiosulphates and thiourea as another sulfur source. Furthermore, the late-stage modification of drug molecules was successfully achieved through this method.

Mesencephalic Astrocyte-Derived Neurotrophic Factor, a Prognostic Factor of Cholangiocarcinoma, Affects Sorafenib Sensitivity of Cholangiocarcinoma Cells by Deteriorating ER Stress.

PURPOSE: Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignant tumor characterized by high malignancy and poor prognosis. Although the efficacy of sorafenib against cholangiocarcinoma cell lines has been demonstrated in vivo and in vitro, limited clinical data are available on the efficacy of sorafenib in patients with cholangiocarcinoma. Sorafenib can enhance endoplasmic reticulum (ER) stress-mediated apoptosis, and ER stress and unfolded protein response are also the mechanisms by which cancer cells resist drug therapy. Mesencephalic astrocyte-derived neurotrophic factor (MANF), initially identified as a neurotrophic factor, can be regulated by ER stress activation. There are no available studies on the diagnostic value and therapeutic significance of MANF in ICC. Hence, the purpose of this study was to evaluate the role of MANF in cholangiocarcinoma, investigating the possibility of whether sorafenib could become a reliable strategy for cholangiocarcinoma therapy. METHODS: In this study, the expression level of MANF in ICC patients was investigated by bioinformatic analysis and the results were verified by tissue microarray assay. Cholangiocarcinoma cell lines were also used to determine how MANF regulates the therapeutic effect of sorafenib and to identify the underlying mechanisms. RESULTS: The results showed that MANF was correlated with poor prognosis and MANF knockdown could facilitate sorafenib-mediated apoptosis and increase the sensitivity of sorafenib treatment by activating excessive ER stress. CONCLUSION: MANF is a prognostic marker of cholangiocarcinoma. MANF knockdown increases sorafenib-mediated ER stress and apoptosis in the cholangiocarcinoma cell lines. This mechanism may lead to a new therapeutic strategy in cholangiocarcinoma.

Diagnostic and Prognostic Values of MANF Expression in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors, and its prognosis is still poor. Mesencephalic astrocyte-derived neurotrophic factor (MANF) plays a key role in endoplasmic reticulum stress. ER stress plays a key role in HCC carcinogenesis. To confirm the clinical and prognostic value of MANF in HCC, we investigated the expression level of MANF in HCC as recorded in databases, and the results were verified by experiment. Survival analysis was probed by the Kaplan-Meier method. Cox regression models were used to ascertain the prognostic value of MANF in HCC tissue microarray. The diagnostic value of MANF in HCC was evaluated by receiver operating characteristic curve analysis. Potential correlation between MANF and selected genes was also analyzed. Results showed that MANF was overexpressed in HCC. Patients with high MANF expression levels had a worse prognosis and higher risk of tumor recurrence. Furthermore, the expression level of MANF had good diagnostic power. Correlation analysis revealed potential regulatory networks of MANF in HCC, laying a foundation for further study of the role of MANF in tumorigenesis. In conclusion, MANF was overexpressed in HCC and related to the occurrence and development of HCC. It is a potential diagnostic and prognostic indicator of HCC.

Screening and Identification of Key Biomarkers for Bladder Cancer: A Study Based on TCGA and GEO Data.

Bladder cancer (BLCA) is a common malignant cancer, and it is the most common genitourinary cancer in the world. The recurrence rate is the highest of all cancers, and the treatment of BLCA has only slightly improved over the past 30 years. Genetic and environmental factors play an important role in the development and progression of BLCA. However, the mechanism of cancer development remains to be proven. Therefore, the identification of potential oncogenes is urgent for developing new therapeutic directions and designing novel biomarkers for the diagnosis and prognosis of BLCA. Based on this need, we screened overlapping differentially expressed genes (DEG) from the GSE7476, GSE13507, and TCGA BLCA datasets. To identify the central genes from these DEGs, we performed a protein-protein interaction network analysis. To investigate the role of DEGs and the underlying mechanisms in BLCA, we performed Gene Ontology (GO) and Kyoto Gene and Genomic Encyclopedia (KEGG) analysis; we identified the hub genes via different evaluation methods in cytoHubba and then selected the target genes by performing survival analysis. Finally, the relationship between these target genes and tumour immunity was analysed to explore the roles of these genes. In summary, our current studies indicate that both cell division cycle 20 (CDC20) and abnormal spindle microtubule assembly (ASPM) genes are potential prognostic biomarkers for BLCA. It may also be a potential immunotherapeutic target with future clinical significance.

A Triple Checked Partial Ambiguity Resolution for GPS/BDS RTK Positioning.

Reliable and accurate carrier phase ambiguity resolution is the key to high-precision Global Navigation Satellite System (GNSS) positioning and application. With the fast development of modern GNSS, the increased number of satellites and ambiguities makes it hard to fix all ambiguities completely and correctly. The partial ambiguity fixing technique, which selects a suitable subset of high-dimensional ambiguities to fix, is beneficial for improving the fixed success rate and reliability of ambiguity resolution. In this contribution, the bootstrapping success rate, bounded fixed-failure ratio test, and the new defined baseline precision defect are used for the selection of the ambiguity subset. Then a model and data dual-driven partial ambiguity resolution method is proposed with the above three checks imposed on it, which is named the Triple Checked Partial Ambiguity Resolution (TC-PAR). The comprehensive performance of TC-PAR compared to the full-fixed LAMBDA method is also analyzed based on several criteria including the fixed rate, the fixed success rate and correct fixed rate of ambiguity as well as the precision defect and RMS of the baseline solution. The results show that TC-PAR could significantly improve the fixed success rate of ambiguity, and it has a comparable baseline precision to the LAMBDA method, both of which are at centimeter level after ambiguities are fixed.

Performance Analysis of Positioning Solution Using Low-Cost Single-Frequency U-Blox Receiver Based on Baseline Length Constraint.

With the rapid development of the satellite navigation industry, low-cost and high-precision Global Navigation Satellite System (GNSS) positioning has recently become a research hotspot. The traditional application of GNSS may be further extended thanks to the low cost of measuring instruments, but effective methods are also desperately needed due to the low quality of the data obtained using these instruments. Thus, in this paper, we propose the analysis and evaluation of the ambiguity fixed-rate and positioning accuracy of single-frequency Global Positioning System (GPS) and BeiDou Navigation Satellite System (BDS) data, collected from a low-cost u-blox receiver, based on the Constrained LAMBDA (CLAMBDA) method with a baseline length constraint, instead of the classical LAMBDA method. Three sets of experiments in different observation environments, including two sets of static short-baseline experiments and a set of dynamic vehicle experiments, are adopted in this paper. The experiment results show that, compared to classical LAMBDA method, the CLAMBDA method can significantly improve the success rate of the GNSS ambiguity resolution. When the ambiguity is fixed correctly, the baseline solution accuracy reaches 0.5 and 1 cm in a static scenario, and 1 and 2 cm on a dynamic platform.

The circular RNA PVT1/miR-203/HOXD3 pathway promotes the progression of human hepatocellular carcinoma.

Accumulating evidence suggests that circular RNAs (circRNAs) play important roles in various physiological and pathological processes. In the present study, we explored the role of circRNA PVT1 in hepatocellular carcinoma (HCC). qRT-PCR was performed to detect the relative expression of circPVT1 in HCC tissues and cell lines. The oncogenic roles of circPVT1 in HCC were evaluated by cell counting kit-8 (CCK-8) assay, ethynyl deoxyuridine (EdU) incorporation assays, transwell assays, flow cytometry and in vivo xenograft growth. Furthermore, bioinformatics, luciferase reporter assays and rescue experiments were conducted to determine the underlying mechanism of circPVT1 in HCC. Enhanced circPVT1 expression was detected in HCC tissues, which was closely associated with poor prognosis of patients with HCC. Knockdown of circPVT1 decreased the proliferation and migration ability of HCC cell lines in vitro Conversely, upregulation of circPVT1 improved the growth and migration in HCC cells. Mechanistically, we found that circPVT1 could bind directly to miR-203 and contributed to the initiation and progression of HCC by regulating miR-203/homebox D3 (HOXD3) pathway. In conclusion, our study reveals that circPVT1 participates in the progression of HCC through the miR-203/homeobox D3 (HOXD3) pathway and might represent a potential therapeutic target for HCC treatment.

Glucocorticoids promote the development of azoxymethane and dextran sulfate sodium-induced colorectal carcinoma in mice.

BACKGROUND: Stress has been suggested as a promoter of tumor growth and development. Glucocorticoids (GCs) are the main stress hormones and widely prescribed as drugs. However, the effect of GCs on the development and progression of colorectal carcinoma (CRC) is unclear. METHODS: We evaluated the effect of corticosterone (CORT) on azoxymethane and dextran sulfate sodium (AOM/DSS)-induced carcinogenesis in the colorectum of C57BL/6 strain mice. Plasma level of CORT was detected by radioimmunoassay. The expression of proliferation markers (Ki-67 and PCNA), nuclear factor (NF)-κB p65 and phosphoto-p65 (P-p65), as well as cyclooxygenase (COX)-2 were determined by immunohistochemistry. Inflammation in colorectum was evaluated by histopathology. RESULTS: CORT feeding in drinking water of mice not only significantly elevated plasma CORT concentration, but also significantly increased the incidence and neoplasms burden (number and size of neoplasms) in colorectum. CORT also significant enhanced the expression of cell proliferation marker (Ki-67 and PCNA), NF-κB p65 and P-p65 as well as COX-2 in colorectal neoplasm of AOM/DSS-treated mice. CONCLUSION: In this study, we have found for the first time that CORT at stress level potentially promotes the growth and development of AOM/DSS-induced colorectal adenoma and carcinoma in mice. Up-regulation of NF-κB and COX-2 may be involved in the promoting effect of CORT.

Genome-wide screening identifies oncofetal lncRNA Ptn-dt promoting the proliferation of hepatocellular carcinoma cells by regulating the Ptn receptor.

Oncofetal genes are genes that express abundantly in both fetal and tumor tissues yet downregulated or undetected in adult tissues, and can be used as tumor markers for cancer diagnosis and treatment. Meanwhile, long noncoding RNAs (lncRNAs) are known to play crucial roles in the pathogenesis of hepatocellular carcinoma (HCC), including tumor growth, proliferation, metastasis, invasion, and recurrence. We performed a genome-wide screening using microarrays to detect the lncRNA expression profiles in fetal livers, adult livers, and liver cancer tissues from mice to identify oncofetal lncRNAs in HCC. From the microarray data analysis, we identified lncRNA Ptn-dt as a possible oncofetal gene. Both in vitro and in vivo experiments results confirmed that overexpression of Ptn-dt significantly promoted the proliferation of mouse HCC cells. RNA pulldown assay showed that Ptn-dt could interact with the HuR protein. Interestingly, miR-96 binds with HuR to maintain its stability as well. Overexpression of lncRNA Ptn-dt led to the downregulation of miR-96, which might be due to the interaction between Ptn-dt and HuR. Meanwhile, previous studies have reported that Ptn can promote tumor growth and vascular abnormalization via anaplastic lymphoma kinase (Alk) signaling. In our study, we found that overexpression of Ptn-dt could promote the expression of Alk through repressing miR-96 via interacting with HuR, thus enhancing the biologic function of Ptn. In summary, a new oncofetal lncRNA Ptn-dt is identified, and it can promote the proliferation of HCC cells by regulating the HuR/miR-96/Alk pathway and Ptn-Alk axis.

Integrated miRNA-risk gene-pathway pair network analysis provides prognostic biomarkers for gastric cancer.

PURPOSE: This study aimed to identify molecular prognostic biomarkers for gastric cancer. METHODS: mRNA and miRNA expression profiles of eligible gastric cancer and control samples were downloaded from Gene Expression Omnibus to screen the differentially expressed genes (DEGs) and differentially expressed miRNAs (DEmiRs), using MetaDE and limma packages, respectively. Target genes of the DEmiRs were also collected from both predictive and experimentally validated target databases of miRNAs. The overlapping genes between selected targets and DEGs were identified as risk genes, followed by functional enrichment analysis. Human pathways and their corresponding genes were downloaded from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database for the expression analysis of each pathway in gastric cancer samples. Next, co-pathway pairs were selected according to the Pearson correlation coefficients. Finally, the co-pathway pairs, miRNA-target pairs, and risk gene-pathway pairs were merged into a complex interaction network, the most important nodes (miRNAs/target genes/co-pathway pairs) of which were selected by calculating their degrees. RESULTS: Totally, 1,260 DEGs and 144 DEmiRs were identified. There were 336 risk genes found in the 9,572 miRNA-target pairs. Judging from the pathway expression files, 45 co-pathway pairs were screened out. There were 1,389 interactive pairs and 480 nodes in the integrated network. Among all nodes in the network, focal adhesion/extracellular matrix-receptor interaction pathways, CALM2, miR-19b, and miR-181b were the hub nodes with higher degrees. CONCLUSION: CALM2, hsa-miR-19b, and hsa-miR-181b might be used as potential prognostic targets for gastric cancer.

Periostin expression in intra-tumoral stromal cells is prognostic and predictive for colorectal carcinoma via creating a cancer-supportive niche.

Periostin (POSTN) expression in cancer cells and circulation has been related to poor prognosis of colorectal carcinoma (CRC). However, the role of POSTN expressed in intra-tumoral stroma on CRC progression remains largely unknown. This study enrolled 1098 CRC patients who received surgical treatment in Shanghai and Guangzhou, Mainland China. In Shanghai cohort, immunohistochemistry score of stromal POSTN expression increased consecutively from adjacent mucosa, primary CRC tissues, to metastatic CRC tissues (P < 0.001), while medium- and high-stromal POSTN expression, rather than epithelial POSTN expression, independently predicted unfavorable prognoses of CRC, adjusted for covariates including TNM stage and postoperative chemotherapy in multivariate Cox models. The results in Shanghai cohort were faithfully replicated in Guangzhou cohort. Stromal POSTN expression dose-dependently predicted an unfavorable prognosis of stage III CRC patients with postoperative chemotherapy in both cohorts. POSTN derived from colonic fibroblasts or recombinant POSTN significantly promoted proliferation, anchorage independent growth, invasion, and chemo-resistance of CRC cells; whereas these effects were counteracted via targeting to PI3K/Akt or Wnt/ß-catenin signaling pathway. CRC cell RKO-derived factor(s) significantly induced POSTN production in colonic fibroblasts and autocrine POSTN promoted proliferation, migration, and anchorage independent growth of fibroblasts. Conclusively, stromal POSTN is prognostic and predictive for CRC via creating a niche to facilitate cancer progression. Targeting POSTN-induced signaling pathways may be therapeutic options for metastatic or chemoresistant CRC.

Testicular metastasis from gastric carcinoma: A case report.

Gastric cancer (GC) is the most prevalent malignancy in the world, especially in China. GC has been postulated to spread via several different routes, including through hematogenous channels, lymphatic vessels, the seeding of peritoneal surfaces, direct extension through the gastric wall, and retrograde extension through the vas deferens or lymphatics. Testicular metastasis is rare. We show here a 53-year-old patient with GC who underwent a radical total gastrectomy approximately 22 mo ago after he presented with a sensation of heaviness and swelling of the right hemiscrotum. The diagnosis of metastatic adenocarcinoma was made after a right-side orchiectomy. We report the first case of testicular metastasis from gastric adenocarcinoma in mainland China and summarize the clinicopathologic features of the disease based on previously published papers.

TSPAN1 functions as an oncogene in gastric cancer and is downregulated by miR-573.

Tetraspanin 1 (TSPAN1) has been reported to be upregulated in gastric cancer (GC). However, whilst TSPAN1 is positively correlated with clinical stage and negatively correlated with survival rates, its function in GC remains elusive. Here we show that expression of TSPAN1 is significantly higher in GC tissues compared to non-cancerous tissues. Furthermore, we demonstrate that RNAi-mediated down-regulation of TSPAN1 expression markedly blocks GC cell proliferation, cell cycle progression and invasive activity. We identified TSPAN1 as a novel target gene of miR-573. Overexpression of miR-573 suppressed proliferation and invasion of GC cells by down-regulation of TSPAN1 expression. Restoration of TSPAN1 rescued the effects of miR-573 overexpression. Therefore, our findings suggest that the miR-573/TSPAN1 axis is important in the control of gastric carcinogenesis.

Inflammation-related factors predicting prognosis of gastric cancer.

Gastric cancer (GC), which is mainly induced by Helicobacter pylori (H. pylori) infection, is one of the leading causes of cancer-related death in the developing world. Active inflammation initiated by H. pylori infection and maintained by inherent immune disorders promotes carcinogenesis and postoperative recurrence. However, the presence with H. pylori in tumors has been linked to a better prognosis, possibly due to the induction of antitumor immunity. Tumor infiltrations of tumor-associated macrophages, myeloid-derived suppressor cells, neutrophils, Foxp3(+) regulatory T cells are correlated with poor prognosis. Tumor infiltrating CD8(+) cytotoxic T lymphocytes, dendritic cells, and CD45RO T cells are generally associated with good prognosis of GC, although some subsets of these immune cells have inverse prognosis prediction values. High ratios of Foxp3(+)/CD4(+) and Foxp3(+)/CD8(+) in tumors are associated with a poor prognosis; whereas high Th1/Th2 ratio in tumors predicts a good prognosis. High levels of interleukin (IL)-6, IL-10, IL-32, and chemokine C-C motif ligands (CCL)7 and CCL21 in circulation, high expression of CXC chemokine receptor 4, chemokine C-C motif receptor (CCR)3, CCR4, CCR5, CCR7, hypoxia-inducible factor-1α, signal transducer activator of transcription-3, cyclooxygenase-2, and orphan nuclear receptor 4A2 in tumors are associated with an unfavorable prognosis. Increased serum levels of matrix metalloproteinases (MMP)-3, MMP-7, and MMP-11 and increased levels of MMP-9, MMP-12, and MMP-21 in tumors are consistently associated with poor survival of GC. Further emphasis should be put on the integration of these biomarkers and validation in large cohorts for personalized prediction of GC postoperative prognosis.

Experimental study on sustained-release 5-Fluorouracil implantation in canine peritoneum and para-aortic abdominalis.

OBJECTIVE: To observe local and systemic toxicity after sustained-release 5-fluorouracil (5-Fu) implantation in canine peritoneum and para-aortic abdominalis and the changes of drug concentration in the local implanted tissue with time. METHODS: 300 mg sustained-release 5-Fu was implanted into canine peritoneum and para-aorta abdominalis. Samples were taken 3, 5, 7 and 10 days after implantation for assessment of changes and systemic reactions. High performance liquid chromatography was applied to detect the drug concentrations of peritoneal tissue at different distances from the implanted site, lymphatic tissue of para-aortic abdominalis, peripheral blood and portal venous blood. RESULTS: 10 days after implantation, the drug concentrations in the peritoneum, lymphatic tissue and portal vein remained relatively high within 5 cm of the implanted site. There appeared inflammatory reaction in the local implanted tissue, but no visible pathological changes such as cell degeneration and necrosis, and systemic reaction like anorexia, nausea, vomiting and fever. CONCLUSIONS: Sustained-release 5-Fu implantation in canine peritoneum and para-aortic abdominalis can maintain a relatively high tumour- inhibiting concentration for a longer time in the local implanted area and portal vein, and has mild local and systemic reactions. Besides, it is safe and effective to prevent or treat recurrence of gastrointestinal tumours and liver metastasis.

Influence of ERCC1 and ERCC4 polymorphisms on response to prognosis in gastric cancer treated with FOLFOX-based chemotherapy.

Polymorphisms in the excision repair cross-complimentary group 1 (ERCC1)-excision repair cross-complimentary group 4 (ERCC4) genes have been implicated in the prognosis of various cancers. We conducted a cohort study to investigate the role of ERCC1-ERCC4 gene polymorphisms on the response to chemotherapy and the role of these two gene polymorphisms on the clinical outcomes of gastric cancer. Four hundred forty-seven patients with newly diagnosed and histopathologically confirmed primary gastric cancer were collected in our study and were followed up until March 2012. ERCC1 (rs11615, rs3212986C>A, and rs2298881) and ERCC4 (rs226466C>G, rs2276465, and rs6498486) were selected and genotyped. The overall chemotherapy response rate for treatment was 68 %. Carriers of the rs11615 TT and T allele and ERCC1 rs2298881 CC and C allele had a marginally significantly higher response rate to the chemotherapy. In the Cox proportional hazard model, the hazard ratios (HRs) for overall survival (OS) in patients carrying ERCC1 rs11615 TT genotype and T allele were 0.53 (0.29-0.95) and 0.63 (0.42-0.94), respectively. Similarly, we found a significant decreased risk of death from gastric cancer among patients carrying ERCC1 rs2298881 CC genotype and C allele when compared with CC genotype, and HRs (95% confidence interval (CI)) of OS were 0.50 (0.24-0.98) and 0.62 (0.40-0.96), respectively. Moreover, individuals carrying ERCC1 rs11615 T allele and rs2298881 C allele could decrease a 0.62-fold risk of death from gastric cancer. This study reported a carriage of ERCC1 rs11615, and rs2298881 polymorphism can be used as a predictor of response to folinic acid/5-fluorouracil (5-FU)/oxaliplatin (FOLFOX)-based chemotherapy in gastric cancer patients.

A GWAS-identified susceptibility locus on chromosome 11q13.3 and its putative molecular target for prediction of postoperative prognosis of human renal cell carcinoma.

Genome-wide association studies have been used to identify single nucleotide polymorphisms (SNPs) associated with renal cell carcinoma (RCC) in European individuals. The current study aimed to evaluate the correlation between significant SNPs identified in European individuals and the occurrence and postoperative prognosis of RCC in Chinese individuals. A total of 400 cases and 806 controls were involved in the current study. rs4765623, rs7105934, rs7579899 and rs1867785 were genotyped using qPCR, and the expression of cyclin D1 in renal tissue and RCCs was determined via western blotting and immunohistochemistry. The correlation between the SNPs/cyclin D1 expression and overall survival was evaluated using multivariate Cox regression analyses. Of the four SNPs, only rs7105934 was found to significantly correlate with RCC risk in Chinese individuals. The rs7105934 GA + AA genotype was correlated with a reduced risk of RCC with an odds ratio of 0.64 (95% confidence interval [CI], 0.43-0.96), following adjustment for age. This genotype was found to independently predict an improved postoperative prognosis in the multivariate analysis, with a hazard ratio (HR) of 0.12 (95% CI, 0.02-0.93). Expression of cyclin D1, a putative regulated protein of rs7105934, did not vary in adjacent renal tissue and tumors when compared with that of various rs7105934 genotypes. However, cyclin D1 expression in RCCs inversely correlated with advanced tumor stage, and moderate to high expression of cyclin D1 in RCCs independently predicted improved postoperative prognosis, with an HR of 0.13 (95% CI, 0.02-0.96). Observations of the present study indicate that the rs7105934 A allele is associated with reduced risk and improved postoperative prognosis of RCC; however, this effect is unlikely to be caused by cyclin D1 expression.

Genetic polymorphisms of XRCC1 gene and susceptibility to gastric cancer in Chinese Han population.

This study aims to evaluate whether the c.1471G > A and c.1686C > G genetic polymorphisms of XRCC1 gene influencing gastric cancer susceptibility. A total of 813 subjects with Chinese Han ethnicity were enrolled. Our data suggest that the allele and genotype frequencies are significantly different from gastric cancer patients with cancer-free controls. We find that c.1471G > A and c.1686C > G genetic polymorphisms statistically increase the risk of gastric cancer. Our findings indicate these two genetic polymorphisms are related with the susceptibility to gastric cancer, and could be used as molecular markers for detecting gastric cancer in Chinese Han ethnicity.

Expression of orphan nuclear receptor NR4A2 in gastric cancer cells confers chemoresistance and predicts an unfavorable postoperative survival of gastric cancer patients with chemotherapy.

BACKGROUND: NR4A2, an orphan nuclear receptor essential in the generation of dopaminergic neurons, has been recently linked to inflammation and cancer. This study sought to identify the role of NR4A2 on chemoresistance and postoperative prognosis of gastric cancer (GC). METHODS: NR4A2 was transfected into GC cells to investigate its effects on chemoresistance to 5-fluorouracil and the tumorigenicity in nude mice. This study also investigated prostaglandin E2 (PGE2 )-induced NR4A2 expression and its effect on chemoresistance. Surgical specimens from patients with stage I through III GC were examined immunohistochemically for NR4A2 expression. Median follow-up time was 76 months for 245 patients. RESULTS: Ectopic expression of NR4A2 significantly increased the chemoresistance and attenuated 5-fluorouracil-induced apoptosis. Transient treatment of GC cells with PGE2 significantly upregulated NR4A2 expression via the protein kinase A pathway and increased the chemoresistance. Ectopic expression of NR4A2 significantly increased the tumorigenicity. In clinical samples, NR4A2 was preferentially expressed in lymphocytes and epithelial cytoplasm in adjacent mucosa. High expression of NR4A2 (immunoreactive score ≥ 3) in cancer cells significantly predicted an unfavorable postoperative disease-specific survival of patients with stage I to III GC (P = .011), especially for those who received 5-fluorouracil-based chemotherapy (P = .016). This effect was not found in those without the chemotherapy. In multivariate Cox analyses, age, TNM (tumor/node/metastasis) stage, and high NR4A2 expression significantly predicted an unfavorable postoperative survival. CONCLUSIONS: High NR4A2 expression in GC cells confers chemoresistance, attenuates 5-fluorouracil-induced apoptosis, and predicts an unfavorable survival, especially for those who received chemotherapy. NR4A2 might serve as a prognostic and predictive factor and therapeutic target for patients with GC. Cancer 2013;119:3436-3445.. © 2013 American Cancer Society.

Nuclear orphan receptor NR4A2 confers chemoresistance and predicts unfavorable prognosis of colorectal carcinoma patients who received postoperative chemotherapy.

BACKGROUND: NR4A2, an orphan nuclear receptor essential in neuron generation, has been recently linked to inflammatory and metabolic pathways of colorectal carcinoma (CRC). However, the effects of NR4A2 on chemo-resistance and postoperative prognosis of CRC remain unknown. METHODS: NR4A2 was transfected into CRC cells to investigate its effects on chemo-resistance to 5-fluorouracil and oxaliplatin and chemotherapeutics-induced apoptosis. We also investigated prostaglandin E2 (PGE2)-induced NR4A2 expression and its effect on chemo-resistance. Tissue microarrays including 51 adenoma, 14 familial adenomatous polyposis with CRC, 17 stage IV CRC with adjacent mucosa and 682 stage I-III CRC specimens were examined immunohistochemically for NR4A2 expression. Median follow-up time for stage I-III CRC patients was 53 months. RESULTS: Ectopic expression of NR4A2 increased the chemo-resistance, and attenuated the chemotherapeutics-induced apoptosis. Transient treatment of PGE2 significantly up-regulated NR4A2 expression via protein kinase A pathway and increased the chemo-resistance. NR4A2 expression in epithelials consecutively increased from adenoma, adjacent mucosa to CRC (P(trend)<0.001). In multivariate Cox regression analyses, high NR4A2 expression in cancer nuclei (immunoreactive score ≥ 4) significantly predicted a shorter disease-specific survival (DSS) of CRC patients (hazard ratio [HR]=1.88, P=0.024). High NR4A2 expression specifically predicted a shorter DSS of colon cancer patients (dichotomisation, HR=2.55, log-rank test P=0.011), especially for those who received postoperative 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOX) chemotherapy (3-score range, HR=1.86, log-rank test P=0.020). CONCLUSION: High expression of NR4A2 in CRC cells confers chemo-resistance, attenuates chemotherapeutics-induced apoptosis, and predicts unfavorable prognosis of colon cancer patients, especially for those who received postoperative chemotherapy. NR4A2 may be prognostic and predictive for colon cancer.