Jing-Yuan Fang

Shanghai Cancer Institute, Shanghai, Shanghai Shi, China

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Publications (114)372.63 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Since observational data in the urban residents are required to better assess the risk factors of colorectal neoplasm occurrence and the effectiveness of colonoscopy screening and surveillance, we conducted a case-control study at multicenters in China to identify patient characteristics and neoplasm features of colorectal adenoma (CRA) and colorectal carcinoma (CRC). A total of 4089 patients who had undergone a colonoscopy from 19 hospitals were enrolled, of which 1106 had CRA and 466 had CRC. They were compared with controls. The analysis provides features and risk factors of colorectal neoplasm using multivariate logistic regression. Increasing age, a family history of colorectal cancer or previous cases of colorectal adenoma or hypertension disease, gastrointestinal surgery, regular intake of pickled food (adjusted odds ratio [aOR] 1.42, 95 % confidence interval [CI], 1.048-1.924), consumption of alcohol, and a positive result of fecal occult blood testing (FOBT; aOR 2.509, 95 % CI 1.485-4.237) were associated with an increased risk of CRA. In the CRC group, increasing age, regular intake of pickled foods, and a positive FOBT result were risk factors. In addition, a positive abdominal computed tomography (CT) before a colonoscopy and physical signs of emaciation were also significantly associated with an increasing risk of colorectal carcinoma. Regular intake of vegetables decreased the risk of both CRA and CRC. Age, pickled foods, and a positive FOBT are risk factors for colorectal neoplasm. Vegetable intake was associated with a decreased risk of CRA and CRC.
    International Journal of Colorectal Disease 12/2014; · 2.24 Impact Factor
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    ABSTRACT: It is increasingly evident that long non-coding RNAs (lncRNA) have causative roles in carcinogenesis. In this study, we report findings implicating a novel lncRNA in gastric cancer (GC), termed GAPLINC, based on the use of global microarray and in situ hybridization (ISH) analyses to identify aberrantly expressed lncRNA in human GC specimens. GAPLINC is a 924-bp long lncRNA that is highly expressed in GC tissues. GAPLINC suppression and with gene expression profiling in GC cells revealed alterations in cell migration pathways, with CD44 expression the most highly correlated. Manipulating GAPLINC expression altered CD44 mRNA abundance and the effects of GAPLINC on cell migration and proliferation were neutralized by suppressing CD44 expression. Mechanistic investigations revealed that GAPLINC regulates CD44 as a molecular decoy for miR211-3p, a microRNA that targets both CD44 and GAPLINC. Tissue ISH analysis suggested that GAPLINC overexpression defines a subgroup of GC patients with very poor survival. Taken together, our results identify a non-coding regulatory pathway for the CD44 oncogene, shedding new light on the basis for GC cell invasiveness.
    Cancer research. 10/2014;
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    ABSTRACT: The impact of cellular oxidative stress in promoting the epithelial-mesenchymal transition (EMT) has been noticed. Our previous study shows that SENP3, a redox-sensitive SUMO2/3-specific protease, accumulates in a variety of cancers, but whether SENP3 and SUMOylation involve in the regulation of EMT is unclear. The present study uncovers a novel role of SENP3 in promoting the EMT process in gastric cancer via regulating an EMT-inducing transcription factor, forkhead box C2 (FOXC2). We demonstrate that the expression of mesenchymal marker genes and cell migration ability are enhanced in SENP3-overexpressing gastric cancer cells and attenuated in SENP3-knockdown cells. A nude mouse model and a set of patient's specimens suggest the correlation between SENP3 and gastric cancer metastasis. Biochemical assays identify FOXC2 as a substrate of SENP3. Meanwhile N-cadherin is verified as a target gene of FOXC2, which is transcriptionally activated by a SUMO-less FOXC2. Additionally, reactive oxygen species-induced de-SUMOylation of FOXC2 can be blocked by silencing endogenous SENP3. In conclusion, SENP3, which is increased in gastric cancer cells, potentiates the transcriptional activity of FOXC2 through de-SUMOylation, in favor of the induction of specific mesenchymal gene expression in gastric cancer metastasis.
    Oncotarget 08/2014; 5(16):7093-7104. · 6.64 Impact Factor
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    ABSTRACT: Serotonin (5-HT) plays pivotal roles in the pathogenesis of post-infectious irritable bowel syndrome (PI-IBS), and luminal 5-HT time-dependently modulates visceral nociception. We found that duodenal biopsies from PI-IBS patients exhibited increased 5-HT and decreased anandamide levels and that decreased anandamide was associated with abdominal pain severity, indicating a link between 5- HT and endocannabinoid signaling pathways in PI-IBS. To understand this, we investigated the role of endocannabinoids in 5-HT modulation of visceral nociception in a rat model. Acute intraduodenally applied 5-HT attenuated the visceromotor response (VMR) to colorectal distention, and this was reversed by the cannabinoid receptor 1 (CB1) antagonist AM251. Duodenal anandamide (but not 2- arachidonoylglycerol) content was greatly increased after luminal 5-HT treatment. This effect was abrogated by the 5-HT3 receptor (5-HT3R) antagonist granisetron, which was luminally delivered to preferentially target vagal terminals. Chemical denervation of vagal afferents blocked 5-HT-evoked antinociception and anandamide release. Chronic luminal 5-HT exposure for 5 days increased baseline VMR and VMR post-5-HT (days 4 and 5). Duodenal levels of anandamide and N-acylphosphatidylethanolamine- specific phospholipase D (NAPE-PLD, the anandamide-synthesizing enzyme) protein gradually declined from day 1 to 5. The time-dependent effects of 5-HT were abolished by daily granisetron pretreatment. Daily pretreatment with CB1 agonists or anandamide from day 3 attenuated 5-HT-induced hyperalgesia. These data suggest that vagal 5-HT3R-mediated duodenal anandamide release contributes to acute luminal 5-HT-induced antinociception via CB1 signaling, whereas decreased anandamide is associated with hyperalgesia upon chronic 5-HT treatment. Further understanding of peripheral vagal anandamide signaling may provide insights into the mechanisms underlying 5-HT-related IBS.
    Pain 05/2014; · 5.64 Impact Factor
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    ABSTRACT: Increasing evidence suggests long non-coding RNAs (lncRNAs) are frequently aberrantly expressed in cancers, however, few related lncRNA signatures have been established for prediction of cancer prognosis. We aimed to develop a lncRNA signature to improve prognosis prediction of colorectal cancer (CRC). Using a lncRNA-mining approach, we performed lncRNA expression profiling in large CRC cohorts from Gene Expression Ominus (GEO), including GSE39582 test series(N=436), internal validation series (N=117); and two independent validation series GSE14333 (N=197) and GSE17536(N=145). We established a set of six lncRNAs that were significantly correlated with the disease free survival (DFS) in the test series. Based on this six-lncRNA signature, the test series patients could be classified into high-risk and low-risk subgroups with significantly different DFS (HR=2.670; P<0.0001). The prognostic value of this six-lncRNA signature was confirmed in the internal validation series and another two independent CRC sets. Gene set enrichment analysis (GSEA) analysis suggested that risk score positively correlated with several cancer metastasis related pathways. Functional experiments demonstrated three dysregulated lncRNAs, AK123657, BX648207 and BX649059 were required for efficient invasion and proliferation suppression in CRC cell lines. Our results might provide an efficient classification tool for clinical prognosis evaluation of CRC.
    Oncotarget 04/2014; 5(8):2230-42. · 6.64 Impact Factor
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    ABSTRACT: Octamer transcription factor 1 (OCT1) was found to be expressed in intestinal metaplasia and gastric cancer (GC), but the exact roles of OCT1 in GC remain unclear. The objective of this study was to determine the functional and prognostic implications of OCT1 in GC. Expression of OCT1 was examined in paired normal and cancerous gastric tissues and the prognostic significance of OCT1 was analysed by univariate and multivariate survival analyses. The functions of OCT1 on synbindin expression and extracellular signal-regulated kinase (ERK) phosphorylation were studied in vitro and in xenograft mouse models. The OCT1 gene is recurrently amplified and upregulated in GC. OCT1 overexpression and amplification are associated with poor survival in patients with GC and the prognostic significance was confirmed by independent patient cohorts. Combining OCT1 overexpression with American Joint Committee on Cancer staging improved the prediction of survival in patients with GC. High expression of OCT1 associates with activation of the ERK mitogen-activated protein kinase signalling pathway in GC tissues. OCT1 functions by transactivating synbindin, which binds to ERK DEF domain and facilitates ERK phosphorylation by MEK. OCT1-synbindin signalling results in the activation of ERK substrates ELK1 and RSK, leading to increased cell proliferation and invasion. Immunofluorescent study of human GC tissue samples revealed strong association between OCT1 protein level and synbindin expression/ERK phosphorylation. Upregulation of OCT1 in mouse xenograft models induced synbindin expression and ERK activation, leading to accelerated tumour growth in vivo. OCT1 is a driver of synbindin-mediated ERK signalling and a promising marker for the prognosis and molecular subtyping of GC.
    Gut 04/2014; · 10.73 Impact Factor
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    ABSTRACT: MicroRNAs (miRs) are promising predictors in colorectal cancer (CRC). We investigated whether miRNAs could predict adenoma recurrence in patients with advanced colorectal adenoma (ACRA) after polypectomy. MiRNA expression profiling was performed by miRNA microarray to identify recurrence related miRNAs. Candidate miRNAs extracted from FFPE blocks of ACRA patients were measured using real-time PCR. Logistic regression analysis was conducted to investigate whether validated miRNA expression profiles were independent from other known adenoma recurrence risk factors. The prognostic values of six miRNAs and three independent risk factors were assessed by the area under the receiver operating characteristic (ROC) curve analysis. The expressions of six candidate miRNAs were significantly decreased from levels in normal colorectal tissue compared to ARCA with adenoma recurrence (RACRA) in this retrospective cohort. However, only miR-194 emerged as a practical predictor. The sensitivity and specificity of miR-194 as a predictor were 71.0% and 78.0%, respectively, at a cut-off value of 0.1311 in the retrospective cohort. Sensitivity and specificity were 76.1% and 77.2%, respectively, in the prospective cohort using the same cut-off value. Low expression levels of miR-194, adenoma size ≥2 cm and ≥3 adenomas were independent risk factors for adenoma recurrence. Moreover, low expression of miR-194 was a better predictor of adenoma recurrence than the adenoma size and numbers according to ROC curve analysis. MiR-194 may be an independent predictor for adenoma recurrence in patients with advanced colorectal adenoma after polypectomy.
    Cancer Prevention Research 04/2014; · 4.89 Impact Factor
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    ABSTRACT: The total enteroscopy rate of single-balloon enteroscopy (SBE) using air insufflation is not satisfactory, and whether carbon dioxide (CO2) insufflation increases the total enteroscopy rate of SBE is unknown. This randomised controlled trial aimed to determine whether CO2 insufflation facilitates the intubation depth and total enteroscopy rate of SBE. A total of 214 eligible patients referred for SBE were randomised to receive either air or CO2 insufflation, and included in the intention-to-test (ITT) analysis. In addition, 199 patients in whom enteroscopy was completed were included in the per-protocol (PP) analysis. Both the patients and endoscopists were blinded, and the intubation depth and total enteroscopy rate were defined as the primary outcomes. The CO2 group showed a superiority of intubation in the ITT analysis (oral route: 323.8±64.2 vs 238.3±68.6 cm; anal route: 261.6±74.2 vs 174.7±62.1 cm, both p<0.001), and the total enteroscopy rate (34.9% vs 17.6%, p=0.006). Similar results were obtained in a PP analysis for both outcomes. In addition, in the PP analysis, the addition of circumference after the procedure was less in the CO2 group (0.8±0.6 vs 3.3±1.8 cm, p=0.005) for the oral route. No serious complications were reported. The overall percentage of procedures with significant pathological findings was 52.8%; the rates were 58.5% and 47.2% (p=0.100, ITT analysis) in the CO2 and air groups, respectively. CO2 insufflation improves the intubation depth and total enteroscopy rate in SBE with a good safety profile and acceptability compared with that of air, and thus is recommended for clinical utilisation. ClinicalTrial.gov identifier: NCT01758900.
    Gut 03/2014; · 10.73 Impact Factor
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    ABSTRACT: C9orf140 is a newly identified and characterized gene which is associated with cell proliferation and tumorigenicity. Expression of C9orf140 is upregulated in human gastric cancer and colorectal cancer (CRC); however, little is known about its role in CRC progression. We have investigated the clinical significance, biological effects and mechanisms of C9orf140 signaling. We found that the expression of C9orf140 is dramatically increased in a subset of CRC and correlates significantly with vascular invasion and lymph node metastasis. Our finding showed that knockdown of C9orf140 significantly reduced cell proliferation and invasion in vitro and dramatically increased overall survival and decreased lung metastasis in vivo. Conversely, overexpression of C9orf140 significantly increased lung metastasis and shortened overall survival when compared with control tumors. C9orf140-induced CRC cell invasion may depend on promoting the epithelial-mesenchymal transition (EMT) progression. STAT5 may directly interact with the enhancer of zeste homolog 2 (EZH2) and β-catenin to enhance C9orf140 gene transactivation. Furthermore, C9orf140 may participate in cell invasion which is induced by STAT5, EZH2 or β-catenin activation. We describe the role of C9orf140 in CRC progression and find that C9orf140 overexpression may be regulated by STAT5, EZH2 and β-catenin interaction.
    Carcinogenesis 03/2014; · 5.64 Impact Factor
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    Jie Xu, Zhaoli Li, Jilin Wang, Haoyan Chen, Jing-Yuan Fang
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    ABSTRACT: Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor commonly inactivated in glioblastoma multiforme (GBM), but the prognostic significance of PTEN remains controversial. Here, we demon- strate significant prognostic value of combined PTEN mutation and expression for the survival of patients with GBM on the basis of analysis of large-scale cancer genomic data. PTEN nonsense mutations associated with sig- nificantly shorter disease-free survival and overexpression of PTEN protein linked to shorter disease-free and overall survival of patients with GBM. PTEN nonsense mutations correlated with decreased p53 and Gata3 protein levels and increased genomic instability in human GBM tissues. Expression of nonsense PTEN mutant decreased p53 and Gata3 levels, producing increased DNA damage both in vitro and in vivo. Mice carrying xenograft tumors with nonsense PTEN mutant displayed significantly shorter survival. Our data demonstrated the prognostic value of combined PTEN mutation and protein expression for patients with GBM and highlighted distinct biologic effects of nonsense and missense mutations of PTEN.
    Translational oncology 03/2014; · 3.40 Impact Factor
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    ABSTRACT: Mutations of p53 cause not only loss of wild-type function but also gain of novel oncogenic functions (GOF). Accumulating evidence suggest that p53 hotspot mutations may confer different types and magnitudes of GOF. Here we add support to the heterogeneity of mutant p53 GOF by showing their unequal association with early tumor onset and spectrum of tumor types. We stratified Li-Fraumeni syndrome (LFS) patients according to carried p53 mutations using data from the updated p53 germline mutation database. When compared to loss-of-function nonsense mutations, the R282 GOF mutation associated with significantly earlier onset, while the G245 mutation displayed later onset. The R175, Y220, R248, R282 and nonsense mutations showed preferential distribution in certain cancer types, which varied in the age of onset. Multivariate COX regression model adjusting for cancer types and patient sex suggested that nonsense and G245 mutations had lower risk than R248 for early onset, suggesting unequal strengths of mutant GOF effects. Our results suggest that Li-Fraumeni syndrome can be subdivided into subtypes linking to unequal GOF effects of p53 mutations. These findings have potential implications in the prevention, early detection and targeted treatment of LFS tumors.
    Scientific Reports 02/2014; 4:4223. · 5.08 Impact Factor
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    ABSTRACT: A higher prevalence of chronic atrophic gastritis (CAG) occurs in younger adults in Asia. We used Stomach Age to examine the different mechanisms of CAG between younger adults and elderly individuals, and established a simple model of cancer risk that can be applied to CAG surveillance.
    BMC Clinical Pathology 01/2014; 14:29.
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    ABSTRACT: Colorectal cancer (CRC) is a heterogeneous disease in terms of clinical behavior and response to therapy. Increasing evidence suggests that long noncoding RNAs (lncRNAs) are frequently aberrantly expressed in cancers, and some of them have been implicated in CRC biogenesis and prognosis. Using an lncRNA-mining approach, we constructed lncRNAs expression profiles in approximately 888 CRC samples. By applying unsupervised consensus clustering to LncRNA expression profiles, we identified five distinct molecular subtypes of CRC with different biological pathways and phenotypically distinct in their clinical outcome in both univariate and multivariate analysis. The prognostic significance of the lncRNA-based classifier was confirmed in independent patient cohorts. Further analysis revealed that most of the signature lncRNAs positively correlated with somatic copy number alterations (SCNAs). This lncRNAs-based classification schema thus provides a molecular classification applicable to individual tumors that has implications to influence treatment decisions.
    Molecular Oncology. 01/2014;
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    ABSTRACT: Covalent modification adding acetyl groups to the C terminus of the p53 protein has been suggested to be required for its functional activation as a tumour suppressor. However, it remains largely unknown how p53 acetylation is deregulated in colorectal cancer (CRC), which is the third most commonly diagnosed cancer worldwide. Here we show that ArhGAP30, a Rho GTPase-activating protein, is a pivotal regulator for p53 acetylation and functional activation in CRC. ArhGAP30 binds to p53 C-terminal domain and P300, facilitating P300-mediated acetylation of p53 at lysine 382. ArhGAP30 expression is required for p53 activation upon DNA damage stress, and the level of ArhGAP30 correlates with p53 acetylation and functional activation in CRC tissues. Moreover, low level of ArhGAP30 expression associates with poor survival of CRC patients. In summary, ArhGAP30 is required for p53 acetylation and functional activation in CRC, and the expression of ArhGAP30 is a potential prognostic marker for CRC.
    Nature Communications 01/2014; 5:4735. · 10.74 Impact Factor
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    ABSTRACT: Recent studies have increasingly linked microRNAs to colorectal cancer (CRC). MiR-194 has been reported deregulated in different tumor types, whereas the function of miR-194 in CRC largely remains unexplored. Here we investigated the biological effects, mechanisms and clinical significance of miR-194. Functional assay revealed that overexpression of miR-194 inhibited CRC cell viability and invasion in vitro and suppressed CRC xenograft tumor growth in vivo. Conversely, block of miR-194 in APC(Min/+) mice promoted tumor growth. Furthermore, miR-194 reduced the expression of AKT2 both in vitro and in vivo. Clinically, the expression of miR-194 gradually decreased from 20 normal colorectal mucosa (N-N) cases through 40 colorectal adenomas (CRA) cases and then to 40 CRC cases, and was negatively correlated with AKT2 and pAKT2 expression. Furthermore, expression of miR-194 in stool samples was gradually decreased from 20 healthy cases, 20 CRA cases, then to 28 CRC cases. Low expression of miR-194 in CRC tissues was associated with large tumor size (P=0.006), lymph node metastasis (P=0.012) and shorter survival (HR =2.349, 95% CI = 1.242 to 4.442; P=0.009). In conclusion, our data indicated that miR-194 acted as a tumor suppressor in the colorectal carcinogenesis via targeting PDK1/AKT2/XIAP pathway, and could be a significant diagnostic and prognostic biomarker for CRC.
    Theranostics 01/2014; 4(12):1193-208. · 7.81 Impact Factor
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    ABSTRACT: MicroRNAs (miRNAs) participate in diverse biological pathways and may act as oncogenes or tumor suppressors. Single nucleotide polymorphisms (SNPs) in miRNAs (MirSNPs) might promote carcinogenesis by affecting miRNA function and/or maturation; however, the association between MirSNPs reported and cancer risk remain inconsistent. Here, we investigated the association between nine common MirSNPs and cancer risk using data from large scale case-control studies. Eight precursor-miRNA (pre-miRNA) SNPs (rs2043556/miR-605, rs3746444/miR-499a/b, rs4919510/miR-608, rs2910164/miR-146a, rs11614913/miR-196a2, rs895819/miR-27a, rs2292832/miR-149, rs6505162/miR-423) and one primary-miRNA (pri-miRNA) SNP (rs1834306/miR-100) were analyzed in 16399 cases and 21779 controls from seven published studies in eight common cancers. With a novel statistic, Cross phenotype meta-analysis (CPMA) of the association of MirSNPs with multiple phenotypes indicated rs2910164 C (P = 1.11E-03), rs2043556 C (P = 0.0165), rs6505162 C (P = 2.05E-03) and rs895819 (P = 0.0284) were associated with a significant overall risk of cancer. In conclusion, MirSNPs might affect an individual's susceptibility to various types of cancer.
    Scientific Reports 01/2014; 4:3648. · 5.08 Impact Factor
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    ABSTRACT: In this study we investigated the biological role and mechanism of miR-198 in colorectal carcinoma (CRC). MiR-198 expression was shown to exhibit a strongly negative correlation with lymph node invasion, distant metastasis and patient survival in examinations of colorectal cancer tissues and paired normal colorectal mucosa tissues. fucosyl transferase 8 (FUT8) was identified as a potential target of miR-198 in bioinformatics analysis and luciferase reporter assays. Overexpression of miR-198 in CRC cell lines decreased FUT8 levels as shown by immunofluorescence analysis, and inhibited cell proliferation, migration, and invasion. These anti-tumor phenotypes were rescued by reconstitution of FUT8 expression. Furthermore, miR-198 was shown to target the 3'UTR of FUT8 directly to downregulate FUT8 expression at both mRNA and protein levels in qRT-PCR and Western blot analyses, respectively. In vivo, restoration of miR-198 significantly inhibited xenograft growth and invasion of CRC tumors in nude mice. Therefore, it could be concluded that miR-198 suppresses the proliferation and invasion of CRC by directly targeting FUT8.
    Scientific reports. 01/2014; 4:6145.
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    ABSTRACT: The development of gastric cancer (GC) is a complex multistep process, including numerous genetic and epigenetic changes. CD24 is associated with enhanced invasiveness of GC and a poor prognosis. However, the mechanism by which CD24 induces GC progression remains poorly characterized. Here, we found that the expression of CD24 gradually increased in samples of normal gastric mucosa, non-atrophic chronic gastritis, chronic atrophic gastritis (CAG), CAG with intestinal metaplasia, dysplasia and GC. Moreover, the knockdown of CD24 induced significant levels of apoptosis in GC cells via the mitochondrial apoptotic pathway. CD24 may also promote cellular invasion and regulate the expression of E-cadherin, fibronectin and vitamin D receptor in GC cells. The activation of signal transducer and activator of transcription 3 (STAT3) may mediate CD24-induced GC survival and invasion in vitro. Furthermore, CD24-induced GC progression and STAT3 activation could also be detected in vivo and in clinical GC tissues samples. Taken together, our results indicate that CD24 mediates gastric carcinogenesis and may promote GC progression by suppressing apoptosis and promoting invasion, with the activation of STAT3 playing a critical role.
    Apoptosis 12/2013; · 4.07 Impact Factor
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    ABSTRACT: Estrogen reportedly facilitates visceral nociception at the spinal or supraspinal level. The present study was aimed to investigate whether estrogen modulates visceral pain through vagal pathway. Ovariectomized rats received estradiol, which was subcutaneously (to act through both vagal and spinal pathways) or intraduodenally (to preferentially act through vagal pathway) administered. Luminally applied estradiol induced a rapid and significant decrease in the visceromotor response (VMR) to colorectal distension (CRD), with increased c-Fos expression in nodose ganglion neurons. Systemically injected estradiol increased VMR and c-Fos expression in both nodose and dorsal root ganglion (T6-12) neurons. The antinociceptive effect of estrogen was abolished by surgically vagotomy or chemical denervation of vagal afferents. Both luminally and systemically administered estradiol elicited selective 5-HT secretion from the duodenum. Granisetron, a 5-hydroxytryptamine 3 receptor (5-HT3R) antagonist, reversed the antinociceptive effect of estrogen. Intestinal mucosal mast cell (IMMC) stabilizers prevented estradiol-induced antinociception and 5-HT secretion. Ultrastructural analysis revealed that estradiol caused piecemeal degranulation of IMMCs. The actions of estradiol were inhibited by an estrogen receptor (ER) β antagonist and mimicked by an ERβ agonist. These results suggest that estrogen can trigger vagus-mediated antinociception, which is masked by its spinally mediated pronociception. This study is the first to show a vagus-mediated estrogenic antinociception, in which the non-genomic ERβ-mediated, IMMC-derived 5-HT/5-HT3R pathway is involved. This work may provide new insights into the sex hormone modulation of visceral sensitivity related to irritable bowel syndrome and indicate potential therapeutic targets to manage this disease.
    The journal of pain: official journal of the American Pain Society 11/2013; · 3.78 Impact Factor
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    ABSTRACT: Persistent infection with Helicobacter pylori (H.pylori) contributes to gastric diseases including chronic gastritis and gastric cancer. However, the pathogenesis of this carcinogenic bacterium has not been completely elucidated. Here, we report that H.pylori rapidly triggers STAT3 signaling and induces STAT3-dependent COX-2 expression both in vitro and in vivo. STAT3 upregulats COX-2 by binding to and increasing the activity of COX-2 promoter. COX-2 in turn regulates IL-6/STAT3 signaling under basal conditions and during H.pylori infection. These findings suggest that a positive feedback loop between STAT3 and COX-2 exists in the basal condition and H.pylori infectious condition. Immunohistochemical staining revealed that H.pylori-positive gastritis tissues exhibited markedly higher levels of pSTAT3(Tyr705) than H.pylori-negative ones. High pSTAT3(Tyr705) levels are correlated with intestinal metaplasia and dysplasia, suggesting pSTAT3(Tyr705) may be useful in the early detection of gastric tumorigenesis. Additionally, a strong positive correlation between STAT3/pSTAT3(Tyr705) levels and COX-2 expression was identified in gastritis and gastric cancer tissues. Together, these findings provide new evidence for a positive feedback loop between STAT3 signaling and COX-2 in H.pylori pathogenesis, and may lead to new approaches for early detection and effective therapy of gastric cancer. © 2013 Wiley Periodicals, Inc.
    International Journal of Cancer 10/2013; · 6.20 Impact Factor

Publication Stats

934 Citations
372.63 Total Impact Points

Institutions

  • 2014
    • Shanghai Cancer Institute
      Shanghai, Shanghai Shi, China
  • 2008–2014
    • Shanghai Jiao Tong University
      • • Institute of Digestive Disease
      • • Department of Gastroenterology and Hepatology (Renji)
      • • State Key Laboratory of Oncogenes and Related Genes
      • • Renji Hospital
      • • School of Medicine
      Shanghai, Shanghai Shi, China
    • Fourth Military Medical University
      Xi’an, Liaoning, China
  • 2008–2013
    • Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
      Shanghai, Shanghai Shi, China
  • 2002–2013
    • Renji Hospital
      Shanghai, Shanghai Shi, China
  • 2004
    • Second Military Medical University, Shanghai
      Shanghai, Shanghai Shi, China