A novel causal model for nasopharyngeal carcinoma.

The development of nasopharyngeal carcinoma (NPC) and its unique geographic distribution have long been attributed to a combination of dietary intake of salt-preserved fish, inherited susceptibility, and early-life infection with the Epstein-Barr virus (EBV). New findings from our large, rigorously designed, population-based case-control study of NPC in southern China have enabled substantial revision of this causal model. Here, we briefly summarize these results and provide an updated model of the etiology of NPC. Our new research identifies two EBV genetic variants that may be causally involved in the majority of NPC in southern China, and suggests the rise of modern environmental co-factors accompanying cultural and economic transformation in NPC-endemic regions. These discoveries can be translated directly into clinical and public health advances, including improvement of indoor air quality and oral health, development of an EBV vaccine, enhanced screening strategies, and improved risk prediction. Greater understanding of the roles of environmental, genetic, and viral risk factors can reveal the extent to which these agents act independently or jointly on NPC development. The history of NPC research demonstrates how epidemiology can shed light on the interplay of genes, environment, and infections in carcinogenesis, and how this knowledge can be harnessed for cancer prevention and control.

Synergistic effects ofα-Fe2O3nanoparticles and Fe-doping on gas-sensing performance of NiO nanowires and interface mechanism.

High surface area nickel oxide nanowires (NiO NWs), Fe-doped NiO NWs andα-Fe2O3/Fe-doped NiO NWs were synthesized with nanocasting pathway, and then the morphology, microstructure and components of all samples were characterized with XRD, TEM, EDS, UV-vis spectra and nitrogen adsorption-desorption isotherms. Owing to the uniform mesoporous template, all samples with the same diameter exhibit the similar mesoporous-structures. The loadedα-Fe2O3nanoparticles should exist in mesoporous channels between Fe-doped NiO NWs to form heterogeneous contact at the interface of n-typeα-Fe2O3nanoparticles and p-type NiO NWs. The gas-sensing results indicate that Fe-dopant andα-Fe2O3-loading both improve the gas-sensing performance of NiO NWs sensors.α-Fe2O3/Fe-doped NiO NWs sensors presented the highest response to 100 ppm ethanol gas (55.264) compared with Fe-doped NiO NWs (24.617) and NiO NWs sensors (3.189). The donor Fe-dopant increases the ground state resistance and the absorbed oxygen content in air.α-Fe2O3nanoparticles in electron depletion region result in the increasing resistance in ethanol gas and decreasing resistance in air. In this way,α-Fe2O3/Fe-doped NiO NWs sensor presents the excellent gas-sensing performance due to the formation of heterogeneous contact at the interface.

[Susceptibility genes and risk prediction model of cardiovascular toxicity related to antineoplastic therapy in tumor patients].

Cardiovascular toxicity of cancer patients in antineoplastic therapy is gradually paid widespread attention. Although many high-risk factors of cardiovascular toxicity associated with chemotherapy, targeted therapy or immunotherapy have been identified, it is still difficult to establish accurate risk prediction model. Traditional risk prediction model cannot adequately explain the differences in cardiovascular toxicity susceptibility among patients, makes it difficult to accurately screen high-risk groups, early diagnose and prevent cardiovascular toxicity. Finding susceptible genes of cardiovascular toxicity associated with antineoplastic therapy and incorporating single-nucleotide polymorphisms into risk prediction model can significantly improve the identification of high-risk population of cardiovascular toxicity.

[Epidemiological characteristics of leptospirosis in Sichuan province, 2004-2018].

Objective: To explore the epidemiological characteristics of leptospirosis in Sichuan province from 2004 to 2018, and provide evidence for the prevention and control of leptospirosis. Methods: The descriptive epidemiology analysis was conducted based on the epidemic data of leptospirosis collected from the national notifiable infectious disease reporting information system (NNIDRIS) and sentinel surveillance system in 11 areas in Sichuan from 2004 to 2018. The ArcGIS 10.2 software was used for mapping. The SaTScan 9.1.1 software was used to analyze spatiotemporal scanning and characteristics of temporal-spatial clusters of leptospirosis. Results: A total of 2 834 cases of leptospirosis, including 41 deaths, were reported in Sichuan from 2004 to 2018, and the reported morbidity rate was 0.23/100 000 and the mortality rate was 0.003/100 000. It revealed that leptospirosis had an overall downward fluctuated trend. The incidence of leptospirosis had obvious seasonality, mainly from the last ten-day of August to the end of September, 1-2 weeks later after rice harvesting time. The reported cases were mainly males, the male to female ratio of the cases was 2.05∶1. The incidence was higher in age group 50-65 years. The majority of reported cases were farmers, accounting for 82.75% (2 345/2 834), followed by students, accounting for 12.74% (361/2 834). However, rare cases in students had been reported since 2011. In recent years, the high-incidence areas were alternating between Mabian, Muchuan counties along the Yangtze River and Yilong county located in the Jialing River basin. According to the spatial-temporal descriptive analyses by SaTScan, there were two clustering areas in the province where most cases occurred (P<0.001). The average density of field rats in 11 sentinel surveillance areas was 5.44%(14 351/263 767), and the predominant field rats included Anourosorexsquamipes (69.07%), Apodemusagrarius (12.73%). Whatmore, the density of the Apodemusagrarius ranged from 4.60% to 0.19%, showing downward trend with the lowest level in 2018. The annual culture rate of Leptospira from rat kidney samples declined. During 2007-2018, the average positive rate of Leptospira antibodies in healthy people was 24.52%(3 271/13 339), and the predominant serogroup was Icterohaemorrhagiae. There was no replacement of Leptospira serogroup in recent years. Conclusions: The incidence of leptospirosis in Sichuan was extremely low during 2004-2018, and the incidence peak of leptospirosis occurred in rice harvesting period. The cases were mainly old farmers, and the high-risk areas were constantly alternating between the Yangtzi River and the Jialing River basin. Both the density and the carriage rate of Leptospira of Apodemusagrarius were low, and the predominant serogroup was Icterohaemorrhagiae. The average positive rate of leptospira antibodies in healthy people was very low.

BDNF activates TrkB/PLCγ1 signaling pathway to promote proliferation and invasion of ovarian cancer cells through inhibition of apoptosis.

OBJECTIVE: Abnormal expression and activation of tropomyosin-related kinase receptor B (TrkB) are observed in many pathological conditions, including many types of cancer. We try to explore the relationship between ovarian cancer and Brain-derived neurotrophic factor (BDNF), a ligand of TrkB. MATERIALS AND METHODS: Human ovarian cancer cell line SKOV-3 was used in this study. qPCR, immunohistochemistry, and immunoblot were used to assay BDNF and TrkB expression level. Scratch assay was used to test the cell motility, and transwell assay was used to test the cell migration ability. RESULTS: We found that BDNF promotes the proliferation and invasion of human ovarian cancer SKOV-3 cells depend on the activation of TrkB. To illuminate the downstream pathway of BDNF/TrkB, we silenced AKT1 and PLCγ1 by siRNA. The functional assay showed that activated PLCγ1 signaling pathway is necessary for the proliferation and invasion of cancer cells other than the AKT pathway. Further study showed that PLCγ1 could inhibit the apoptosis of cancer cells. CONCLUSIONS: BDNF triggers TrkB/PLCγ1 signaling pathway to promote proliferation and invasion of ovarian cancer cells through inhibition of apoptosis.

[Influence of fracture resistance of prosthesis with different thickness of ferrule restored with fiber post and resin core and crown].

Objective: To evaluate the influence of fracture resistance of endodontically treated teeth with different thickness of ferrule by mechanical fatigue test and static loading test, and so as to provide a reference for the clinical treatment planning. Methods: Fifty bovine incisors were divided into 5 groups by random number table method (n=10). Group A was the control group in which the incisors were prepared without a ferrule design (0 mm). The other four groups (B, C, D, E) were experimental groups, and the thickness of the dentin ferrule prepared for specimens in each group was 0.5, 1.0, 1.5, and 2.0 mm. The height of ferrules in all the specimens was 2 mm. Cyclic fatigue loading (2.33 Hz, 50 N) was applied on each specimen until either the specimen was dislodged/fractured or the 300 000 cycles were finished. After fatigue loading, the mode of failure was observed. Those intact specimen after fatigue loading were tested under a gradually increasing force using a universal testing machine (0.05 mm/min) until fracture occurred. The forces required to fracture and failure model was recorded. Results: The results of cyclic loading tests showed that: all specimens survived the 300 000 cycles of intermittent loading. The results of static loading tests showed that: the fracture force of A, B, C, D and E groups respectively were (226.4±67.7), (369.7±34.5), (400.7±48.2), (528.1±56.3), and (555.4±98.5) N (F=15.227, P=0.000). There was a significant difference in fracture resistance between group A and the other four groups, and between group B, C and group D, E (P<0.05). No statistical difference were found in fracture resistance among the other groups (P>0.05). There was strong correlation between the thickness of ferrule and the fracture force by Pearson correlation analysis (r=0.973, P=0.002). Conclusions: Within the limitations of this study, the following conclusions can be drawn: The different thickness of ferrule can influence the fracture resistance of the teeth, and when the height of the ferrule is 2.0 mm, the fracture force increased significantly with an increasing ferrule thickness.

[Expression of anaplastic lymphoma kinase fusion gene in patients with lung sarcomatoid carcinoma and treatment analysis].

Objective: To investigate the expression status of anaplastic lymphoma kinase (ALK) fusion gene in lung sarcomatoid carcinoma (LSC) and the role of ALK inhibitors for treatment. Methods: Total of 84 cases of LSC confirmed by histopathology were detected for ALK fusion gene from January 2011 to December 2014 in the Cancer Hospital of Chinese Academy of Medical Science&Peking Union Medical College and Shandong Zibo Wanjie Cancer Hospital. All patients were primarily treated by the multi-disciplinary mode in combination with chemotherapy or targeted therapy based on surgery. Postoperative adjuvant chemotherapy was given on platinum based two-drug combination regimen. In ALK fusion gene (+ ) patients with recurrence or metastasis, crizotinib target therapy was prefered. Chi-square test was applied for the comparison of 1, 3, 5-year survival rates between the two groups. Results: Eighty-two cases completed the follow-up. ALK fusion gene was found in 9(10.7%) patients. After application of crizotinib, 1 case was evaluated as complete remission, 6 cases as partial response, 2 cases as stable disease; the 1, 3, 5-year survival rate was 100% (9/9), 100% (9/9) and 88.9% (8/9) for the patients with ALK fusion gene, and it was 65.8% (48/73), 15.1% (11/73) and 6.8% (5/73) respectively for patients without ALK fusion gene. There was significant difference in the survival rate between the two groups (χ(2)=1.56, 1.56, 0.83, all P<0.05). Conclusion: ALK fusion gene maybe expressed in LSC patients. Compared with conventional chemotherapy, crizotinib can significantly prolong the survival time of patients with ALK fusion gene.

[Analysis of treatment and prognosis in post-operative patients with urachal carcinoma].

OBJECTIVE: Urachal carcinoma is a kind of urogenital tract malignancy with a very low incidence. The objective of this study was to observe the clinical presentation, pathological condition, treatment method and outcome of patients with urachal carcinoma. METHODS: A retrospective analysis of thirty-six cases of urachal carcinoma diagnosed over a period of 10 years from 2003 to 2013 was carried out. All pathologic specimens were reviewed by two separate pathologists. Clinical and histological features, treatment condition, patient follow-up and survival outcome was reviewed and calculated. RESULTS: The mean age at diagnosis was 53 years. Of the thirty-six patients, twenty-five were male. All patients underwent partial cystectomy with bilateral pelvic lymph node dissection. All cases were adenocarcinoma, including 20 mucinous adenocarcinoma, 7 moderately differentiated adenocarcinoma, 5 poorly differentiated adenocarcinoma, 1 signet ring cell carcinoma, 3 hybrid adenocarcinoma. The Sheldon pathologic stage was stage Ⅱ in 11, Ⅲ in 16 and Ⅳa in 9 cases. All patients received medical oncological therapy. The median follow-up period was 27 months. The median overall survival was 36 months. One-year survival rate was 70% and five-year survival rate was 28%. CONCLUSIONS: Urachal carcinomas are rare and usually at locally advanced stage at diagnosis with a high tendency of metastases. Surgery is a key method of primary treatment and medical oncological therapy may play a role in decreasing the chances of recurrence which still needs to be explained by prospective clinical trials.

Overexpression of maelstrom promotes bladder urothelial carcinoma cell aggressiveness by epigenetically downregulating MTSS1 through DNMT3B.

We have recently identified and characterized a novel oncogene, maelstrom (MAEL) from 1q24, in the pathogenesis of hepatocellular carcinoma. In this study, MAEL was investigated for its oncogenic role in urothelial carcinoma of the bladder (UCB) tumorigenesis/aggressiveness and underlying molecular mechanisms. Here, we report that overexpression of MAEL in UCB is important in the acquisition of an aggressive and/or poor prognostic phenotype. In UCB cell lines, knockdown of MAEL by short hairpin RNA is sufficient to inhibit cell growth, invasiveness/metastasis and suppressed epithelial-mesenchymal transition (EMT), whereas ectopic overexpression of MAEL promoted cell growth, invasive and/or metastatic capacity and enhanced EMT both in vitro and in vivo. We further demonstrate that MAEL could induce UCB cell EMT by downregulating a critical downstream target, the metastasis suppressor 1 (MTSS1) gene, ultimately leading to an increased invasiveness of cancer cells. Notably, overexpression of MAEL in UCB cells substantially enhanced the enrichment of DNA methyltrans-ferase (DNMT)3B and histone deacetylase (HDAC)1/2 on the promoter of the MTSS1, and thereby epigenetically suppressing the MTSS1 transcription. Downregulation of MTSS1 by MAEL in UCB cells is partially dependent on DNMT3B. Furthermore, we identify that beside the gene amplification of MAEL, miR-186 is a key negative regulator of MAEL and downregulation of miR-186 is another important mechanism for MAEL overexpression in UCBs. These data suggest that overexpression of MAEL, caused by gene amplification and/or decreased miR-186, has a critical oncogenic role in UCB pathogenesis by downregulation of MTSS1, and MAEL could be used as a novel prognostic marker and/or effective therapeutic target for human UCB.

Mapping quantitative trait loci for sheath blight disease resistance in Yangdao 4 rice.

Rice sheath blight (ShB), which is caused by Rhizoctonia solani, has become the most serious rice disease in China. Yangdao 4, a cultivar with partial resistance to ShB, was crossed with Lemont, a susceptible cultivar, to develop mapping populations that were used to analyze quantitative trait loci (QTL) that confer resistance to ShB. QTL analysis were performed in 3 environments (E1-E3) using 2 F2 and 1 F2:3 populations, respectively. Three traits were recorded to evaluate ShB resistance, including disease rating (DR), lesion height (LH), and percentage of lesion height (PLH). Based on field evaluation of ShB resistance and the 2 genetic maps constructed, we identified a total of 8 QTLs for DR (4 in E1, 4 in E2, and 3 in E3), 6 QTLs for LH (1 in E1, 3 in E2, and 2 in E3), and 7 QTLs for PLH (1 in E1, 4 in E2, and 2 in E3). Sixteen of the ShB-QTLs co-localized as 6 clusters on chromosomes 3, 7, 11, and 12. Four of the 6 clusters contained ShB-QTLs that were detected in 2 environments, while the other 2 clusters with ShB-QTLs were detected in 1 environment. Three ShB-QTLs (qSBD-3-2, qSBL-3-1, and qSBPL-3-1) were delimited to a 581-kb region flanked by markers D333B and D334 on chromosome 3. The resistance alleles of Yangdao 4 at the qSBD-3-2 locus decreased DR by 0.68 and 0.79 in E2 and E3, respectively.

MiR-29c mediates epithelial-to-mesenchymal transition in human colorectal carcinoma metastasis via PTP4A and GNA13 regulation of ß-catenin signaling.

BACKGROUND: Distant metastasis is the major cause of cancer-related death, and epithelial-to-mesenchymal transition (EMT) has a critical role in this process. Accumulating evidence indicates that EMT can be regulated by microRNAs (miRNAs). miR-29c has been implicated as a tumor suppressor in several human cancers. However, the role of miR-29c in the progression of colorectal cancer (CRC) metastasis remains largely unknown. PATIENTS AND METHODS: The expression of miR-29c was examined by qRT-PCR in a cohort of primary CRC (PC) and distant liver metastasis (LM) tissues. A series of in vivo and in vitro assays were carried out in order to elucidate the functions of miR-29c and the molecular mechanisms underlying the pathogenesis of metastatic CRC. RESULTS: miR-29c was markedly downregulated in PCs with distant metastasis and determined to be an independent predictor of shortened patient survival. But LM tissues showed higher levels of miR-29c than that in PC tissues. In CRC cells, miR-29c dramatically suppressed cell migration and invasion abilities in vitro and cancer metastasis in vivo. In addition, miR-29c inhibited EMT and negatively regulated Wnt/ß-catenin signaling pathway. Guanine nucleotide binding protein alpha13 (GNA13) and protein tyrosine phosphatase type IVA (PTP4A) were identified as direct targets of miR-29c, which acted through ERK/GSK3ß/ß-catenin and AKT/GSK3ß/ß-catenin pathways, respectively, to regulate EMT. Furthermore, significant associations between miR-29c, its target genes (GNA13 and PTP4A) and EMT markers were validated in both PC and LM tissues. CONCLUSION: Our findings highlight the important role of miR-29c in regulating CRC EMT via GSK-3ß/ß-catenin signaling by targeting GNA13 and PTP4A and provide new insights into the metastatic basis of CRC.

Development of 1047 insertion-deletion markers for rice genetic studies and breeding.

In this study, a total of 1047 insertion-deletion (InDel) primer pairs distributed across the rice genome were developed and experimentally validated. The primer pairs were designed based on the InDel length polymorphisms between 93-11 (Oryza sativa ssp indica cv.) and Nipponbare (Oryza sativa ssp japonica cv.), aiming for utilization between indica and japonica rice, or between other inter-subspecific rice cultivars. The 1047 primer pairs were dispersed across all 12 of the rice chromosomes, with one InDel marker found every 371.3 kb on average. The InDel length of the markers varied from 3 to 39 bp: 88.2% of the markers contained 6 to 25 bp, only 6.2% of markers were ≤ 5 bp, and 5.6% were ≥ 26 bp. Six hundred and twenty-three (59.5%) of the 1047 InDel markers were shown to amplify well and were polymorphic between Taichung65 and IR8, and 476 (45.5%) markers were polymorphic between Lemont and Yangdao4, while 398 (38.0%) were polymorphic in both combinations. These results demonstrated that the polymerase chain reaction-based InDel markers developed in this study could be of immediate use for rice genetic studies and breeding programs.

Foxo3a transcription factor is a negative regulator of Skp2 and Skp2 SCF complex.

Skp2 (S-phase kinase-associated protein-2) SCF complex displays E3 ligase activity and oncogenic activity by regulating protein ubiquitination and degradation, in turn regulating cell cycle entry, senescence and tumorigenesis. The maintenance of the integrity of Skp2 SCF complex is critical for its E3 ligase activity. The Skp2 F-box protein is a rate-limiting step and key factor in this complex, which binds to its protein substrates and triggers ubiquitination and degradation of its substrates. Skp2 is found to be overexpressed in numerous human cancers, which has an important role in tumorigenesis. The molecular mechanism by which the function of Skp2 and Skp2 SCF complex is regulated remains largely unknown. Here we show that Foxo3a transcription factor is a novel and negative regulator of Skp2 SCF complex. Foxo3a is found to be a transcriptional repressor of Skp2 gene expression by directly binding to the Skp2 promoter, thereby inhibiting Skp2 protein expression. Surprisingly, we found for the first time that Foxo3a also displays a transcription-independent activity by directly interacting with Skp2 and disrupting Skp2 SCF complex formation, in turn inhibiting Skp2 SCF E3 ligase activity and promoting p27 stability. Finally, we show that the oncogenic activity of Skp2 is repressed by Foxo3a overexpression. Our results not only reveal novel insights into how Skp2 SCF complex is regulated, but also establish a new role for Foxo3a in tumor suppression through a transcription-dependent and independent manner.

Anthracyclines disrupt telomere maintenance by telomerase through inducing PinX1 ubiquitination and degradation.

Telomere maintenance is essential for cancer growth. Induction of telomere dysfunction, for example, by inhibition of telomeric proteins or telomerase, has been shown to strongly enhance cancer cells' sensitivity to chemotherapies. However, it is not clear whether modulations of telomere maintenance constitute cancer cellular responses to chemotherapies. Furthermore, the manner in which anti-cancer drugs affect telomere function remains unknown. In this study, we show that anthracyclines, a class of anti-cancer drugs widely used in clinical cancer treatments, have an active role in triggering telomere dysfunction specifically in telomerase-positive cancer cells. Anthracyclines interrupt telomere maintenance by telomerase through the downregulation of PinX1, a protein factor responsible for targeting telomerase onto telomeres, thereby inhibiting telomerase association with telomeres. We further demonstrate that anthracyclines downregulate PinX1 by inducing this protein degradation through the ubiquitin-proteasome-dependent pathway. Our data not only reveal a novel action for anthracyclines as telomerase functional inhibitors but also provide a clue for the development of novel anti-cancer drugs based on telomerase/telomere targeting, which is actively investigated by many current studies.

EZH2 supports nasopharyngeal carcinoma cell aggressiveness by forming a co-repressor complex with HDAC1/HDAC2 and Snail to inhibit E-cadherin.

The enhancer of zeste homolog 2 (EZH2) is upregulated and has an oncogenic role in several types of human cancer. However, the abnormalities of EZH2 and its underlying mechanisms in the pathogenesis of nasopharyngeal carcinoma (NPC) remain unknown. In this study, we found that high expression of EZH2 in NPC was associated closely with an aggressive and/or poor prognostic phenotype (P<0.05). In NPC cell lines, knockdown of EZH2 by short hairpin RNA was sufficient to inhibit cell invasiveness/metastasis both in vitro and in vivo, whereas ectopic overexpression of EZH2 supported NPC cell invasive capacity with a decreased expression of E-cadherin. In addition, ablation of endogenous Snail in NPC cells virtually totally prevented the repressive activity of EZH2 to E-cadherin, indicating that Snail might be a predominant mediator of EZH2 to suppress E-cadherin. Furthermore, co-immunoprecipitation (IP), chromatin IP and luciferase reporter assays demonstrated that in NPC cells, (1) EZH2 interacted with HDAC1/HDAC2 and Snail to form a repressive complex; (2) these components interact in a linear fashion, not in a triangular fashion, that is, HDAC1 or HDAC2 bridge the interaction between EZH2 and Snail; and (3) the EZH2/HDAC1/2/Snail complex could closely bind to the E-cadherin promoter by Snail, but not YY1, to repress E-cadherin. The data provided in this report suggest a critical role of EZH2 in the control of cell invasion and/or metastasis by forming a co-repressor complex with HDAC1/HDAC2/Snail to repress E-cadherin, an activity that might be responsible, at least in part, for the development and/or progression of human NPCs.

hSSB1 binds and protects p21 from ubiquitin-mediated degradation and positively correlates with p21 in human hepatocellular carcinomas.

Downregulation of hSSB1, a single-stranded DNA-binding protein, causes increased radiosensitivity, defective checkpoint activation and genomic instability. However, the mechanisms of hSSB1 function in these responses remain to be uncovered. Here, we present evidence that hSSB1 directly binds p21 and this interaction may prevent p21 from ubiquitin-mediated degradation. Furthermore, both promotion of the G1/S transition and abrogation of the G2/M checkpoints induced by hSSB1 knockdown are partially dependent on p21. Most importantly, hSSB1 and p21 levels are positively correlated in human hepatocellular carcinomas (HCC), as determined by immunostaining. Therefore, hSSB1 may positively modulate p21 to regulate cell cycle progression and DNA damage response, implicating hSSB1 as a novel, promising therapeutic target for cancers such as HCC.

PKB/Akt promotes DSB repair in cancer cells through upregulating Mre11 expression following ionizing radiation.

An elevated DNA-repair capacity in cancer cells leads to radiation resistance and severely limits the efficacy of radiation therapy. Activation of Akt is tightly associated with resistance to radiotherapy, and Mre11 protein has important role during the repair of DNA double-strand breaks (DSBs). In this report, our results showed that inhibition of Akt activity impaired the repair of DSBs in CNE2 cells, whereas activated Akt promoted the repair of DSBs in HeLa cells. Knockdown of Mre11 also impaired the process of DSB repair in both these two cell lines. More importantly, we found that Akt could regulate Mre11 expression. Inhibition of Akt activity by small interfering RNA or LY294002 efficiently downregulated the Mre11 expression in CNE2 cells, and transfection with myr-Akt plasmid in HeLa cells upregulated the Mre11 expression. In addition, luciferase reporter analysis revealed that Mre11 reporter activity increased after transfection with myr-Akt1 plasmids, and this myr-Akt1-induced transcriptional activity was blocked in the presence of LY294002. Further study showed GSK3ß/ß-catenin/LEF-1 pathway was involved in this regulation. Knockdown of ß-catenin or LEF-1 led to the downregulation of Mre11, whereas overexpression of ß-catenin led to upregulation of Mre11. The chromatin immunoprecipitation assay assay showed ß-catenin/LEF-1 heterodimer could directly bind to the promoter of Mre11 in vivo. And the luciferase activity of the pGL3-Mre11 and pGL3-Lef increased in HeLa cells following ß-catenin plasmid co-transfected, but was abolished when the LEF-1-binding conserved sequences of Mre11 promoter were mutated. These results together support Akt can upregulate the expression of Mre11 through GSK3ß/ ß-catenin/LEF pathway to elevate DSB-repair capacity in cancer cells.

Overexpression of AIB1 negatively affects survival of surgically resected non-small-cell lung cancer patients.

BACKGROUND: The amplified in breast cancer 1 (AIB1) gene has been considered to play an oncogenic role in human cancers, but its clinical/prognostic significance in non-small-cell lung cancer (NSCLC) is still unclear. PATIENTS AND METHODS: The methods of immunohistochemistry and FISH were utilized to examine protein expression and amplification of AIB1 in 230 informative surgically resected NSCLCs and in 30 samples of normal lung tissues. RESULTS: Overexpression and amplification of AIB1 were found in 48.3% and 8.2% of NSCLCs, respectively. AIB1 overexpression was associated with AIB1 gene amplification and cell proliferation but not related to estrogen receptor (ER)-alpha, ER-beta, progesterone receptor or androgen receptor status. A positive correlation between AIB1 overexpression and an ascending pathologic node stage in lung adenocarcinoma (ADC) was observed (P = 0.043). Univariate survival analysis demonstrated a significant association of AIB1 overexpression with shortened patient survival, especially for those with stage III disease (P < 0.001). Importantly, AIB1 expression was evaluated as the most significant predictor for survival in multivariate analysis (hazards ratio = 2.069, P < 0.001). CONCLUSION: Overexpression of AIB1 might provide a selective advantage for lymph node metastasis of lung ADC and serve as a useful biomarker for poor prognosis for NSCLC patients.

The pivotal role of c-Jun NH2-terminal kinase-mediated Beclin 1 expression during anticancer agents-induced autophagy in cancer cells.

The c-Jun NH2-terminal kinase (JNK) pathway represents one subgroup of MAP kinases that are activated primarily by cytokines and exposure to environmental stress. Autophagy is a protein-degradation system characterized by the formation of double-membrane vacuoles termed autophagosomes. Autophagy-related gene beclin 1 plays a key role in autophagosome formation. However, the relationships between activation of JNK pathway, autophagy induction and Beclin 1 expression remain elusive. In this study, we used human cancer cell lines CNE2 and Hep3B to investigate the role of JNK-mediated Beclin 1 expression in ceramide-induced autophagic cell death. Ceramide-treated cells exhibited the characteristics of autophagy (that is, acidic vesicular organelle formation and the LC3-II generation). JNK was activated in these two cell lines exposed to ceramide and the phosphorylation of c-Jun also increased. In the meantime, we found that ceramide upregulated Beclin 1 expression in cancer cells. The upregulation of Beclin 1 expression could be blocked by SP600125 (a specific inhibitor of JNK) or a small interfering RNA (siRNA) directed against JNK1/2 or c-Jun. Chromatin immunoprecipitation and luciferase reporter analysis revealed that c-Jun was involved in the regulation of beclin 1 transcription in response to ceramide treatment. In addition, inhibition of JNK activity by SP600125 could inhibit autophagy induction by ceramide. Furthermore, Beclin 1 knockdown by siRNA also inhibited ceramide-mediated autophagic cell death. JNK-mediated Beclin 1 expression was also observed in topotecan-induced autophagy. These data suggest that activation of JNK pathway can mediate Beclin 1 expression, which plays a key role in autophagic cell death in cancer cells.

Epigenetic disruption of interferon-gamma response through silencing the tumor suppressor interferon regulatory factor 8 in nasopharyngeal, esophageal and multiple other carcinomas.

16q24 is frequently deleted in multiple tumors including cancers of nasopharynx, esophagus, breast, prostate and liver. By array comparative genomic hybridization (aCGH), we refined a 16q24 hemizygous deletion in nasopharyngeal carcinoma (NPC) cell lines. Semi-quantitative RT-PCR analysis revealed interferon regulatory factor 8 (IRF8) as the only downregulated gene within this deletion. IRF8 belongs to a family of interferon (IFN) regulatory factors that modulate various important physiologic processes including host defense, cell growth and differentiation and immune regulation. In contrast to the broad expression of IRF8 in normal adult and fetal tissues, transcriptional silencing and promoter methylation of IRF8 were frequently detected in multiple carcinoma (except for hepatocellular) cell lines (100% in NPC, 88% in esophageal and 18-78% in other carcinoma cell lines) and in a large collection of primary carcinomas (78% in NPC, 36-71% in other carcinomas). Methylation of the IRF8 promoter led to the disruption of its response to IFN-gamma stimulation. Pharmacological and genetic demethylation could restore IRF8 expression, indicating a direct epigenetic mechanism. Ectopic expression of IRF8 in tumor cells lacking its expression strongly inhibited their clonogenicity, confirming its tumor suppressor function. Thus, IRF8 was identified as a functional tumor suppressor, which is frequently silenced by epigenetic mechanism in multiple carcinomas.