IRE1α Expedites the Progression of Castration-Resistant Prostate Cancers via the Positive Feedback Loop of IRE1α/IL-6/AR.

Castration-resistant prostate cancer (CRPC) is the lethal form of prostate cancer (PCa), and the underlying molecular mechanism has not been fully elucidated. Inositol requiring enzyme 1 alpha (IRE1α), a key regulator of unfolded protein response (UPR), is intimately associated with PCa progression. However, whether IRE1α is implicated in CRPC development remains unknown. Here, we showed that IRE1α expression was significantly increased in CRPC tissues and high-grade PCa tissues. Overexpression of IRE1α promoted PCa cell proliferation under the androgen deficiency condition in vitro and in vivo. Mechanistically, increased IRE1α expression induced IL-6 secretion via the IRE1α/XBP-1s signal pathway. IRE1α-induced IL-6 activated androgen receptor (AR), and the activation of AR by IL-6, in turn, promoted IRE1α expression. IRE1α formed a positive feedback loop with IL-6 and AR to promote prostate cancer cell proliferation under the androgen-deficient condition. In clinical PCa samples, high IRE1α expression correlated with elevated IL-6 and increased PSA expression. Our findings demonstrated a novel mechanism of CRPC progression and suggest targeting IRE1α may be a potential target for the prevention and treatment of CRPC.

Mitochondrial fission-induced mtDNA stress promotes tumor-associated macrophage infiltration and HCC progression.

Tumor-associated macrophages (TAMs) contribute to hepatocellular carcinoma (HCC) progression. However, the molecular mechanism underlying the infiltration of TAMs into HCC microenvironment is largely unclear. Recent studies have reported that alteration of mitochondrial nucleoid structures induces mitochondrial DNA (mtDNA) release into the cytosol, which is recognized as mtDNA stress, and consequently regulates innate immunity. Here we aimed to investigate whether mitochondrial fission induces mtDNA stress and then promotes TAM infiltration and HCC progression. Confocal microscopy and real-time PCR were used to detect cytosolic mtDNA content in HCC cells. The relationship between the expression of mitochondrial fission key regulator dynamin-related protein 1 (Drp1) and the percentage of CD163 (a marker of TAMs)-positive cells was investigated in HCC tissues using immunohistochemistry. Finally, the effect of Drp1 overexpression in HCC cells on recruitment and polarization of TAMs was investigated. Our data showed that increased Drp1 expression was positively correlated with the infiltration of TAMs into HCC tissues. Drp1-mediated mitochondrial fission induced the cytosolic mtDNA stress to enhance the CCL2 secretion from HCC cells by TLR9-mediated NF-κB signaling pathway, and thus promoted the TAM recruitment and polarization. Depleting cytosolic mtDNA using DNase I or blocking TLR9 pathway by TLR9 antagonist, siRNA for TLR9 or p65 in HCC cells with Drp1 overexpression significantly decreased the recruitment and polarization of TAMs. Blocking CCR2 by antagonist significantly reduced TAM infiltration and suppressed HCC progression in mouse model. In conclusion, our findings reveal a novel mechanism of TAM infiltration in HCC by mitochondrial fission-induced mtDNA stress.

An orally-active adiponectin receptor agonist mitigates cutaneous fibrosis, inflammation and microvascular pathology in a murine model of systemic sclerosis.

The hallmarks of systemic sclerosis (SSc) are autoimmunity, microangiopathy and fibrosis. Skin fibrosis is accompanied by attrition of the dermal white adipose tissue layer, and alterations in the levels and function of adiponectin. Since these findings potentially implicate adiponectin in the pathogenesis of SSc, we employed a novel pharmacological approach to augment adiponectin signaling using AdipoRon, an orally active adiponectin receptor agonist. Chronic treatment with AdipoRon significantly ameliorated bleomycin-induced dermal fibrosis in mice. AdipoRon attenuated fibroblast activation, adipocyte-to-myofibroblast transdifferentiation, Th2/Th17-skewed polarization of the immune response, vascular injury and endothelial-to-mesenchymal transition within the lesional skin. In vitro, AdipoRon abrogated profibrotic responses elicited by TGF-ß in normal fibroblasts, and reversed the inherently-activated profibrotic phenotype of SSc fibroblasts. In view of these broadly beneficial effects on all three cardinal pathomechanisms underlying the clinical manifestations of SSc, pharmacological augmentation of adiponectin signaling might represent a novel strategy for the treatment of SSc.

Hsp60 exerts a tumor suppressor function by inducing cell differentiation and inhibiting invasion in hepatocellular carcinoma.

Heat shock protein 60 (Hsp60), a typical mitochondrial chaperone, is associated with progression of various cancers. However, its expression and significance in hepatocellular carcinoma (HCC) remain largely unclear. In the present study, the mRNA and protein expression of Hsp60 in HCC tissues were detected by quantitative RT-PCR (n=24), western blot (n=7), and immunohistochemical staining (n=295), respectively. The correlation between Hsp60 expression and clinicopathological characteristics of HCC patient was also analyzed. Meanwhile, the influence of Hsp60 on malignant phenotype of HCC cells was further investigated. We found that expression of Hsp60 was significantly downregulated in HCC tissues compared to peritumor tissues. Hsp60 expression was significantly correlated with serum alpha -foetoprotein (AFP) level and tumor differentiation grade. Moreover, high Hsp60 expression cancer/pericancer (C/P) ratio was associated with a better overall survival rate (P=0.035, n=295). The prognostic implication of Hsp60 in HCC was further confirmed in another cohort of 107 HCC patients (P=0.027). Up-regulation of Hsp60 remarkably induced the cell differentiation and inhibited the invasive potential of HCC in vitro and in vivo. Intriguingly, the down-regulation of Hsp60 significantly impaired mitochondrial biogenesis. Although more data are required to clarify the underling mechanism responsible for function of Hsp60, our results suggested that the effect of Hsp60 on differentiation and invasion of HCC cells might be associated with mitochondrial biogenesis. Collectively, our findings indicated that Hsp60 exerted a tumor suppressor function, and might serve as a potential therapeutic target in the treatment of HCC.

High leukocyte mtDNA content contributes to poor prognosis through ROS-mediated immunosuppression in hepatocellular carcinoma patients.

Compelling epidemiological evidences indicate a significant association between leukocyte mitochondrial DNA (mtDNA) content and incidence risk of several malignancies, including hepatocellular carcinoma (HCC). However, whether leukocyte mtDNA content affect prognosis of HCC patients and underlying mechanism has never been explored. In our study, leukocyte mtDNA content was measured in 618 HCC patients and its prognostic value was analyzed. Moreover, we detected the immunophenotypes of peripheral blood mononuclear cells (PBMCs) and plasma concentrations of several cytokines in 40 HCC patients and assessed the modulating effects of mtDNA content on immunosuppression in cell models. Our results showed that HCC patients with high leukocyte mtDNA content exhibited a significantly worse recurrence-free survival (RFS) and overall survival (OS) than those with low leukocyte mtDNA content. Leukocyte mtDNA content and TNM stage exhibited a notable joint effect in prognosis prediction. Furthermore, we found that patients with high leukocyte mtDNA content exhibited a higher frequency of CD4+CD25+FOXP3+ regulatory T (Treg) cells and lower frequency of NK cells in PBMCs and had higher TGF-ß1 and lower TNF-α and IFN-γ plasma concentration when compared with those with low leukocyte mtDNA content, which suggests an immunosuppressive status. High leukocyte mtDNA content significantly enhanced the ROS-mediated secretion of TGF-ß1, which accounted for higher Treg and lower NK frequency in PBMCs. In a conclusion, our study for the first time demonstrates that leukocyte mtDNA content is an independent prognostic marker complementing TNM stage and associated with an ROS-mediated immunosuppressive phenotype in HCC patients.

Toll-like Receptor 9 Signaling Is Augmented in Systemic Sclerosis and Elicits Transforming Growth Factor ß-Dependent Fibroblast Activation.

OBJECTIVE: Although transforming growth factor ß (TGFß) is recognized as being a key trigger of fibroblast activation in systemic sclerosis (SSc), prominent innate immunity suggests that additional pathways contribute to disease persistence. Toll-like receptor 9 (TLR9) is implicated in autoimmunity and fibrosis; however, the expression, mechanism of action, and pathogenic role of TLR9 signaling in SSc remain uncharacterized. The aim of this study was to explore the expression, activity, and potential pathogenic role of TLR9 in the context of skin fibrosis in SSc and in mouse models of experimental fibrosis. METHODS: Expression and localization of TLR9 were evaluated in SSc skin biopsy specimens and explanted skin fibroblasts. Fibrotic responses elicited by type A CpG oligonucleotide and mitochondrial DNA (mtDNA) were examined in human skin fibroblasts by a combination of real-time quantitative polymerase chain reaction, Western blot analysis, transient transfection, immunofluorescence microscopy, and functional assays. Expression of TLR9 was examined in 2 distinct mouse models of experimental fibrosis. RESULTS: Skin biopsy specimens obtained from 2 independent cohorts of SSc patients showed up-regulation of TLR9, and myofibroblasts were the major cellular source. Moreover, SSc skin biopsy specimens showed evidence of TLR9 pathway activation. CpG induced robust TLR9-dependent fibrotic responses in explanted normal fibroblasts that could be blocked by bortezomib and were mediated through the action of endogenous TGFß. Mice with experimental fibrosis showed a time-dependent increase in TLR9 localized primarily to myofibroblasts in the dermis. CONCLUSION: In isolated fibroblasts, TLR9 elicits fibrotic responses mediated via endogenous TGFß. In patients with SSc, mtDNA and other damage-associated TLR9 ligands in the skin might trigger localized activation of TLR9 signaling, TGFß production, and consequent fibroblast activation. Disrupting this fibrotic process with inhibitors targeting TLR9 or its downstream signaling pathways might therefore represent a novel approach to SSc therapy.

Ultrathin PdTe nanowires anchoring reduced graphene oxide cathodes for efficient hydrogen evolution reaction.

The design and synthesis of efficient electrocatalysts for hydrogen evolution reaction under all pH conditions is extremely desirable but still remains a challenge. Here a facile method to decorate PdTe nanowires on reduced graphene oxide nanosheets (PdTe NWs/rGO) has been developed. As a robust integrated 2D hydrogen-evolving cathode catalyst, the Pd3.02Te NWs/rGO shows a low onset potential of -7 mV and maintains its catalytic activity for at least 48 h in alkaline media. It requires overpotentials (η) of 97 and 355 mV to afford current densities of 10 and 100 mA cm(-2), respectively. The Pd3.02Te NWs/rGO also exhibits a high activity and excellent durability in acidic media.

Polymorphisms in Genes of Tricarboxylic Acid Cycle Key Enzymes Are Associated with Early Recurrence of Hepatocellular Carcinoma.

Alterations of activity and expression in tricarboxylic acid (TCA) cycle key enzymes have been indicated in several malignancies, including hepatocellular carcinoma (HCC). They play an important role in the progression of cancer. However, the impact of single nucleotide polymorphisms (SNPs) in genes encoding these key enzymes on the recurrence of HCC has not been investigated. In this study, we genotyped 17 SNPs in genes encoding TCA cycle key enzymes and analyzed their association with recurrence-free survival (RFS) in a cohort of 492 Chinese HCC patients by Cox proportional hazard model and survival tree analysis. We identified 7 SNPs in SDHC, SDHD, FH, and IDH2 genes to be significantly associated with the RFS of HCC patients. Moreover, all these SNPs were associated with the early recurrence (within 2 years after surgery) risk of diseases. Cumulative effect analysis showed that these SNPs exhibited a dose-dependent effect on the overall and early recurrence. Further stratified analysis suggested that number of risk genotypes modified the protective effect on HCC recurrence conferred by transcatheter arterial chemoembolization treatment. Finally, the survival tree analysis revealed that SNP rs10789859 in SDHD gene was the primary factor contributing to HCC recurrence in our population. To the best of our knowledge, we for the first time observed the association between SNPs in genes encoding TCA cycle key enzymes and HCC recurrence risk. Further observational and functional studies are needed to validate our findings and generalize its clinical usage.

Genetic variants in genes of tricarboxylic acid cycle key enzymes are associated with prognosis of patients with non-small cell lung cancer.

INTRODUCTION: Non-small cell lung cancer (NSCLC) is characterized by poor prognosis and only a few molecular markers may be potentially used to predict the outcome. Metabolic reprogramming is a hallmark of cancer, including the alterations of tricarboxylic acid (TCA) cycle key enzymes. However, the significance of single nucleotide polymorphisms (SNPs) in genes encoding these key enzymes has not been investigated in NSCLC. PATIENTS AND METHODS: In this study, we genotyped 18 potentially functional SNPs in 7 genes belonging to 3 TCA cycle enzyme families (SDH, FH and IDH) using Sequenom iPLEX genotyping system in a cohort of 500 NSCLC patients. Multivariate Cox proportional hazards model and Kaplan-Meier curve were used for the survival analysis. RESULTS: Our results showed that SDHC gene: SNP rs12064957, IDH2 gene: SNP rs11540478 and FH gene: SNP rs1414493 were associated with overall survival (OS) and SDHA gene: SNP rs13173911, IDH2 gene: SNP rs4932158 were associated with recurrence-free survival (RFS) of NSCLC patients. Unfavorable genotypes of these SNPs showed a significant cumulative effect on OS and RFS of NSCLC patients (both P<0.001). Furthermore, survival tree analysis indicated that FH: rs1414493 was the primary risk factor contributing to OS of NSCLC patients and the IDH2: rs4932158 was the primary risk factor contributing to RFS of NSCLC patients. CONCLUSION: Our data suggest that SNPs in TCA cycle key enzyme genes may serve as potential biomarkers to predict the outcomes of NSCLC. Further studies with different ethnicities are needed to validate our findings and generalize their clinical utility.

Genetic variations in monocarboxylate transporter genes as predictors of clinical outcomes in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is characterized by poor prognosis and only a few molecular markers may be potentially used to predict clinical outcomes. Previous studies have demonstrated that monocarboxylate transporters (MCTs) play important roles in the development and progression of many cancers. The purpose of this study was to assess the effects of single nucleotide polymorphisms (SNPs) of MCT genes on prognosis of NSCLC patients in Chinese Han population. Nine functional SNPs in MCT1, MCT2, and MCT4 genes were selected and genotyped using Sequenom iPLEX genotyping system in 500 Chinese NSCLC patients receiving surgery. Multivariate Cox proportional hazards model and Kaplan-Meier curve were used for the prognostic analysis. TT genotype of SNP rs1049434 (MCT1) was significantly associated with better overall survival (OS) (HR = 0.56, P = 0.026) and recurrence-free survival (RFS) (HR = 0.57, P = 0.016) of NSCLC patients. TT genotype of another SNP rs995343 (MCT2) exhibited an association with worse RFS of NSCLC patients (HR = 1.46, P = .039). Unfavorable genotypes of SNP rs1049434 and rs995343 showed a significant cumulative effect on OS and RFS of NSCLC patients. Moreover, we found that patients carrying AA+AT genotypes of rs1049434 showed significant OS and RFS benefits from adjuvant chemotherapy, but those with TT genotype did not. Our findings suggest that SNPs in MCT1 and MCT2 genes may affect clinical outcomes and can be used to predict the response to adjuvant chemotherapy in NSCLC patients who received surgical treatment once validated in future study.

Loss of CD155 expression predicts poor prognosis in hepatocellular carcinoma.

AIMS: CD155 is an important ligand in triggering tumour rejection by immune cells. However, the expression of CD155 and its clinical significance in hepatocellular carcinoma (HCC) remains unknown. METHODS AND RESULTS: We examined the expression level of CD155 in 174 HCC tissue samples by immunohistochemical staining and in HCC cell lines by flow cytometry; 63.8% (111 of 174) of HCC tissue samples showed negative CD155 expression. When compared with adjacent peritumour tissues, HCC tissues exhibited a significantly lower expression of CD155 (P < 0.001). Flow cytometry analysis indicated that HCC cell lines had low levels of CD155 expression. Moreover, negative CD155 expression was associated significantly with higher serum α-fetoprotein level (P = 0.016) and a higher incidence of portal vein tumour thrombus (P = 0.050). Importantly, patients with positive CD155 expression had better overall survival after surgery than those with negative CD155 expression (P = 0.005). Furthermore, Cox regression analyses showed that CD155 expression was an independent prognostic factor for HCC (P = 0.049). CONCLUSIONS: Our findings suggest that loss of CD155 expression may play an important role in the immune escape of HCC cells and thus CD155 may serve as a prognostic marker as well as a potential therapeutic target for HCC.

Low expression of CD112 is associated with poor overall survival in patients with hepatocellular carcinoma.

CD112 as an important ligand of CD226 can stimulate the natural killer (NK) cell-mediated target cell lysis. Previous studies have reported that CD112 is involved in cancer initiation and progression. However, its expression and clinical significance in hepatocellular carcinoma (HCC) have never been investigated. In this study, we used immunohistochemistry to examine CD112 expression in cancer and pericancer tissues from 159 HCC cases. Western blot and immunofluorescence were used to detect CD112 expression in HCC cell lines. χ(2) Test was used to assess the association of CD112 expression with clinicopathological characteristics, whereas Kaplan-Meier survival function and Cox proportional hazards regression model were used to explore the association between CD112 expression and clinical outcome of patients with HCC. Overall, CD112 expression was significantly reduced in HCC tissues when compared with adjacent pericancer liver tissues (P < .001). Western blot and immunofluorescence analyses showed that most HCC cell lines had low CD112 expression level. Furthermore, low CD112 expression was significantly associated with high serum α-fetoprotein level (P = .004) in patients with HCC. Kaplan-Meier analysis showed that patients with low CD112 expression had poorer postsurgery overall survival than those with high CD112 expression (log-rank P = .045). In conclusion, our findings demonstrate that the down-regulation of CD112 may be an important mechanism through which HCC cells evade the natural killer cell-mediated immunosurveillance, and thus, CD112 may be a useful biomarker to assess the immunologic niche of HCC.

Loss of expression of MHC class I-related chain A (MICA) is a frequent event and predicts poor survival in patients with hepatocellular carcinoma.

Natural killer (NK) cells are important effector cells for the first line of defense against tumor. Distant MHC class I homolog MICA has been identified as human ligand for NK cell activating receptor NKG2D. Engagement of MICA triggers NK cells and augments antigen-specific CTL anti-tumor immunity. However, the expression level of MICA and its clinical significance in hepatocellular carcinoma remains to be elucidated. In the present study, a hospital-based study cohort of 143 HCC patients was involved. MICA expression levels were determined by immunohistochemical staining. The association of MICA expression with tumor clinicopathologic features, disease-free survival, and overall survival of HCC patients were analyzed. Significantly decreased expression of MICA was detected in tumor specimens. MICA expression was significantly associated with AFP level (P < 0.001) and tumor node metastasis stage (P = 0.003). Patients with reduced level of MICA had a statistically significantly shorter disease-free survival and overall survival duration than patients with preserved expression of MICA. However, in multivariate analysis, MICA expression level was found not to be an independent prognostic factor for both disease-free survival and overall survival of HCC patients. Our findings suggest that decreased MICA expression may play an important role in HCC tumor evasion of host immunity, which warrants further investigation in future studies.

Increased expression of TIGIT on CD4+ T cells ameliorates immune-mediated bone marrow failure of aplastic anemia.

Aplastic anemia (AA) is an autoimmune disease in which T cell activation is suspected to play an important role. T cell immunoglobulin and ITIM (immunoreceptor tyrosine-based inhibition motif) domain (TIGIT) is an inhibitory receptor, which exhibits inhibitory functions on the immune response. However, its role in AA has not been clearly determined. In the current study, we showed that the frequency of TIGIT-positive CD4(+) T cells was reduced in the vast majority of AA patients (85%, 17/20). In TIGIT-silenced human CD4(+) T cells, stimulation of agonistic anti-TIGIT monoclonal antibody significantly facilitated cell proliferation, increased production of IL-2 and IFN-γ, and inhibited production of IL-10. However, in TIGIT-overexpressed human CD4(+) T cells, cell proliferation and the production of IL-2, IFN-γ, and TNF-α were significantly hindered; in contrast, the secretion of IL-10 was improved. RT-PCR and Western blotting showed that T-bet expression in human CD4(+) T cells was significantly decreased by TIGIT overexpression, but only slightly altered by TIGIT knockdown. In mouse models, lentivirus-mediated TIGIT-overexpressed CD4(+) T cell transfer significantly rescued the decreased red blood cell count, attenuated the increase in serum INF-γ and TNF-α levels, and lengthened the median survival time. The mRNA levels of CD34, stem cell factor (SCF), and granulocyte/macrophage-colony-stimulating factor (GM-CSF) in bone marrow mononuclear cells were also up-regulated. In conclusion, increased expression of TIGIT could inhibit the function of CD4(+) T cells in vitro and ameliorate immune-mediated bone marrow failure of AA in vivo providing a new potential strategy for the treatment of AA.

Genetic variations in the HIF1A gene modulate response to adjuvant chemotherapy after surgery in patients with colorectal cancer.

BACKGROUND: Hypoxia-inducible factor 1α (HIF-1α) plays an important role in regulating cell survival and angiogenesis, which are critical for tumor growth and metastasis. Genetic variations of HIF1A have been shown to influence the susceptibility to many kinds of human tumors. Increased expression of HIF-1α has also been demonstrated to be involved in tumor progression. However, the prognostic value of single nucleotide polymorphisms (SNPs) in the HIF1A gene remains to be determined in most cancer types, including colorectal cancer (CRC). In this study, we sought to investigate the predictive role of HIF1A SNPs in prognosis of CRC patients and efficacy of chemotherapy. MATERIALS AND METHODS: We genotyped two functional SNPs in HIF1A gene using the Sequenom iPLEX genotyping system and then assessed their associations with clinicopathological parameters and clinical outcomes of 697 CRC patients receiving radical surgery using Cox logistic regression model and Kaplan Meier curves. RESULTS: Generally, no significant association was found between these 2 SNPs and clinical outcomes of CRC. In stratified analysis of subgroup without adjuvant chemotherapy, patients carrying CT/TT genotypes of rs2057482 exhibited a borderline significant association with better overall survival when compared with those carrying CC genotype [Hazard ratio (HR), 0.47; 95% confidence interval (95% CI): 0.29-0.76; P < 0.01]. Moreover, significant protective effects on CRC outcomes conferred by adjuvant chemotherapy were exclusively observed in patients carrying CC genotype of rs2057482 and in those carrying AC/CC genotype of rs2301113. CONCLUSIONS: Genetic variations in HIF1A gene may modulate the efficacy of adjuvant chemotherapy after surgery in CRC patients.

LIM and SH3 domain protein 1 (LASP-1) overexpression was associated with aggressive phenotype and poor prognosis in clear cell renal cell cancer.

BACKGROUND: LIM and SH3 protein 1 (LASP-1) is a specific focal adhesion protein that is known to be involved in numerous biological and pathological processes. LASP-1 overexpression has been described in several types of cancers, but its expression and role in clear cell renal cell cancer (ccRCC) remains unknown. METHODS: Using immunohistochemistry, we analyzed LASP-1 protein expression in 216 clinicopathologically characterized ccRCC cases. We also examined LASP-1 expression in 20 paired ccRCC tissues and in 2 cell lines by real-time PCR and Western blot. Using RNA interference, we investigated the effects of LASP-1 depletion on tumor cell behavior in vitro. Statistical analyses were used to determine the associations between LASP-1 levels, tumor features and patient outcomes. RESULTS: LASP-1 overexpression was observed in ccRCC tissues (P<0.0001) compared to adjuvant nontumorous tissues, and its expression levels were closely correlated with overall survival and recurrence-free survival (P = 0.044 and 0.006, respectively) in patients with ccRCC. RNA interference-mediated silencing of the LASP-1 gene in 786-0 ccRCC cells significantly inhibited cell migration. CONCLUSIONS: The results of the present study indicate that LASP-1 may serve as a prognostic biomarker for ccRCC patients and may be a promising target for the treatment of ccRCC.

MAGEC2, an epithelial-mesenchymal transition inducer, is associated with breast cancer metastasis.

MAGEC2 is a member of melanoma antigen (MAGE) family of cancer-testis antigens and associated with tumor relapse and metastasis. Here, we investigated the expression of MAGEC2 in patients with breast cancer and its clinical effects with underlying mechanisms. The expression levels of MAGEC2 were compared between 420 invasive ductal carcinoma (IDC) and 120 ductal carcinoma in situ of the breast. Correlations between MAGEC2 expression and clinico-pathologic factors or survival of patients with IDC were analyzed. In addition, MAGEC2 expression levels in tumor tissues dissected from the primary focus and matched tumor-invaded axillary lymph nodes were analyzed in 8 breast cancer patients. The functional effects of MAGEC2 overexpression were assessed in vitro using scratch assay and transwell chamber assay. MAGEC2 expression was increased in metastatic breast cancer in comparison to the non-metastatic. MAGEC2 expression was significantly associated with ER negative expression (P = 0.037), high tumor grade (P = 0.014) and stage (P = 0.002), high incidence of axillary lymph node metastasis (P = 0.013), and distant metastasis (P = 0.004). Patients with tumor with MAGEC2 positive expression have a worse prognosis and a shorter metastasis free interval. Multivariate analyses showed that MAGEC2 expression was an independent risk factor for patient overall survival and metastasis-free survival. Breast cancer cells that overexpressed MAGEC2 had stronger migratory and invasive potential than control-treated cells. Epithelial markers (E-cadherin and cytokeratin) were down-regulated in MAGEC2-overexpressing cells compared to controls, whereas mesenchymal markers (vimentin and fibronectin) were upregulated. Our results indicate that MAGEC2 has a role in breast cancer metastasis through inducing epithelial-mesenchymal transition. In addition, MAGEC2 is a novel independent poor prognostic factor in patients with IDC. Thus, targeting MAGEC2 may provide a novel therapeutic strategy for breast cancer treatment.

The ratio of second to fourth digit length (2D:4D) and coronary artery disease in a Han Chinese population.

BACKGROUND: The association between index finger to ring finger length ratio (2D:4D) and cardiac disorders has been reported, however it has not been discussed in terms of coronary artery disease (CAD). We investigated whether 2D:4D could be used as a marker for predisposition to CAD as assessed by coronary angiography in Chinese men and women. METHODS: This study included 1764 persons divided into 4 groups, 441 cases with CAD and 441 persons without CAD as control in each sex of the same age. Finger lengths were measured twice for both hands using electronic calipers. Student t test was used to detect the difference of 2D:4D among groups. The receiver operator characteristic curves (ROCs) were used to detect the diagnostic effect of 2D:4D for CAD. RESULTS: There were no significant differences in age among the four groups. A significant difference of 2D:4D ratios between right and left hand were observed only in men in both control and CAD groups. On the right hand in the control group and on both hands in the CAD group, the 2D:4D ratios were higher in women than in men (all, P < 0.001). In men with CAD, mean 2D:4D was higher than mean 2D:4D in control men (right hand 0.962±0.042:0.927±0.038; left hand 0.950±0.044:0.934±0.048; both hands, P < 0.001), but this was not observed in women. No relationship was found between 2D:4D and age (all, P >0.05). The area under the curve of right hand 2D:4D in male was 0.72 (95% CI 0.683-0.753, p<0.001), while it was 0.602 (95% CI 0.565-0.639, p<0.001) in left hand. CONCLUSIONS: The present study showed an association between high 2D:4D ratio and CAD in both hands in men. There were no significant differences in mean 2D:4D between women with CAD and controls.

[Expressions of EZH2 and RUNX3 in renal cell carcinoma and their clinical significance].

OBJECTIVE: To investigate the expression levels of enhancer of zeste homolog 2 (EZH2) and human runt-related transcription factor 3 (RUNX3) in renal cell carcinoma (RCC), and analyze their clinical significance and expression correlation. METHODS: Expressions of EZH2 and RUNX3 proteins were analyzed by immunohistochemistry in 56 RCC tissues and corresponding adjacent normal renal tissues, respectively. Statistic analysis was conducted using SPSS17.0 software. RESULTS: Immunohistochemistry revealed that the positive rates of EZH2 and RUNX3 expressions were 67.9% and 37.5% in RCC tissues, respectively, and they were 28.6% and 67.3% in adjacent normal renal tissues. The expressions of EZHZ and RUNX3 between RCC and normal renal tissues were significantly different (P<0.05). High expression of EZH2 and low expression of RUNX3 in RCC were associated with the clinical stage (P<0.05), but not associated with pathological differentiation, age or gender (P>0.05). No statistically significant negative correlation was observed in the expressions of EZH2 and RUNX3 in RCC (P>0.05). CONCLUSION: Both EZH2 and RUNX3 may play important roles in the development and progression of RCC, and the detection on EZH2 and RUNX3 expressions will be helpful for early diagnosis and prognosis prediction of RCC.

Heterogeneous expression of CT10, CT45 and GAGE7 antigens and their prognostic significance in human breast carcinoma.

OBJECTIVE: The goal of this study was to detect the intertumoral heterogeneity of CT10, CT45 and GAGE7 expression and further to analyze their prognostic value. METHODS: The intertumoral heterogeneity of three cancer/testis antigens was examined by immunohistochemistry using 120 samples from patients with infiltrating ductal breast carcinoma. The expression patterns were classified and correlated with the clinicopathologic variables and outcome of the patients. RESULTS: CT10 showed punctate, focal and diffuse expression patterns according to the characteristic of its distribution. CT45 showed cytoplasmic, nuclear or combined cytoplasmic and nuclear expression patterns according to its subcellular location. GAGE7 exhibited nuclear, cytoplasmic and nucleolar expression patterns. Three cancer/testis antigens were also observed coordinately expressed in infiltrating ductal breast carcinoma. Patients with tumors with CT10 expression was significantly correlated with nodal metastases (P < 0.001) and advanced clinical stages (P = 0.001). Patients with tumors with cytoplasmic GAGE7 and with the expression of two or more cancer/testis antigens were significantly correlated with advanced clinical stages (P = 0.001 and P = 0.030). No significant difference was identified between the different expression patterns of CT45 and clinicopathologic variables. In addition, Kaplan-Meier analysis revealed that diffuse CT10 expression and coexpression of three cancer/testis antigens were related to the poor prognosis of patients with infiltrating ductal breast carcinoma. CONCLUSIONS: Diffuse CT10 expression and the coexpression of three cancer/testis antigens can be used as a biomarker to distinguish patients with a poorer outcome of the breast carcinoma. Our finding may provide useful data for evaluating the prognosis of this disease and improving the effectiveness of therapeutic application based on the three cancer/testis antigens.