Shu Zhao

The expression and clinical significance of microRNA-1258 and heparanase in human breast cancer

OBJECTIVES To investigate the expression profile of miR-1258 and heparanase (HPSE) in breast cancer and to assess their clinicopathological significance. DESIGN AND METHODS The expression levels of miR-1258 and HPSE were analyzed in normal, benign and malignant breast tissues. Their serum levels were evaluated in healthy women and in patients with benign and malignant breast disease. We studied the correlation between the expression of miR-1258 and HPSE and the clinical features presented by the patients. RESULTS MiR-1258 was down-regulated and HPSE was up-regulated in breast cancer, with a significant inverse correlation. A reduced miR-1258 expression and an elevated HPSE expression were associated with the lymph node status, late clinical stages, a short overall survival and a short relapse-free survival. In frozen fresh tissue samples, the miR-1258 levels in breast cancer with lymph node metastasis were significantly lower than that of breast cancer without lymph node metastasis and benign disease (BD). In contrast, the HPSE levels in breast cancer with lymph node metastasis were the highest. In serum samples, the miR-1258 levels in metastatic breast cancer (M1) were lower than that of primary breast cancer (M0) and BD. However, serum HPSE levels of M1 patients were significantly higher than that of M0 patients and BD patients. CONCLUSIONS MiR-1258 may play an important role in breast cancer development and progression by regulating the expression of HPSE, and they might be potential prognostic biomarkers for breast cancer.

The clinicopathological and prognostic significance of PD-L1 expression in gastric cancer: a meta-analysis of 10 studies with 1,901 patients

The prognostic value of programmed death-ligand 1 (PD-L1) in gastric cancer (GC) remains controversial. To clarify this problem, we performed a meta-analysis of research studies identified in the PubMed, EMBASE and the Cochrane Library databases. A total of 1,901 patients in 10 studies were enrolled in this meta-analysis, and the pooled hazard ratio (HR) of 1.64 (95% CI 1.11 to 2.43; P = 0.01) indicated that PD-L1 expression is associated with a shorter overall survival (OS). The pooled odds ratios (ORs) indicated that PD-L1 expression was associated with tumour size (OR = 1.87, 95% CI 1.25 to 2.78; P = 0.002) and lymph node status (OR = 2.17, 95% CI 1.04 to 4.52; P = 0.04). However, PD-L1 had no correlation with gender, age, cancer location, differentiation, depth of invasion, and tumour stage. This meta-analysis indicates that PD-L1 expression is a valuable predictor of the prognosis of patients with GC. PD-L1 expression could be used for identifying a subgroup of patients, who would potentially benefit from targeted therapy against PD-1 or PD-L1. Well-designed large-cohort studies are needed to confirm these findings.

miRNA-24-3p promotes cell proliferation and inhibits apoptosis in human breast cancer by targeting p27Kip1

MicroRNAs (miRNAs) are often aberrantly expressed in breast cancer and are postulated to play a role in its initiation and progression. In the present study, we found that the expression level of miR-24-3p was upregulated in breast cancer in comparison with the level in adjacent normal tissues. Overexpression of miR-24-3p was able to promote cell proliferation and inhibit cell apoptosis in MDA-MB-435 and MDA-MB-468 cells. With the bioinformatic method, we further identified that p27Kip1 is a direct target of miR-24-3p, and its protein level was negatively regulated by miR-24-3p. Therefore, the data reported here demonstrate that miR-24-3p is an important regulator in breast cancer, and imply that the miR-24-3p/p27Kip1 axis has potential as a therapeutic target for breast cancer.

A Polymorphism at the 3'-UTR Region of the Aromatase Gene Is Associated with the Efficacy of the Aromatase Inhibitor, Anastrozole, in Metastatic Breast Carcinoma

Estrogen-related genes and the fat mass and obesity-associated (FTO) gene play a critical role in estrogen metabolism, and those polymorphisms are associated with a poor prognosis in breast cancer. However, little is known about the association between these polymorphisms and the efficacy of anastrozole. The aim was to investigate the impact of the genetic polymorphisms, CYP19A1, 17-β-HSD-1 and FTO, on the response to anastrozole in metastatic breast carcinoma (MBC) and to evaluate the impact of those polymorphisms on various clinicopathologic features. Two-hundred seventy-two women with hormone receptor-positive MBC treated with anastrozole were identified retrospectively. DNA was extracted from peripheral blood and genotyped for five variants in three candidate genes. Time to progression was improved in patients carrying the variant alleles of rs4646 when compared to patients with the wild-type allele (16.40 months versus 13.52 months; p = 0.049). The rs4646 variant alleles were significantly associated with longer overall survival (37.3 months versus 31.6 months; p = 0.007). This relationship was not observed with the rs10046, rs2830, rs9926298 and rs9939609 polymorphisms. The findings of this study indicate that rs4646 polymorphism in the CYP19A1 gene may serve as a prognostic maker of the response to anastrozole in patients with MBC who are treated with anastrozole.

Bisphosphonate Use and the Risk of Breast Cancer: A Meta-Analysis of Published Literature

Bisphosphonates are widely used in clinical practice to prevent and treat osteoporosis and cancer-induced bone loss. Recently, analysis of results of several published observational studies found that women who used bisphosphonates had a significant reduction in the risk of breast cancer compared with nonusers. However, the findings were inconsistent. We systematically searched MEDLINE and EMBASE databases through June 1, 2011. The eligibility determination and the data extraction were conducted independently by 2 of the authors. A random-effect model was used to obtain the pooled estimates of effect. We identified 2 cohort studies and 2 case-control studies that were eligible for analysis, which involved 15,363 patients with breast cancer and 84,931 bisphosphonate users. The results of our meta-analysis revealed that women who received bisphosphonates have a 15% risk reduction of any breast cancer (pooled risk ratio [RR], 0.85 [95% confidence interval {CI}, 0.74-0.98]; P = .03) and a 32% risk reduction of invasive breast cancer (pooled RR, 0.68 [95% CI, 0.59-0.80]; P < .001) compared with nonusers. In addition, there was a significant dose-response relationship between the duration of bisphosphonate use and breast cancer risk. A significantly protective effect of bisphosphonates was observed in patients who used bisphosphonates for more than 1 year before the diagnosis of breast cancer compared with nonusers. The bisphosphonate users had a risk reduction of breast cancer by 8% (pooled RR, 0.92 [95% CI, 0.87-0.96]; P = .001) for each additional year of the duration of bisphosphonate use. The use of bisphosphonates may have a beneficial effect on breast cancer risk.

PD-L1 expression in lung cancer and its correlation with driver mutations: a meta-analysis

Although many studies have addressed the prognostic value of programmed cell death-ligand 1 (PD-L1) expression in lung cancer, the results remain controversial. A systematic search of the PubMed, EMBASE, and Cochrane Library databases was performed to identify the correlation between PD-L1 expression and driver mutations and overall survival (OS). This meta-analysis enrolled a total of 11,444 patients for 47 studies, and the pooled results showed that increased PD-L1 expression was associated with poor prognosis (HR = 1.40, 95% CI: 1.19–1.65, P < 0.001). In subgroup analysis stratified according to histology types, the pooled results demonstrated that increased PD-L1 expression was an unfavorable prognostic factor for non-small cell lung cancer (NSCLC) (HR = 1.26, 95% CI: 1.05–1.52, P = 0.01) and pulmonary lymphoepithelioma-like carcinoma (LELC) (HR = 3.04, 95% CI: 1.19–7.77, P = 0.02), rather than small cell lung cancer (SCLC) (HR = 0.62, 95% CI: 0.27–1.39, P = 0.24). The pooled ORs indicated that PD-L1 expression was associated with gender, smoking status, histology, differentiation, tumour size, lymph nodal metastasis, TNM stage and EGFR mutation. However, PD-L1 expression was not correlated with ALK rearrangement and KRAS mutations.

Identification of proteins responsible for adriamycin resistance in breast cancer cells using proteomics analysis

Chemoresistance is a poor prognostic factor in breast cancer and is a major obstacle to the successful treatment of patients receiving chemotherapy. However, the precise mechanism of resistance remains unclear. In this study, a pair of breast cancer cell lines, MCF-7 and its adriamycin-resistant counterpart MCF-7/ADR was used to examine resistance-dependent cellular responses and to identify potential therapeutic targets. We applied nanoflow liquid chromatography (nLC) and tandem mass tags (TmT) quantitative mass spectrometry to distinguish the differentially expressed proteins (DEPs) between the two cell lines. Bioinformatics analyses were used to identify functionally active proteins and networks. 80 DEPs were identified with either up- or down-regulation. Basing on the human protein-protein interactions (PPI), we have retrieved the associated functional interaction networks for the DEPs and analyzed the biological functions. Six different signaling pathways and most of the DEPs strongly linked to chemoresistance, invasion, metastasis development, proliferation, and apoptosis. The identified proteins in biological networks served to resistant drug and to select critical candidates for validation analyses by western blot. The glucose-6-phosphate dehydrogenase (G6PD), gamma-glutamyl cyclotransferase (GGCT), isocitrate dehydrogenase 1 (NADP+,soluble)(IDH1), isocitrate dehydrogenase 2 (NADP+,mitochondrial) (IDH2) and glutathione S-transferase pi 1(GSTP1), five of the critical components of GSH pathway, contribute to chemoresistance.

Toll-like Receptor 11 (TLR11) Prevents Salmonella Penetration into the Murine Peyer Patches

Background: The role of different TLRs in response to pathogen infection in the gut remains elusive. Results: TLR11 works as a blocker of Salmonella penetration. Remarkably, in mice lacking TLR11, highly invasive Salmonella induced apparent hemorrhage at Peyer patches. Conclusion: TLR11 plays an important role in preventing murine intestinal infection. Significance: TLR11 knock-out mice can serve as a good animal model to study Salmonella infection. Toll-like receptors (TLRs) are key molecular sensors used by the mammalian innate immune system to detect microorganisms. Although TLR functions in colonic immune homeostasis and tolerance to commensal bacteria have been intensively researched, the precise roles of different TLRs in response to pathogen infection in the gut remain elusive. Peyer patches are the major entrance of Salmonella infection and antigen transportation in intestine. Here, we report that, in contrast to TLR5 as a “carrier of Salmonella,” TLR11 works as a “blocker of Salmonella” to prevent highly invasive Salmonella from penetrating into the murine Peyer patches and spreading systemically. TLR11 plays an important role in mediating TNF-α induction and systemic inflammation in response to Salmonella infection. Remarkably, in mice lacking TLR11, apparent hemorrhages at Peyer patches are induced by highly invasive Salmonella, a phenotype resembling human Salmonella infection. Therefore, our results indicate a potentially important role for TLR11 in preventing murine intestinal infection and modulating antigen transportation in the gut and imply an important role for various TLRs in cooperation with tight control of pathogens penetrating into Peyer patches. The TLR11 knock-out mouse can serve as a good animal model to study Salmonella infection.

Altered glycometabolism affects both clinical features and prognosis of triple-negative and neoadjuvant chemotherapy-treated breast cancer

Glycometabolism is a distinctive aspect of energy metabolism in breast cancer, and key glycometabolism enzymes/pathways (glycolysis, hexosamine biosynthetic pathway, and pentose phosphate pathway) may directly or indirectly affect the clinical features. In this study, we analyzed the particular correlation between the altered glycometabolism and clinical features of breast cancer to instruct research and clinical treatment. Tissue microarrays containing 189 hollow needle aspiration samples and 295 triple-negative breast cancer tissues were used to test the expression of M2 isoform of pyruvate kinase (PKM2), glutamine-fructose-6-phosphate transaminase 1 (GFPT1), glucose-6-phosphate dehydrogenase (G6PD), and p53 by immunohistochemistry and the intensity of these glycometabolism-related protein was evaluated. Chi-square test, Kaplan-Meier estimates, and Cox proportional hazards model were used to analyze the relationship between the expression of these factors and major clinical features. PKM2, GFPT1, and G6PD affect the pathologic complete response rate of neoadjuvant chemotherapy patients in different ways; pyruvate kinase muscle isozyme 2 (PKM2) and G6PD are closely associated with the molecular subtypes, whereas GFPT1 is correlated with cancer size. All these three factors as well as p53 have impacts on the progression-free survival and overall survival of triple-negative breast cancer patients. Cancer size shows significant association with PKM2 and GFPT1 expression, while the pN stage and grade are associated with PKM2 and G6PD expression. Our study support that clinical characteristics are reflections of specific glycometabolism pathways, so their relationships may shed light on the orientation of research or clinical treatment. The expression of PKM2, GFPT1, and G6PD are hazardous factors for prognosis: high expression of these proteins predict worse progression-free survival and overall survival in triple-negative breast cancer, as well as worse pathologic complete response rate in neoadjuvant chemotherapy breast cancer. However, p53 appears as a protective factor only in the patients receiving neoadjuvant chemotherapy. All the four proteins, PKM2, GFPT1, G6PD and p53, are prognostic markers of breast cancer. The correlation among them suggests that there may be crosstalk of the four proteins in breast cancer.

Analysis of 31 Cases of Primary Breast Lymphoma: The Effect of Nodal Involvement and Microvascular Density

BACKGROUND We analyzed a database from our hospital comprised of 31 cases of primary breast lymphoma (PBL) that included treatment and follow-up information during the past 30 years, and investigated the correlation between microvessel density (MVD) and survival in patients with PBL. PATIENTS AND METHODS We reviewed all patients diagnosed with primary breast lymphoma from June 1977 to March 2007. Patient demographics such as survival, recurrence, and time to follow-up were recorded, in addition to surgical, radiation, and/or chemotherapy treatment(s). We also assessed microvessel density (MVD) in the pretreatment breast lump of 31 previously untreated patients using α-CD34 immunohistochemical staining. RESULTS All 31 patients were female ranging in age from 37 years to 75 years. Diffuse large B-cell lymphoma was the most common histologic diagnosis. According to the staging of Wiseman and Liao, 17 patients (55%) were stage IE, and 14 patients (45%) were stage IIE. Treatment that included radiation therapy in stage I patients (node negative) improve the survival rate and lowered the recurrence rates. Treatment that included chemotherapy in stage II patients (node positive) showed benefits in terms of higher survival rate and lower recurrence rate. Increasing microvessel density is a weak but statistically significant predictor of lower survival overall. CONCLUSION Nodal status predicts the outcome and guides the use of radiation and chemotherapy. There is no statistical difference between the different types of operative methods. Patients with high MVD measured in the microenvironment had worse survival overall than PBL patients with low expression.