Jingxuan Wang

Antiangiogenic Effect of Capecitabine Combined with Ginsenoside Rg3 on Breast Cancer in Mice

Capecitabine is a novel fluoropyrimidine carbamate, which has a broader spectrum of antitumor activity than other fluoropyrimidines, such as 5-FU, DFUR, or UFT; it has proved effective over a wide dose range. Recent research has suggested that frequent administration of lower doses of certain chemotherapeutic drugs might enhance their antiangiogenic effect. The present study investigated the antiangiogenic effect of capecitabine on breast cancer. In order to augment its efficacy, we combined capecitabine chemotherapy with ginsenoside Rg3. Our results indicate that a metronomic regimen of capecitabine inhibited angiogenesis in breast cancer, and its antiangiogenic effects may be further enhanced by the concurrent administration of ginsenoside Rg3. As an antiangiogenic method, this regimen presented better antitumor effects, less toxicity, and reduced susceptibility to drug resistance.

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.

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.

Lymphocyte-to-monocyte ratio is associated with prognosis of diffuse large B-cell lymphoma: correlation with CD163 positive M2 type tumor-associated macrophages, not PD-1 positive tumor-infiltrating lymphocytes

The research aims to examine the prognostic value of the lymphocyte-to-monocyte ratio (LMR), neutrophil-to- lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in diffuse large B-cell lymphoma (DLBCL). The relation of these hematologic indicators to poor antitumor immunity and prognosis must be investigated. Clinicopathologic data and survival information of 355 patients with DLBCL was retrospectively analyzed. Univariate analysis revealed that lower LMR (<2.71), higher NLR (≥2.81), CD163+ M2 tumor-associated macrophages (TAM) content ≥9.5% and programmed cell death 1 (PD-1)+ tumor-infiltrating lymphocytes (TILs) content < 4.5 cells per high power field(HPF) were significantly related to unfavorable overall survival (OS) and progression free survival (PFS). When considering the prognostic indexes of IPI, multivariate analysis confirmed that LMR of <2.71 and CD163+ M2 TAM content ≥9.5% significantly affected the prognosis of DLBCL. Spearman correlation test showed LMR was negatively correlated with CD163+ M2 TAM content. However, there were no correlation was found between LMR and PD-1+ TIL as well as between NLR and PD-1+ TIL content. These results indicated that decreased LMR lead to a weak anti-tumor immunity and could be used as a bad prognosis biomarker of DLBCL.

Long non-coding RNA HOXA-AS2 promotes proliferation and invasion of breast cancer by acting as a miR-520c-3p sponge

The long non-coding RNA (lncRNA) HOXA cluster antisense RNA2 (HOXA-AS2) has recently been shown to be dysregulated and involved in the progression of several cancers. However, the biological role and clinical significance of HOXA-AS2 in the carcinogenesis of breast cancer are still unclear. In the present study, we found that HOXA-AS2 was up-regulated in human breast cancer tissues and cell lines and associated with clinicopathological characteristics. Silencing of HOXA-AS2 inhibited the progression of breast cancer cells in vitro and in vivo. Furthermore, microarray profiling indicated that HOXA-AS2 serves as an endogenous sponge by directly binding to miR-520c-3p and down-regulating miR-520c-3p expression. We demonstrated that HOXA-AS2 controls the expression of miR-520c-3p target genes, TGFBR2 and RELA, in breast cancer cells. Therefore, our study may provide a better understanding of the pathogenesis of breast cancer and suggests that HOXA-AS2 may be a potential prognostic and therapeutic target in breast cancer.

CD20-negative diffuse large B cell lymphoma: a comprehensive analysis of 695 cases

CD20 expression is absent in a variety of diffuse large B cell lymphomas (DLBCLs), including plasmablastic lymphoma, primary effusion lymphoma, anaplastic lymphoma, kinase-positive DLBCL, and large B cell lymphoma arising in human herpesvirus 8-associated multicentric Castleman disease. These rare and heterogeneous tumors are characterized by the presence of proliferating immunoblasts with similar transcriptional profiles as those of plasma cells and are typically associated with highly aggressive pathologies, with high levels of chemotherapy resistance and low survival rates; thus, they pose significant diagnostic and treatment challenges. We conducted a systematic literature review of the limited existing clinical data to summarize the current knowledge regarding the biological basis, diagnostic limits, and potential therapeutic targets of distinct variants of CD20-negative DLBCL. This review will hopefully increase the awareness of these rare disorders among clinicians and pathologists and prompt basic and clinical research.

RANKL and OPG Polymorphisms Are Associated with Aromatase Inhibitor-Related Musculoskeletal Adverse Events in Chinese Han Breast Cancer Patients

Background Breast cancer patients treated with aromatase inhibitors (AIs) may experience musculoskeletal adverse events (MS-AEs). Several studies have confirmed that the RANKL/RANK/OPG signaling pathway plays a dominant role in bone health. Therefore, this study aimed to analyze the relationship between the serum levels of RANKL, OPG and their SNPs (single nucleotide polymorphisms) with AI-related MS-AEs. Methodology and Principal Findings Patients with early stage, hormone-sensitive breast cancer who were receiving AI therapy were enrolled. We included 208 cases with AI-related MS-AEs and 212 without (controls). The levels of estradiol, bone-turnover markers, multiple inflammatory cytokines, RANKL,OPG and lumbar spine BMD were measured, and questionnaires were completed. We analyzed 29 SNPs of RANKL, RANK and OPG using Sequenom MassARRAY assays and PCR-based TaqMan assays. The levels of bone-turnover markers and RANKL and the ratio of RANKL/OPG were higher in patients with AI-related MS-AEs than controls (all p < 0.05). A genetic assay showed that the RANKL SNP rs7984870 and OPG SNP rs2073618 were associated with AI-related MS-AEs. In patients with AI-related MS-AEs, rs7984870 CC and rs2073618 CC were risk genotypes. Carriers of the rs7984870 CC genotype were more likely to have a higher RANKL level and RANKL/OPG ratio than carriers of the GG genotype, and carriers of the rs2073618 CC genotype were more likely to have a lower OPG level and a higher RANKL/OPG ratio than carriers of the GG genotype (all p < 0.05). Moreover, risk genotypes were associated with higher levels of serum CTX and PINP and a lower lumbar spine BMD (all p < 0.05). Conclusions and Significance In conclusion, the RANKL and OPG risk genotypes synergize to negatively impact bone health and predispose breast cancer patients to AI-related MS-AEs.

Prognostic role of HOTAIR in four estrogen-dependent malignant tumors: a meta-analysis.

Background HOX transcript antisense intergenic RNA (HOTAIR), a long non-coding RNA transcribed from the antisense strand of the HOXC gene locus, has been shown to be overexpressed in various carcinomas and is thought to be an indicator of poor prognosis. Recently, HOTAIR was found to be an estrogen-responsive gene. We therefore conducted a meta-analysis to systematically summarize and clarify the association between HOTAIR expression and prognosis in the four main estrogen-dependent tumors. Methods A systematic search of studies that examined the association and prognostic impact of HOTAIR in four of the main estrogen-dependent tumors was conducted in PubMed and Embase. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated to pool the effect size. Results A total of 1,200 patients from eight eligible studies were included. The current study found an association between HOTAIR expression and overall survival (OS) in four estrogen-dependent tumor types (HR, 1.99; 95% CI: 1.02–3.90; PHeterogeneity=0.001). Subgroup analyses indicated that high HOTAIR expression appeared to be a potential prognostic biomarker in non-breast cancer patients (HR, 2.72; 95% CI: 1.65–4.48). There was also an increased risk in Asian populations (HR, 2.55; 95% CI: 1.62–4.00) compared with Caucasian populations (HR, 1.19; 95% CI: 0.16–8.83) and in patients without preoperative treatment (HR, 2.55; 95% CI: 1.62–4.00) compared with patients with preoperative treatment (HR, 1.19; 95% CI: 0.16–8.83). In addition, the HRs of patients with high HOTAIR expression for metastasis-free survival (MFS), relapse-free survival (RFS), and disease-free survival (DFS) were 2.30 (P=0.120), 1.39 (P=0.000), and 2.53 (P=0.714), respectively, but there were insufficient data to fully confirm these associations. Conclusion HOTAIR may be a predictor of poor prognosis in four of the main estrogen-dependent tumors, especially in cervical, ovarian, and endometrial cancer patients without preoperative treatment in Asian populations. It is important to note that the prognostic value of HOTAIR in MFS, RFS, and DFS should be interpreted with caution due to the limited sample size and sample heterogeneity. Well-designed and larger-scale studies are needed to validate our findings.

Jagged1 promotes aromatase inhibitor resistance by modulating tumor-associated macrophage differentiation in breast cancer patients

PurposeEndocrine resistance limits the efficacy of anti-estrogen therapies. Notch signaling is involved in modulating tumor-associated macrophage (TAM) differentiation and is upregulated in endocrine-resistant breast cancer cells. Here, we analyzed the role of Jagged1 in the regulation of TAM polarization to investigate whether the Jagged1-Notch pathway promotes the acquisition of aromatase inhibitor (AI) resistance by upregulating TAM infiltration.MethodsThe Jagged1 expression levels and M2 TAM infiltration density, in 203 tumor samples from ER-positive postmenopausal patients, who received AI treatment, were evaluated by immunohistochemical staining and the results were compared with clincopathological parameters and survival. The Jagged1 protein and mRNA levels were analyzed in MCF-7 and long-term endocrine-depleted (LTED) cell lines. The phenotypes of macrophage after macrophages were co-cultured with either MCF-7 or LTED cells, were evaluated using flow cytometry. Cell migration assay was performed to evaluate the mobility of cancer cells. Notch gama secretase inhibitor (GSI) RO4929097 was employed to investigate whether modulation of Notch signaling affects M2 polarization.ResultsIn the tumor samples, Jagged1 expression was found to be associated with a large tumor size, high histological grade, lymphatic invasion, and high Ki67 expression. Jagged1 expression was also correlated with reduced disease-free and overall survival and was positively associated with the stromal M2 TAM infiltration density in primary tumor tissues. In AI-resistance patients, M2 TAM infiltration was denser in metastatic lesions than in primary tumors. Higher Jagged1 protein and mRNA levels were also found in LTED cells, which model AI-resistant conditions in patients, compared with MCF-7 cells. Macrophages co-cultured with LTED cells expressed higher levels of M2 marker and IL-10. M2 TAM proportion was reduced when macrophages were pre-treated with GSI before co-culture.ConclusionsThe Jagged1-Notch pathway showed elevated expression in AI-resistant breast cancer cells, resulting in macrophage differentiation towards M2 TAMs and there contributing to the acquisition of AI resistance.

Biweekly CHOP therapy improves therapeutic effect in the non-GCB subtype of diffuse large B-cell lymphoma

CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) is accepted as the best available standard treatment for diffuse large B-cell lymphoma (DLBCL) patients; however, the therapeutic efficacy seems unsatisfactory. Additional rituximab will improve the cure rate, but it is not popular in China because of its increased medical cost. Germinal center B-cell (GCB) and non-GCB subtypes distinction have been described as independent prognostic factors, and provides likelihood for cure with chemotherapy. The aim of the study is to explore the association between Immunophenotype and treatment regimen. Between August 2003 and May 2006, 66 patients with DLBCL were enrolled, according to immunohistochemistry results (GCB and non-GCB phenotype), randomly assigned to receive either six to eight cycles of CHOP every 2 weeks or standard CHOP every 3 weeks. After a median follow-up duration of 32 months (range of 4 to 42 months), an estimated 3-year overall survival (OS) rate for the GCB patients were 68.2% and 55.6% for the biweekly CHOP regimen and standard CHOP regimen respectively, while the data were 62.8% and 37.9% respectively for the non-GCB cases. The biweekly CHOP therapy showed higher efficacy than standard treatment, and its superiority was more obvious with the non-GCB subgroup. All rights reserved.