Therapeutic potential of anti-miR29a in breast cancer patients with type 2 diabetes: an in vitro and xenograft mouse-model study.

Background: MicroRNAs (miRNAs) acting as tumour suppressors or oncogenes, known as oncomiRs, are a promising new focus in targeted therapies for cancer. Approximately 16% of breast cancer patients have pre-existing diabetes. Breast cancer with type 2 diabetes mellitus (BDM) is provided with its unique biological characteristics and clinical characteristics. This study primarily investigated the therapeutic potential and regulatory mechanism of miR-29a in patients with BDM. Methods: The significance of miR-29a in BDM was analyzed by real-time reverse transcriptase polymerase chain reaction (qRT-PCR) in breast tissues. A cell model for BDM was established by using MDA-MB-231 cells cultured in 3T3-L1 adipocytes cultured with high levels of glucose and insulin. A type 2 diabetes mellitus (T2DM) mouse model was induced in female BALB/c mice through a high-fat diet plus low doses of streptozotocin (STZ). The xenograft mouse-model for BDM was established on these T2DM mouse by using MDA-MB-231 cells. Then the biological effects of miR-29a knockdown mediated by lentivirus-shRNAs on cell proliferation, apoptosis, cell cycle, and migration were investigated. Results: Our results indicated that miR-29a was upregulated in patients with BDM, which correlated with a worse prognosis. In human breast cancer cells, miR-29a knockdown reduced cell proliferation and cell migration and invasion in BDM. In the T2DM xenograft, miR-29a knockdown suppressed MDA-MB-231 cells tumorigenesis and metastasis. We also demonstrated that miR-29a promoted BDM cell growth and metastasis by targeting Sirtuin 1 (SIRT1). Conclusions: Our findings indicated that anti-miR-29a inhibited cell proliferation and invasion in BDM by targeting SIRT1. We believe anti-miR-29a may represent a novel therapeutic approach for the management of patients with BDM.

Erianin inhibits human lung cancer cell growth via PI3K/Akt/mTOR pathway in vitro and in vivo.

Erianin is a small-molecule compound that is isolated from Dendrobium chrysotoxum Lindl. In recent years, it has been found to have evident antitumor activity in various cancers, such as bladder cancer, cervical cancer, and nasopharyngeal carcinoma. In this study, we assessed the effect of erianin on lung cancer in terms of cell growth inhibition and the related mechanism. First, erianin at a concentration of less than 1 nmol/L exhibited cytotoxicity in H1975, A549, LLC lung cancer cells, did not cause marked growth inhibition in normal lung and kidney cells, induced obvious apoptosis and G2/M phase arrest of cells, and inhibited the migration and invasion of lung cancer cells in vitro. Second, in a mouse xenograft model of lewis lung cancer (LLC), oral administration of erianin (50, 35, and 10 mg kg-1  day-1 for 12 days) substantially inhibited nodule growth, reduced the fluorescence counts of lewis cells and the percentage vascularity of tumor tissues, increased the number of apoptotic tumor cells, the thymus indices, up-regulated the levels of interleukin (IL)-2 and tumor necrosis factor-α (TNF-α), decreased IL-10 levels and the spleen index, and enhanced immune function. Lastly, the possible targets of erianin were determined by molecular docking and verified via western blot assay. The results indicated that erianin may achieve the above effects via inhibiting the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway in vitro and vivo. Taken together, the results showed that erianin had obvious antitumor effects via inhibiting the PI3K/Akt/mTOR pathway in vitro and vivo and may have potential clinical value for the treatment of lung cancer.

Feasibility and efficacy of microwave ablation for treating breast fibroadenoma.

BACKGROUND: To investigate the safety, efficacy, and follow-up outcomes of microwave ablation (MWA) in patients with breast fibroadenoma. METHODS: An institutional review board-approved this study of patients treated with MWA for breast fibroadenoma from October 2017 to March 2019. Clinical features of patients and breast fibroadenoma were analyzed. At follow-up all patients received physical examination and ultrasound imaging. RESULTS: In total, 171 patients with 271 lesions were enrolled. The mean lesion diameter was 1.35 ± 0.47 cm. The results revealed differential lesion states, including stability, enlargement, reduction, and complete regression, at 1-6, 6-12, and >12 months of follow-up. The size was reduced in 22.14% (31/140), 26.36% (29/110), and 36.36% (16/44) of the lesions at 1-6, 6-12, and >12 months of follow-up, respectively. The proportion of lesions with complete regression was 24.29% (34/140) at 1-6 months, 45.45% (50/110) at 6-12 months, and 40.91% (18/44) at >12 months of follow up. There was no significant relationship between the curative effect and age, lesion location, and blood flow in patients with breast fibroadenoma after MWA (p > .05), but there was statistically significant relationship with lesion diameter (categorized as <1.5 cm and ≥1.5 cm) (p < .05). CONCLUSIONS: The current evidence indicates that MWA is a safe and effective method for treating breast fibroadenoma. Nevertheless, further large-scale prospective trials and well-designed future studies are warranted to validate our findings.

Aconitine induces cardiotoxicity through regulation of calcium signaling pathway in zebrafish embryos and in H9c2 cells.

Fuzi, the processed lateral roots of Aconitum carmichaelii Debx., is a traditional herbal medicine that is well known for its excellent pharmacological effects and acute toxicity. Aconitine is one of the diester-diterpene alkaloids and well-known for its arrhythmogenic effects. However, the effects of aconitine in zebrafish have rarely been studied. Therefore, we investigated the effects of aconitine on zebrafish embryos and H9c2 cells. Zebrafish embryos at 48 hours postfertilization were exposed to aconitine, and then, cardiac function and apoptosis were measured. Through transcriptomic analysis, the cardiotoxicity of aconitine in zebrafish embryos was involved in regulating Ca2+ signal pathways. A reverse transcription-polymerase chain reaction was performed to verify the expression of Ca2+ pathway-related genes after 12, 24, 36 and 48 hours of treatment. Meanwhile, intracellular Ca2+ concentrations and cell apoptosis were observed in H9c2 cells treated with half-maximal inhibitory concentration values of aconitine for 30 minutes. The protein levels of troponin T (TnT), caspase 3, Bcl-2 and Bax were detected by western blot analysis. In vivo, 2.0 and 8.0 µm aconitine decreased the heart rate and inhibited the contraction of ventricles and atria in a dose- and time-dependent manner. Furthermore, aconitine increased expression of cacna1c, RYR2, atp2a2b, Myh6, troponin C, p38, caspase 3, Bcl-2 and Bax for 12 hours. In vitro, 1.5 and 4.5 mm aconitine caused intracellular Ca2+ ion oscillation, increased rates of apoptosis, inhibited TnT and Bcl-2 protein expression, and promoted caspase 3 and Bax protein expression. These data confirmed that aconitine at various concentrations induced cardiac dysfunction and apoptosis were related to the Ca2+ signaling pathway.

MicroRNA-204 inhibits the proliferation and metastasis of breast cancer cells by targeting PI3K/AKT pathway.

PURPOSE: Breast cancer is one of the deadliest malignancies in women. Lack of biomarkers and the unavailability of reliable therapeutic targets are main hurdles in the treatment of breast cancer. The present study was therefore designed to assess the role and therapeutic potential of miR-204 in the treatment of breast cancer. METHODS: The expression of miR-204 was checked by qRT-PCR. The transfections were performed by Lipofectamine 2000 reagent. Cell viability was determined by WST-1 colorimetric assay. The effect of miR-204 was evaluated on the breast cancer metastasis by cell migration and invasion transwell assays. Immunoblotting was used to determine the protein expression in breast cancer cells. RESULTS: The results revealed that the expression of miR-204 was downregulated in all the tested breast cancer cell lines. Overexpression of miR-204 in the MCF7 breast cancer cell line suppressed the proliferation of these cells by triggering apoptotic cell death and G2/M cell cycle arrest. Furthermore, miR-204 overexpression inhibited the migration and invasion of the MCF7 breast cancer cells. Bioinformatic analysis revealed PTEN to be the target of miR-204. Since, PTEN regulates the PI3K/AKT signalling pathway, the effect of miR-204 overexpression was also assessed on this pathway and showed that miR-204 overexpression inhibits the expression of p-AKT and p-PI3K significantly in MCF7 breast cancer cells. CONCLUSION: We conclude that miR-204 regulates the proliferation and metastasis of the breast cancer cells and as such may prove to be an important therapeutic target.

Deleted in breast cancer 1 as a potential prognostic biomarker in human cancers: a pooled analysis of 2,254 patients.

BACKGROUND: Deleted in breast cancer 1 (DBC1) is believed to be involved in human cancers. However, it is still uncertain whether DBC1 expression can be regarded as a prognostic factor in patients with various cancers. This meta-analysis aimed to evaluate the relationship between high levels of DBC1 and prognosis in tumor patients. METHODS: Electronic databases were searched and 14 studies meeting the selection criteria were included. Overall survival (OS), relapse-free survival (RFS), and 95% CIs were extracted and analyzed. HRs from individual studies were pooled using fixed-or random-effects models, depending on the heterogeneity of the included studies, and publication bias analyses were also performed to increase the reliability of the results. RESULTS: A total of 2,254 patients with tumors from 14 published studies were included in the meta-analysis. DBC1 overexpression was associated with worse OS (univariate analysis: HR=2.94; 95% CI: [2.38-3.63]; multivariate analysis: HR=1.98, 95% CI: [1.21-3.25]) and RFS (univariate analysis: HR=2.83, 95% CI: [2.30-3.49]; multivariate analysis: HR=2.71, 95% CI: [2.07-3.53]) for various tumors. No publication bias was observed according to test of funnel plot asymmetry and Egger's test. CONCLUSION: Current evidence supports the conclusion that the upregulation of DBC1 is correlated with poor survival among tumor patients, suggesting that DBC1 represents an independent prognostic factor significantly associated with OS and RFS, and could serve as a novel therapeutic target in patients with tumors. Nevertheless, further large-scale prospective trials and well-designed studies are warranted to confirm this finding.

LncRNA MALAT1 promotes relapse of breast cancer patients with postoperative fever.

Postoperative fever is prevalent in many breast cancer patients. Some retrospective studies proposed that postoperative fever might also be considered as a rapid rough indicator for the poor prognosis of breast cancer patients. This study aims to explore the possible molecular mechanisms underlying the relapse of breast cancer patients with early postoperative fever. Our results indicated plasma levels of lncRNA MALAT1 were elevated in breast cancer patients with early postoperative fever and were associated with RFS. Lipopolysaccharide (LPS) was able to induce fever and systemic inflammatory responses in 4T1 xenograft mice, and promote lung metastasis. But after knocking down lncRNA MALAT1, the inflammatory responses and metastasis of lung were significantly reduced. Moreover, after knocking down lncRNA MALAT1 in the 4T1 cells, TNF-α level in the supernatants was sharply decreased, and the invasion and migration induced by LPS was also weakened. Cumulatively, our data indicates that MALAT1 is closely related to recurrence and metastasis of breast cancer patients with early postoperative fever.

miR-29a regulated ER-positive breast cancer cell growth and invasion and is involved in the insulin signaling pathway.

Increasing amounts of evidence show that insulin can activate different insulin signaling pathways to promote breast cancer growth and invasion. miR-29a plays crucial roles in decreasing glucose-stimulated insulin secretion, as well as in regulating breast cancer cell proliferation and EMT. However, the mechanism responsible for the regulatory effects of miR-29a on breast cancer growth and invasion and the relationship between these effects and insulin signaling remains unclear. Herein, we showed that human insulin increased miR-29a expression in ER-positive breast cancer cells and that miR-29a facilitated the ability of insulin to promote breast cancer cell proliferation and migration. We found that miR-29a-induced cell proliferation and metastasis acceleration occurred primarily through ERK phosphorylation. The IGF-1R is the upstream target gene of miR-29a, while CDC42 and p85α are the downstream target genes of miR-29a. These results have provided us with information regarding the molecular mechanisms by which hyperinsulinemia promotes breast cancer occurrence and development and thus leads to a poor prognosis in breast cancer patients and indicate that miR-29a plays an important role in breast cancer development and invasion.

miR-34a expression in human breast cancer is associated with drug resistance.

miR-34a is significantly down-regulated in breast cancer tissues and cell lines, which may be correlated with breast cancer multi-drug resistance (MDR). Here, we conducted cell-based experiments and clinical studies in a cohort of 113 breast cancer samples to analyze miR-34a expression and breast cancer MDR. Expression of miR-34a is down-regulated in the multi-drug resistant MDR-MCF-7 cells compared with its parental cells. Patients with miR-34a low expression had poorer overall survival (OS) and disease free survival (DFS) in comparison with those with high expression. Transfecting miR-34a mimics into MDR-MCF-7 breast cancer cells led to partial MDR reversal. Compared with the control group, miR-34a significantly reduced both the mRNA and protein expressions of BCL-2, CCND1 and NOTCH1, but no obvious changes were found in P53 or TOP-2a expression. In breast cancer tissue samples, the expression of miR-34a was related to BCL-2, CCND1 and NOTCH1, but not to HER-2, P53 and TOP-2a. Altogether, our findings suggest that miR-34a is an MDR and prognosis indicator of breast cancer, which may participate in the regulation of drug-resistant breast cancer by targeting BCL-2, CCND1, and NOTCH1.

[Correlation between Tau expression and clinicopathological characteristics of breast invasive ductal carcinomas].

OBJECTIVE: To explore the expression of Tau protein in breast invasive ductal carcinomas and examine the correlation between its expression and clinicopathological characteristics of breast cancer. METHODS: The clinicopathological data of 150 breast cancer patients at Third Municipal Hospital from October 2007 to June 2011 were collected and analyzed. Immunohistochemical method was used to detect the expressions of estrogen receptor (ER), progesterone receptor (PR), HER-2 and Tau protein. RESULTS: No correlations existed between the expression of Tau protein and age, tumor size or node metastasis of breast cancer patients (χ(2) = 0.02, P = 0.88; χ(2) = 0.55, P = 0.46; χ(2) = 1.02, P = 0.31). The expressions of Tau in ER positive patients were significantly higher than ER negative patients. And this trend extended to PR positive and HER-2 negative patients (χ(2) = 15.77, P = 0.00; χ(2) = 5.03, P = 0.03; χ(2) = 8.00, P = 0.01). The expression of Tau protein in Luminal A subtype was significantly higher than in Luminal B subtype, HER-2 over-expression subtype and basal like subtype (χ(2) = 7.26, P = 0.01). CONCLUSIONS: Over-expressed in breast cancer, Tau protein is associated with ER, PR and HER-2. However, the relation between Tau protein and prognosis of breast cancer requires further researches.

Tau proteins expressions in advanced breast cancer and its significance in taxane-containing neoadjuvant chemotherapy.

Tau is a microtubule-associated protein and expressed in normal breast epithelial cells and breast cancer. Tau expression in breast cancer may be important for chemotherapy optimization. This study is to investigate the expression of Tau in advanced breast cancer and its significance in taxane-containing neoadjuvant chemotherapy. Levels of Tau protein in advanced breast cancer were detected immunohistochemically. The chemotherapeutic efficacy indexes in Tau(-) group, which includes the remission rate, Miller-Payne pathological reactive grade, and pathologic complete response rate, were improved compared with that in Tau(+) group. There was difference in the efficacy indexes among ER+ subgroups but not among ER- patients. In addition, Tau expression was positively correlated (r = 0.32, P < 0.00). In multivariate analysis, when age, clinical stage, postoperative lymph node metastasis, ER, PR, HER2, Ki-67, TP53, or Tau status were included, postoperative lymph node metastasis and Tau-negative status were identified as independent predictors of pathologic complete response. In conclusion, negative Tau protein expression may be an effective predictor for taxane-containing neoadjuvant chemotherapy, especially in ER+ subgroups. Further study on the molecular mechanism and utility of Tau for individualizing adjuvant chemotherapy is warranted.