Our previous study found that mediator complex subunit 19 (Med19) is upregulated and involved in breast cancer tumorigenesis; however, the detailed effects and mechanism of Med19 in breast cancer ...require further study. In this study, we found that Med19 was obviously elevated in human breast cancer tissues, which was significantly associated with larger tumors, high-grade malignant features and poor prognosis. Furthermore, Med19 enhanced breast cancer cell proliferation, epithelial–mesenchymal transition, invasion and migration in vitro and in vivo. Med19 interacted with epidermal growth factor receptor (EGFR) and increased EGFR expression. Moreover, Med19 activated the EGFR/mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway and exerted its oncogenic activity in an EGFR signaling-mediated manner. In addition, Med19 expression was regulated by miR-101–3p and miR-422a. Med19 expression positively correlated with EGFR expression and negatively correlated with miR-101–3p and miR-422a expression in human breast cancer tissues. Med19 mediated the crosstalk between miR-101–3p/miR-422a and the EGFR/MEK/ERK signaling pathway. This study revealed a new miR-101–3p/miR-422a-Med19-EGFR/MEK/ERK axis that plays a significant role in breast cancer progression. These results help elucidate the potential mechanisms of Med19 in human breast cancer progression.
•Mediator complex subunit 19 (Med19) was elevated in breast cancer and predicted a poor prognosis for breast cancer patients.•Med19 enhanced breast cancer cell proliferation, epithelial–mesenchymal transition, invasion and migration.•Med19 was targeted by microRNA-101–3p/microRNA-422a and exerted oncogenic activity in an EGFR-mediated manner.•Therapeutic inhibition of Med19 expression could hinder breast cancer growth and metastasis.
Adriamycin (ADM)‐based regimens are the most effective chemotherapeutic treatments for breast cancer. However, intrinsic and acquired chemoresistance is a major therapeutic problem. Our goal was to ...clarify the role of mediator complex subunit 19 (Med19) in chemotherapy resistance and to elucidate the related molecular mechanisms. In this study, ADM‐resistant human cells (MCF‐7/ADM) and tissues exhibited increased Med19 expression and autophagy levels relative to the corresponding control groups. Additionally, MCF‐7/ADM cells showed changes in two selective markers of autophagy. There was a dose‐dependent increase in the light chain 3 (LC3)‐II/LC3‐I ratio and a decrease in sequestosome 1 (P62/SQSTMl) expression. Furthermore, lentivirus‐mediated Med19 inhibition significantly attenuated the LC3‐II/LC3‐I ratio, autophagy‐related gene 3 (Atg3) and autophagy‐related gene 5 (Atg5) expression, P62 degradation, and red fluorescent protein‐LC3 dot formation after treatment with ADM or rapamycin, an autophagy activator. Furthermore, the antiproliferative effects of ADM, cisplatin (DDP), and taxol (TAX) were significantly enhanced after suppressing Med19 expression. Notably, the effects of Med19 on autophagy were mediated through the high‐mobility group box‐1 (HMGB1) pathway. Our findings suggest that Med19 suppression increased ADM chemosensitivity by downregulating autophagy through the inhibition of HMGB1 signaling in human breast cancer cells. Thus, the regulatory mechanisms of Med19 in autophagy should be investigated to reduce tumor resistance to chemotherapy.
Polycystic ovary syndrome (PCOS) is a complex endocrine disorder that often coexists with a metabolic disorder. Studies have demonstrated that the malfunction of adipose tissue, particularly ...abdominal adipose tissue, could exacerbate reproductive and metabolic problems in PCOS patients. Adipose tissue-secreted signaling mediators (e.g., lipids and metabolites) would then interact with other body organs, including the ovary, to maintain the systemic equilibrium.
In this study, we examined adipose samples from PCOS patients and unaffected individuals using a liquid chromatography-mass spectrometry-based metabonomics approach (LC-MS/MS). PCOS biomarkers were selected using multivariate statistical analysis.
Our pathway analysis revealed that these differential metabolites could be engaged in inflammatory diseases and mitochondrial beta-oxidation. We further developed an in vitro PCOS cell model to examine the effects of hyperandrogenism on granulosa cells and related metabolic disorders. We noted that isoleucine recovered the promotive effect on cell apoptosis, inhibitory effect on cell proliferation, sex hormone secretion, and mitochondrial function induced by dehydroepiandrosterone. Our gas chromatography-mass spectrometry targeted analysis (GC-MS/MS) revealed that isoleucine was significantly decreased in PCOS patients.
Based on these results, we speculate that metabolome alterations are vital in ameliorating PCOS symptoms. This may be a novel therapeutic target for PCOS treatment. Our study provides preliminary evidence that these findings will enhance our ability to accurately diagnose and intervene in PCOS.
Emerging research has indicated that circular RNAs (circRNAs), a novel class of non‐coding RNAs, play a vital role in human tumorigenesis and progression. Our previous results suggested that ...hsa_circ_0006528 (circ_0006528), a circRNA with an unknown function, mediates adriamycin resistance in human breast cancer cells. However, the role of circ_0006528 in breast cancer progression remains unknown. Here, we investigated the probable involvement of circ_0006528 in breast cancer. We analyzed a cohort of 97 patients and found that circ_0006528 expression was significantly upregulated in human breast cancer tissues compared with that in adjacent non‐tumorous tissues and was significantly associated with advanced tumor‐node‐metastasis (TNM) stage and poor prognosis. In addition, we found that in breast cancer cells, circ_0006528 could promote DNA synthesis and cell proliferation, invasion, and migration. Downregulating circ_0006528 induced G2 phase arrest and cell apoptosis. Further mechanistic studies revealed that circ_0006528 could sponge endogenous miR‐7‐5p and inhibit its activity. We also identified Raf1, which activates the MAPK/ERK signaling pathway, as a target of miR‐7‐5p and determined that circ_0006528 promotes breast cancer growth, invasion, and migration by promoting the expression of Raf1 and activates the MAPK/ERK pathway. Thus, this study provides the first evidence of the circ_0006528/miR‐7‐5p/Raf1/MEK/ERK regulatory network in the development of breast cancer and suggests that circ_0006528 is a potential therapeutic target and prognostic predictor for breast cancer.
We aimed to identify circular RNAs (circRNAs) associated with breast cancer chemoresistance.
CircRNA microarray expression profiles were obtained from Adriamycin (ADM) resistant MCF-7 breast cancer ...cells (MCF-7/ADM) and parental MCF-7 cells and were validated using quantitative real-time reverse transcription PCR. The expression data were analyzed bioinformatically.
We detected 3093 circRNAs and identified 18 circRNAs that are differentially expressed between MCF-7/ADM and MCF-7 cells; after validating by quantitative real-time reverse transcription PCR, we predicted the possible miRNAs and potential target genes of the seven upregulated circRNAs using TargetScan and miRanda. The bioinformatics analysis revealed several target genes related to cancer-related signaling pathways. Additionally, we discovered a regulatory role of the
axis in ADM-resistant breast cancer.
These results revealed that circRNAs may play a role in breast cancer chemoresistance and that
might be a promising candidate for further functional analysis.
Abstract
Long non-coding RNAs (lncRNAs) are regarded as important functional regulators of various biological processes and are also known to be involved in the occurrence and development of human ...cancers, including breast cancer (BC). In our present study, the RNA expression profiling data for a large cohort of human BC samples were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, and the differentially expressed lncRNAs were screened out. We found that the expression of ST8SIA6-AS1 was elevated in BC tumour tissues compared with the adjacent normal tissues in the samples from the TCGA and GEO datasets, as well as in 138 BC tissue samples obtained by us. The high expression of ST8SIA6-AS1 was associated with estrogen receptor-negative, progesterone receptor-negative, advanced tumour-node-metastasis stage and worse survival in BC patients. In vitro functional studies revealed that high expression of ST8SIA6-AS1 promoted proliferation, invasion and migration of BC cell lines. The results of the in vivo studies indicated that upregulation of ST8SIA6-AS1 promoted xenograft tumour growth of BC. Mechanistically, ST8SIA6-AS1 regulated AKT1 and p38 mitogen-activated protein kinase (MAPK) gene expression by affecting their mRNA and protein levels, respectively, and it also affected the phosphorylation of AKT1 protein. Rescue experiments indicated that ST8SIA6-AS1 promoted BC cell proliferation, invasion and migration in a p38 MAPK signalling-mediated manner. Together, our data suggest that ST8SIA6-AS1 plays an important role in the occurrence and development of BC and may therefore serve as a promising therapeutic target.
Our findings highlight the importance of ST8SIA6-AS1 as an oncogenic lncRNA in BC. The current discovery of the role of ST8SIA6-AS1 in vitro and in vivo in BC provides a theoretical basis for further clinical applications. Besides, these findings provide insights into ST8SIA6-AS1 as a new prognostic marker and candidate target for BC therapy.
Synchronous bilateral multiple chromophobe cell renal carcinoma is rare; here we report a case diagnosed with bilateral renal multiple tumors complicated with a cyst in the right kidney. ...Retroperitoneal laparoscopic bilateral nephron sparing surgery was performed and there was no serious postoperative renal dysfunction. Pathological and immunohistochemical diagnoses of both tumors were chromophobe cell renal carcinoma. The patient has been doing well without any evidence of recurrence or metastasis for 6 months.
Purpose We determined the characteristics of Chinese men undergoing initial prostate biopsy and evaluated the relationship between prostate specific antigen levels and prostate cancer/high grade ...prostate cancer detection in a large Chinese multicenter cohort. Materials and Methods This retrospective study included 13,904 urology outpatients who had undergone biopsy for the indications of prostate specific antigen greater than 4.0 ng/ml or prostate specific antigen less than 4.0 ng/ml but with abnormal digital rectal examination results. The prostate specific antigen measurements were performed in accordance with the standard procedures at the respective institutions. The type of assay used was documented and recalibrated to the WHO standard. Results The incidence of prostate cancer and high grade prostate cancer was lower in the Chinese cohort than the Western cohorts at any given prostate specific antigen level. Around 25% of patients with a prostate specific antigen of 4.0 to 10.0 ng/ml were found to have prostate cancer compared to approximately 40% in U.S. clinical practice. Moreover, the risk curves were generally flatter than those of the Western cohorts, that is risk did not increase as rapidly with higher prostate specific antigen. Conclusions The relationship between prostate specific antigen and prostate cancer risk differs importantly between Chinese and Western populations, with an overall lower risk in the Chinese cohort. Further research should explore whether environmental or genetic differences explain these findings or whether they result from unmeasured differences in screening or benign prostate disease. Caution is required for the implementation of prostate cancer clinical decision rules or prediction models for men in China or other Asian countries with similar genetic and environmental backgrounds.
Background Surgical resection is the most effective treatment for renal cell carcinoma （RCC）.Currently several prognostic factors and models are used for outcome prediction.However,whether ...intratumoral changes are independent prognostic factors for RCC or not remains unclear.The aim of the study was to investigate the prognostic roles of intratumoral changes in surgical treated localized clear cell renal cell carcinoma （ccRCC）.Methods Patients who received partial or radical nephrectomy between 2004 and 2009 in our center were retrospectively reviewed.Univariate and multivariate analyses were used to assess gender,age,body mass index （BMI）,intratumoral hemorrhage,tumor necrosis,cystic degeneration,sarcomatoid change,Ki-67 expression,Fuhrman grade,and T stage on recurrence-free survival （RFS） and cancer-specific survival （CSS）.Results A total of 378 patients were included in our study.In univariate analysis,age,BMI,intratumoral hemorrhage,tumor necrosis,sarcomatoid change,Ki-67 expression level,Fuhrman grade,and T stage were prognostic factors for RFS.Age,BMI,tumor necrosis,sarcomatoid change,Ki-67 expression level,Fuhrman grade,and T stage were prognostic factors effecting CSS.In multivariate analysis,age,BMI,tumor necrosis,sarcomatoid change,Ki-67,Fuhrman grade,and T stage were independent prognostic factors for both RFS and CSS.Conclusion Intratumoral changes such as tumor necrosis and sarcomatoid change are independent prognostic factors for ccRCC.
Objective： To investigate the antitumor activity of tumor lysate-pulsed dendritic cells vaccine in RM-1 prostate cancer mice model with the survival time of mice calculated and the tumor size ...measured in DC vaccine therapy. Methods： C57BL/6 mice were immunized on the dorsal flank by s.c. inoculation of Lysate-DC, ova-DC, and non-DC on day -7. On day 0, 2× 10^6cells of RM-1 tumor cells （H-2b） were injected s.c. in C57BL/6 mice pre-treated by s.c. inoculation of modified DCs, correspondingly. DTH assay was performed with modified DCs. In partial test, for the determination of which immune cells were required for antitumor activity, mice were immunodepleted of CD4, CDS, or natural killer （NK） NK1.1 cells with the corresponding monoclonal antibodies. The survival time of nude mice loaded with tumor cells was calculated and the size of tumor measured. Results： In RM-1 mice prostate cancer model, immunized with lysate-DC, compared with ova-DC and non-DC, the pre-infection vaccine resulted in 100% clearance of primary tumors, whereas on day 0 of injection vaccine cleared 40-60% of primary tumors. On day 0, C57BL/6 mice （H-2b） were immunized with Lysate-DC, compared with ova-DC and non-DC by caudal vein injection, then on day 15, RM-1 cells were inoculated. On day 30, average diameters of tumor in different groups of modified DC were 23.7±5.4 mm, 22.1±4.9 mm, 4.3±2.6 mm, respectively. Lysate-DC, compared with ova-DC and non-DC, can greatly depressed RM-1 tumor cell growth （P〈0.01）. The mean survival time of C57BL/6 mice in Lysate-DC, ova-DC and non-DC groups were 15.8±2.6, 16.6±3.2, 39.0±5.6, respectively, and there was a significant difference in the mean survival time in lysate-DC group between ova-DC and non-DC group （P〈0.01）. DTH test showed that lysate-DC could prime T lymphocyte and elicit tumor antigen specific immune response, and over 80% mice in groups of lysate-DC showed obvious swelling in their foot pad. This response was strengthened with repeating inoculation, whereas DTH response was not seen in control group. In vivo depletion of NK cells resulted in a 40-60% reduction in growth suppression within the primary tumor, and depletion of CD4^＋ cells resulted in a 20% reduction in growth suppression. Conclusion： The minor lysate-pulsed dendritic cells vaccine could elicit antitumor activity in RM-1 loaded C57BL/6 mice, and prolong the duration of RM-1 loaded C57BL/6 mice. So DC-based immunotherapy with hormone-refractory prostate carcinoma yielded protective immunity, generated efficient cellular antitumor responses, thereby providing further preclinical support for feasible immunotherapy approaches for prostate cancer.
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