KIF17 maintains the epithelial phenotype of breast cancer cells and curbs tumour metastasis.

Kinesin superfamily motor protein 17 (KIF17) was previously identified downregulated in breast cancer and correlated with patient prognosis. However, its pathophysiological role in tumours remains unknown. Here, we confirmed that KIF17 was significantly under-expressed in breast cancer tissues and low KIF17 expression correlated with poor outcomes in patients with breast cancer. In vitro and in vivo experiments demonstrated that KIF17 overexpression in breast cancer cell lines significantly inhibited breast cancer invasion and metastasis. By establishing the lung metastatic MDA-MB-231 cell lines, we found a transient silence of KIF17 during the initiation of breast cancer metastasis. Further experiments revealed that KIF17 might suppress metastasis by regulating the level of acetylated tubulin to maintain cytoskeleton stability. Eventually, we found that the low expression of KIF17 in breast cancer is regulated by DNMT1-mediated 5-mC DNA methylation and epigenetic silencing. Decitabine can effectively improve the expression level of KIF17 in breast cancer cells. Our study demonstrates that KIF17 mediates microtubule acetylation to maintain the stability of microtubules, thereby inhibiting tumour invasion and metastasis.

Protein phosphatase 1 regulatory inhibitor subunit 14C promotes triple-negative breast cancer progression via sustaining inactive glycogen synthase kinase 3 beta.

Triple-negative breast cancer (TNBC) is fast-growing and highly metastatic with the poorest prognosis among the breast cancer subtypes. Inactivation of glycogen synthase kinase 3 beta (GSK3ß) plays a vital role in the aggressiveness of TNBC; however, the underlying mechanism for sustained GSK3ß inhibition remains largely unknown. Here, we find that protein phosphatase 1 regulatory inhibitor subunit 14C (PPP1R14C) is upregulated in TNBC and relevant to poor prognosis in patients. Overexpression of PPP1R14C facilitates cell proliferation and the aggressive phenotype of TNBC cells, whereas the depletion of PPP1R14C elicits opposite effects. Moreover, PPP1R14C is phosphorylated and activated by protein kinase C iota (PRKCI) at Thr73. p-PPP1R14C then represses Ser/Thr protein phosphatase type 1 (PP1) to retain GSK3ß phosphorylation at high levels. Furthermore, p-PPP1R14C recruits E3 ligase, TRIM25, toward the ubiquitylation and degradation of non-phosphorylated GSK3ß. Importantly, the blockade of PPP1R14C phosphorylation inhibits xenograft tumorigenesis and lung metastasis of TNBC cells. These findings provide a novel mechanism for sustained GSK3ß inactivation in TNBC and suggest that PPP1R14C might be a potential therapeutic target.

LncRNA LGALS8-AS1 Promotes Breast Cancer Metastasis Through miR-125b-5p/SOX12 Feedback Regulatory Network.

BACKGROUND: Metastasis is a major factor weakening the long-term survival of breast cancer patients. Increasing evidence revealed that long non-coding RNAs (lncRNAs) were involved in the occurrence and development of breast cancer. In this study, we aimed to investigate the role of LGALS8-AS1 in the metastatic progression of breast cancer cells and its potential mechanisms. RESULTS: The lncRNA LGALS8-AS1 was highly expressed in breast cancer and associated with poor survival. LGALS8-AS1 functioned as an oncogenic lncRNA that promoted the metastasis of breast cancer both in vitro and in vivo. It upregulated SOX12 via competing as a competing endogenous RNA (ceRNA) for sponging miR-125b-5p and acted on the PI3K/AKT signaling pathway to promote the metastasis of breast cancer. Furthermore, SOX12, in turn, activated LGALS8-AS1 expression via direct recognition of its sequence binding enrichment motif on the LGALS8-AS1 promoter, thereby forming a positive feedback regulatory loop. CONCLUSION: This study manifested a novel mechanism of LGALS8-AS1 facilitating the metastasis of breast cancer. The LGALS8-AS1/miR-125b-5p/SOX12 reciprocal regulatory loop dyscrasia promoted the migration and invasion of breast cancer cells. This signaling axis could be applicable to the design of novel therapeutic strategies against this malignancy.

AHNAK2 promotes thyroid carcinoma progression by activating the NF-κB pathway.

Thyroid carcinoma metastasis is the main reason for treatment failure; therefore, understanding the regulatory mechanisms of thyroid carcinoma metastasis is critical to treat patients with thyroid carcinoma. The present study aimed to investigate the role of AHNAK Nucleoprotein 2 (AHNAK2) in thyroid carcinoma metastasis. AHNAK2 was found to be upregulated in thyroid carcinoma tissues, especially in metastatic thyroid carcinoma tissues. Patients with high AHNAK2 expression had poor prognosis. AHNAK2 knockdown inhibited thyroid carcinoma migration, invasion, and metastasis. Mechanistic analysis showed that AHNAK2 knockdown reduced thyroid carcinoma progression by inhibiting nuclear factor kappa B (NF-κB) pathway activity. The results identified a novel target to treat metastatic thyroid carcinoma.

Tripartite motif-containing 3 (TRIM3) enhances ER signaling and confers tamoxifen resistance in breast cancer.

Tamoxifen resistance remains a clinical problem in estrogen receptor (ER)-positive breast cancer. SUMOylation of ERα enhances ERα-induced transcription activity. Tripartite motif-containing (TRIM) proteins are a new class of SUMO E3 ligases, which regulate the SUMOylation of proteins. However, the precise molecular mechanism and function of TRIM3 in SUMOylation and the response to tamoxifen remain unclear. In the present study, we observed that TRIM3 was dramatically overexpressed in breast cancer, which correlated with tamoxifen resistance. Furthermore, TRIM3 overexpression significantly correlated with poor survival of patients with ER+ breast cancer treated with tamoxifen. TRIM3 overexpression conferred cell survival and tumorigenesis, whereas knocking down of TRIM3 reduced these capabilities. Moreover, TRIM3, as a ubiquitin carrier protein 9 (UBC9) binding protein, promoted SUMO modification of estrogen receptor 1 (ESR1) and activated the ER pathway. Silencing UBC9 abolished the function of TRIM3 in regulating tamoxifen resistance. These results suggest TRIM3 as a novel biomarker for breast cancer therapy, indicating that inhibiting TRIM3 combined with tamoxifen might provide a potential treatment for breast cancer.

Overexpression of kinesin superfamily members as prognostic biomarkers of breast cancer.

BACKGROUND: Kinesin superfamily (KIFs) has a long-reported significant influence on the initiation, development, and progress of breast cancer. However, the prognostic value of whole family members was poorly done. Our study intends to demonstrate the value of kinesin superfamily members as prognostic biomarkers as well as a therapeutic target of breast cancer. METHODS: Comprehensive bioinformatics analyses were done using data from TCGA, GEO, METABRIC, and GTEx. LASSO regression was done to select tumor-related members. Nomogram was constructed to predict the overall survival (OS) of breast cancer patients. Expression profiles were testified by quantitative RT-PCR and immunohistochemistry. Transcription factor, GO and KEGG enrichments were done to explore regulatory mechanism and functions. RESULTS: A total of 20 differentially expressed KIFs were identified between breast cancer and normal tissue with 4 (KIF17, KIF26A, KIF7, KIFC3) downregulated and 16 (KIF10, KIF11, KIF14, KIF15, KIF18A, KIF18B, KIF20A, KIF20B, KIF22, KIF23, KIF24, KIF26B, KIF2C, KIF3B, KIF4A, KIFC1) overexpressed. Among which, 11 overexpressed KIFs (KIF10, KIF11, KIF14, KIF15, KIF18A, KIF18B, KIF20A, KIF23, KIF2C, KIF4A, KIFC1) significantly correlated with worse OS, relapse-free survival (RFS) and distant metastasis-free survival (DMFS) of breast cancer. A 6-KIFs-based risk score (KIF10, KIF15, KIF18A, KIF18B, KIF20A, KIF4A) was generated by LASSO regression with a nomogram validated an accurate predictive efficacy. Both mRNA and protein expression of KIFs are experimentally demonstrated upregulated in breast cancer patients. Msh Homeobox 1 (MSX1) was identified as transcription factors of KIFs in breast cancer. GO and KEGG enrichments revealed functions and pathways affected in breast cancer. CONCLUSION: Overexpression of tumor-related KIFs correlate with worse outcomes of breast cancer patients and can work as potential prognostic biomarkers.

KCTD12 promotes G1/S transition of breast cancer cell through activating the AKT/FOXO1 signaling.

BACKGROUND: Sustaining proliferation is the most fundamental step for breast cancer tumor genesis. Accelerated proliferation is usually linked to the uncontrolled cell cycle. However, the internal and external factors linked to the activation of breast cancer cell cycle are still to be investigated. METHODS: quantitative PCR (qPCR) and Western blotting assay were used to detect the expression of potassium channel tetramerization domain containing 12 (KCTD12) in breast cancer. MTT and colony formation assays were performed to evaluate the effect of KCTD12 on cell proliferation of breast cancer. Anchorage-independent growth assay was used to examine the in vitro tumorigenesis of breast cancer cells. Flow cytometry assay, qPCR, and Western blotting were used to investigate the detailed mechanisms of KCTD12 on breast cancer progression. RESULTS: Herein, the result showed that the level of KCTD12 is significantly decreased in breast cancer tissues and cells, and lower level of KCTD12 predicts poorer survival for patients with breast cancer. Further cell function tests illustrated that downregulation of KCTD12 significantly promotes cell proliferation and in vitro tumor genesis. Besides, molecular biologic experiments showed that downregulation of KCTD12 can enhance the G1/S transition through activating the AKT/FOXO1 signaling. CONCLUSION: Our study inferred that downregulation of KCTD12 can be a novel factor for poor prognosis in breast cancer.

Correction to: IGFBP7 inhibits cell proliferation by suppressing AKT activity and cell cycle progression in thyroid carcinoma.

[This corrects the article DOI: 10.1186/s13578-019-0310-2.].

Prospect for Application of PARP Inhibitor in Patients with HER2 Negative Breast Cancer.

Human epidermal growth factor receptor (HER2) negative metastatic breast cancer (BC) accounts for 73% of BC. The molecular analysis of this disease is essential for potential options for targeted therapy. Several promising clinical strategies are being evaluated which includes endocrine therapy, modified chemotherapy, angiogenesis inhibitors, immune checkpoint inhibitors, and anti-androgens. New therapeutic approaches are being developed that target BC patients with germline mutations in either BRCA1, BRCA2 as well as BRCAness, a condition in which tumors have molecular similarity to BRCA-mutated tumors. Poly (ADP-ribose) polymerase inhibitors (PARPi) which are effective therapy in germline BRCA1 and BRCA2 mutations, are also observed to be effective in somatic mutations. Germline mutations in the homologous recombination pathway genes could also contribute to PARPi sensitivity. PARPi act as chemo- and radio-sensitizers by limiting the DNA-damage response and potentiating the activity of chemo- and radio-therapy when used alone or in combination with chemotherapy. Apart from PARPi as monotherapy, additional researches are ongoing in combination with cytotoxic chemotherapeutics and targeted agents in HER2 negative BC. This review aims at the most recent developments in the targeted therapy, summarizes the recent clinical trials outcomes, along with the overview of ongoing clinical trials in HER2 negative patients with BRCA1/2 mutations and sporadic tumors with BRCAness.

IGFBP7 inhibits cell proliferation by suppressing AKT activity and cell cycle progression in thyroid carcinoma.

BACKGROUND: Thyroid cancer is the most common malignant endocrine tumor and is classified into papillary thyroid cancer (PTC), follicular thyroid cancer (FTC) and anaplastic thyroid cancer (ATC), which have substantially different characteristics. Insulin-like growth factor binding protein 7 (IGFBP7) has recently been recognized as a tumor suppressor in many cancer types. However, the expression pattern of IGFBP7 and its biological function in various types of thyroid carcinoma remain poorly understood. RESULTS: We found that the protein levels of IGFBP7 in FTC and ATC tissues were significantly lower or even absent compared with those in normal thyroid, benign thyroid adenoma and classical PTC tissues. Moreover, overexpression of IGFBP7 in two undifferentiated ATC cell lines, ARO and FRO, and one differentiated FTC cell line, WRO, significantly inhibited cell proliferation in vitro. In vivo experiments revealed that ectopic IGFBP7 expression markedly suppressed growth of tumor xenografts derived from these thyroid cancer cell lines, while IGFBP7 silencing accelerated tumor growth. At the mechanistic level, overexpression of IGFBP7 dramatically suppressed phosphorylation-mediated activation and kinase activity of AKT, causing an upregulation of cyclin-dependent kinase (CDK) inhibitors p27Kip1 and p21Cip1 and induction of G1/S cell cycle arrest, while silencing IGFBP7 exerted the opposite effects. CONCLUSIONS: IGFBP7 expression is decreased or even absent in FTC and ATC. Acting as a cell cycle repressor, IGFBP7 plays an important tumor-suppressive role in human thyroid cancer, especially in FTC and ATC subtypes and may represent a promising biomarker and therapeutic target for human thyroid cancer treatment.

Long Noncoding RNA LOC100129940-N Is Upregulated in Papillary Thyroid Cancer and Promotes the Invasion and Progression.

Thyroid cancer is the most common endocrine malignancy, and its incidence has increased rapidly in recent decades worldwide. Papillary thyroid cancer (PTC) is the most common type of all thyroid cancers. The molecular mechanisms underlying the disease still need to be further investigated. Long noncoding RNAs (lncRNAs), a class of noncoding RNAs (ncRNAs) longer than 200 nucleotides, are aberrantly expressed in malignant diseases, including PTC. Here, we identified a novel isoform of LOC100129940 and designated it as LOC100129940-N. We demonstrated that the expression level of LOC100129940-N was elevated in PTC, indicating that LOC100129940-N may be involved in PTC development and progression. Moreover, our results showed that overexpression of LOC100129940-N promoted, whereas silencing of LOC100129940-N suppressed, PTC cell proliferation, invasion, and migration. Mechanistically, LOC100129940-N played an important role in activating Wnt/ß-catenin signaling and upregulating downstream target genes. Taken together, we demonstrate that LOC100129940-N promotes the activation of Wnt/ß-catenin signaling, which in turn regulates the downstream target genes, thereby enhancing invasion and progression of PTC.

Comparison of the 7th and 8th edition of American Joint Committee on Cancer (AJCC) staging systems for breast cancer patients: a Surveillance, Epidemiology and End Results (SEER) Analysis.

BACKGROUND: The 8th edition of the American Joint Committee on Cancer (AJCC) staging system for breast cancer has incorporated tumor grade, estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 status as staging biologic factors reflecting prognosis. The purpose of this study was to compare the 7th and 8th edition of AJCC staging system for prognostic impact. MATERIALS AND METHODS: Primary breast cancer patients diagnosed from 2010 to 2014 were identified using the Surveillance, Epidemiology and End Results 18 registries research database. Breast cancer-specific survival (BCSS) and overall survival (OS) between stages were estimated using the Kaplan-Meier method and compared using the log-rank test. Multivariable analysis was performed using Cox proportional hazards regression analysis to identify factors independently associated with outcome. Akaike's information criterion (AIC) was calculated to estimate how well the staging system fitted the data and the complexity of the model. RESULTS: A total of 184,221 primary breast cancer patients were identified in the 7th AJCC staging system; 16,145 (8.8%) patients could not be categorized according to 8th AJCC prognostic staging system leaving 168,076 patients included for final analyses. The 8th AJCC performed well with the BCSS and OS concordant with stage. A total of 89,494 (53.2%) of patients were restaged to a different stage group in the 8th AJCC; stage IIIA in the 7th AJCC migrated to stage IB with a worse prognosis than IIA and IIB in the 8th AJCC. Nevertheless, the 8th AJCC had a better AIC than the 7th staging system. CONCLUSION: The prognostic accuracy of the 8th AJCC staging system was generally superior to the 7th AJCC, although subtle differences between the two systems should be noted in comparative studies.

AFF3 upregulation mediates tamoxifen resistance in breast cancers.

BACKGROUND: Although tamoxifen is a highly effective drug for treating estrogen receptor-positive (ER+) breast cancer, nearly all patients with metastasis with initially responsive tumors eventually relapse, and die from acquired drug resistance. Unfortunately, few molecular mediators of tamoxifen resistance have been described. Here, we describe AFF3 (AF4/FMR2 family member 3), which encodes a nuclear protein with transactivation potential that confers tamoxifen resistance and enables estrogen-independent growth. METHODS: We investigated AFF3 expression in breast cancer cells and in clinical breast cancer specimens with western blot and Real-time PCR. We also examined the effects of AFF3 knockdown and overexpression on breast cancer cells using luciferase, tetrazolium, colony formation, and anchorage-independent growth assays in vitro and with nude mouse xenografting in vivo. RESULTS: AFF3 was overexpressed in tamoxifen-resistant tumors. AFF3 overexpression in breast cancer cells resulted in tamoxifen resistance, whereas RNA interference-mediated gene knockdown reversed this phenotype. Furthermore, AFF3 upregulation led to estrogen-independent growth in the xenograft assays. Mechanistic investigations revealed that AFF3 overexpression activated the ER signaling pathway and transcriptionally upregulated a subset of ER-regulated genes. Clinical analysis showed that increased AFF3 expression in ER+ breast tumors was associated with worse overall survival. CONCLUSIONS: These studies establish AFF3 as a key mediator of estrogen-independent growth and tamoxifen resistance and as a potential novel diagnostic and therapeutic target.

Graphene oxide-hydroxyapatite nanocomposites effectively deliver HSV-TK suicide gene to inhibit human breast cancer growth.

Gene therapy with herpes simplex virus thymidine kinase gene (HSV-TK), which is also known as "suicide" gene therapy, is effective in various tumor models. The lack of a safe and efficient gene delivery system has become a major obstacle to "suicide" gene therapy. In this study, the cytotoxicity and transfection efficiency of graphene oxide-hydroxyapatite (GO-Hap) were analyzed by MTS and flow cytometry, respectively. A series of assays were performed to evaluate the effects of GO-HAp/p-HRE/ERE-Sur-TK combined with ganciclovir treatment on growth of human breast normal and cancer cells. The results showed that GO-HAp nanocomposites effectively transfected cells with minimum toxicity. GO-HAp/p-HRE/ERE-Sur-TK combined with ganciclovir treatment inhibited the proliferation and induced cell apoptosis in cancer cells, while the cytotoxic effects are tolerable in normal breast cells. We conclude that the GO-HAp nanocomposites have significant potential as a gene delivery vector for cancer therapy.

TNNT1 facilitates proliferation of breast cancer cells by promoting G1/S phase transition.

AIMS: Breast cancer is the major diagnosed cancer and the leading reason of cancer related death among women, and the tumor size is one of the risk factors. Therefore, it is significant to reveal the principle of breaking the subtle homeostasis of cell cycle and sustaining chronic proliferation of cancer cells. MAIN METHODS: The expression of TNNT1 was examined by qPCR and western blotting. The effect of TNNT1 on cell proliferation was detected by MTT, colony formation and anchorage-independent growth assay. The percent of cells in different cell phase was analyzed by Flow cytometry. The mRNA and protein expression of genes involved in G1/S transition was assayed using qPCR and western blotting, respectively. KEY FINDINGS: The results showed that TNNT1 expression is significantly increased in breast cancer tissues and closely correlated with clinical stage, T and N classification. Further experiments demonstrate that TNNT1 contributes to proliferation of breast cells by promoting G1/S transition. SIGNIFICANCE: Our results extend the mechanisms of controlling cell cycle and may provide a novel therapeutic target to therapy breast cancer.

INAVA promotes aggressiveness of papillary thyroid cancer by upregulating MMP9 expression.

BACKGROUND: Innate immunity activator (INAVA) has been shown to be elevated in lung adenocarcinoma. However, its expression pattern and function in papillary thyroid cancer (PTC) are unknown. This study aimed to identify the clinical, biological, and mechanistic impacts of INAVA on PTC. METHODS: Using The Cancer Genome Atlas dataset, real time PCR, and immunohistochemistry, the expression of INAVA in PTC was analyzed. Gain- and loss-of-function assays were performed to investigate the role of INAVA in PTC cell invasion, migration, and metastasis. We explored the molecular mechanisms underlying the roles of INAVA in PTC cells using transcriptome resequencing, real time PCR, western blotting and immunohistochemistry. RESULTS: We found that INAVA expression was significantly upregulated in PTC and was significantly associated with lymph node metastasis. Loss- and gain-of-function experiments demonstrated that INAVA promoted the aggressive phenotype of PTC cells in vitro and in vivo. Mechanistic study suggested that upregulation of INAVA resulted in elevated fibroblast growth factor 1 (FGF1), which in turn increased the expression level of matrix metalloproteinases 9 (MMP9). We further identified that the level of INAVA was positively correlated with the levels of FGF1 and MMP9 in clinical PTC specimens. CONCLUSION: These data establish a novel role for INAVA in promoting PTC progression and suggest that INAVA may represent a therapeutic target for the disease.

Prognostic value of tumor-infiltrating Foxp3+ regulatory T cells in patients with breast cancer: a meta-analysis.

PURPOSE: The prognostic value of tumor-infiltrating Foxp3+ regulatory T cells (Tregs) in breast cancer remains controversial. Therefore, we performed this meta-analysis to determine the impact of Foxp3+ Tregs infiltration on survival outcomes. METHODS: Relevant literature was retrieved from Pubmed, Web of science and Cocohrane until May 30, 2016. Meta-analysis was performed using hazard ratios (HRs), odds ratio (OR) and 95 % confidence intervals (CI) as effect measures. RESULTS: Fourteen studies (10,259 patients) were included. Meta-analysis showed that high Foxp3+ Tregs infiltration was correlated with high histological grade (OR= 2.96, 95%CI [2.03-4.31]), estrogen receptor (ER) negativity (OR= 0.38, 95%CI [0.23-0.60]), human epidermal growth factor receptor type 2 (HER2) positivity (OR=2.43, 95%CI [1.69-3.51]). The detection of FOXP3+ Tregs was significantly associated with recurrence-free survival (RFS) of patients (HR = 1.58, 95 % CI [1.03-2.44]). CONCLUSION: Our meta-analysis suggests that high Foxp3+ Tregs infiltration is associated with poor RFS in breast cancer patients and predicts histological grade, estrogen receptor and HER-2 status.

Overexpression of microRNA-96-5p inhibits autophagy and apoptosis and enhances the proliferation, migration and invasiveness of human breast cancer cells.

MicroRNAs (miRNA/miR) are short non-coding RNAs that function in the endogenous regulation of genes. miRNAs serve important roles in cellular events such as apoptosis, cell proliferation, migration, invasion, autophagy and the cell cycle. They also control the genesis and progression of tumors. Autophagy is a self-digestive process that occurs as a response to stress, and serves two opposite roles in tumor promotion or inhibition that may result in resistance to therapy. A number of studies have revealed that miRNAs control autophagic activity by targeting autophagy-associated genes, particularly in cancer. These previous studies demonstrated that miR-96-5p is upregulated in several types of malignant tumors. However, other functions of miR-96-5p in breast cancer, particularly those that are associated with autophagy, remain unknown. miR-96-5p expression was demonstrated to be upregulated in breast cancer cells compared with in normal breast epithelial cells. The overexpression of miR-96-5p inhibited autophagy, particularly starvation-induced autophagy, in MCF-7 and MDA-MB-231 cells. In addition, this inhibitory effect may have resulted in the suppression of Forkhead box O1. Additionally, the overexpression of miR-96-5p may promote cell proliferation, migration and invasion and inhibit apoptosis in MCF-7 and MDA-MB-231 cells. These data indicate that miR-96-5p is involved in the progression of breast cancer cells and may represent a potential therapeutic target for the treatment of breast cancer.

RING1 and YY1 binding protein suppresses breast cancer growth and metastasis.

Evidence suggests that RING1 and YY1 binding protein (RYBP) functions as a tumor suppressor. However, its role in breast cancer remains unclear. In the present study, the expression of RYBP was assessed in breast cancer patients and cell lines. Disease-free survival durations of breast cancer patients with high RYBP expression were determined based on the ATCG dataset. The effects of RYBP overexpression on cell growth, migration and invasive potency were also assessed. Nude mouse xenograft and lung metastasis models were also used to confirm the role of RYBP. The involvement of SRRM3 in RYBP-mediated breast cancer suppression was explored using SRRM3 siRNA. The potential relationship between RYBP, SRRM3, and REST-003 was examined by qPCR. The results showed that RYBP was downregulated in breast cancer patients and in several breast cancer cell lines. Breast cancer patients with high expression levels of RYBP displayed better disease-free survival. Overexpression of RYBP in MDA-MB-231 and SK-BR-3 cells significantly decreased cell proliferation, migration, and invasion ability, and increased the proportion of cells arrested in S-phase compared with the negative control cells. Additionally, upregulation of proliferation-related cell cycle proteins (cyclin A and cyclin B1) and E-cadherin, and downregulation of snail were observed in RYBP-overexpressing cells. Overexpression of RYBP reduced tumor volume and weight as well as metastatic foci in the lungs of nude mice. SRRM3 knockdown by siRNA, which is downregulated after RYBP overexpression, suppressed cell growth and metastasis in MDA-MB-231 and SK-BR-3 cells. Furthermore, qPCR analysis revealed that REST-003 ncRNA was downregulated in cells overexpressing RYBP and in SRRM3-inhibited cells. Moreover, cell invasion ability and growth were increased after SRRM3 upregulation in RYBP-overexpressing cells, but they were decreased following si-REST-003 transfection. In conclusion, overexpression of RYBP suppresses breast cancer growth and metastasis both in vitro and in vivo. SRRM3 and REST-003, which are downregulated in cells overexpressing RYBP, may be involved in RYBP-mediated breast cancer progression.

Protective and anti­angiopathy effects of ginsenoside Re against diabetes mellitus via the activation of p38 MAPK, ERK1/2 and JNK signaling.

The present study aimed to determine the protective and anti-angiopathy effects of ginsenoside (GSS) on Wistar rats with diabetes mellitus (DM). Diabetic angiopathy occurs during the early stage of diabetes, and in type 1 DM (T1DM) and type 2 DM (T2DM). In the present study, early DM, T1DM and T2DM were induced by treatment with a high­sucrose­high­fat diet, alloxan monohydrate or streptozocin, respectively. The levels of blood glucose, insulin, lipid metabolism markers [total cholesterol (TC), triglyceride (TG), high­density lipoprotein (HDL) and lipoprotein(a) (Lp­a)], and endothelial cell function markers [endothelin, nitric oxide, vascular endothelial growth factor (VEGF) and interleukin­6 (IL­6)] were determined following treatment with GSS. In addition, oral glucose tolerance test and insulin tolerance test were performed. The phosphorylation levels of p38 mitogen­activated protein kinase (MAPK), extracellular signal­regulated kinase 1/2 (ERK1/2) and c­Jun N­terminal kinase (JNK) were detected in aorta samples harvested from T2DM rats by western blot analysis. The present study determined that GSS treatment effectively decreased the levels of blood glucose, TC, TG, Lp­a, VEGF, IL­6, phosphorylated (p)­p38, p­ERK1/2 and p­JNK; however, treatment with GSS increased insulin and HDL levels. Therefore, it is possible that GSS exerts protective and anti­angiopathy effects against the early stage of diabetes, T1DM and T2DM in vivo via the activation of p38 MAPK, ERK1/2 and JNK signaling.