scholarly journals Potential Role of CCN Proteins in Breast Cancer: Therapeutic Advances and Perspectives

2021 ◽  
Vol 28 (6) ◽  
pp. 4972-4985
Author(s):  
Kazi Ahsan Ahmed ◽  
Tasnin Al Hasib ◽  
Shamrat Kumar Paul ◽  
Md. Saddam ◽  
Afsana Mimi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Multiple Roles ◽  
Matricellular Protein ◽  
Ccn Proteins ◽  
Biological Interactions ◽  
Ccn Family ◽  
Dual Nature ◽  
Functional Activities ◽  
And Migration

CCNs are a specific type of matricellular protein, which are essential signaling molecules, and play multiple roles in multicellular eukaryotes. This family of proteins consists of six separate members, which exist only in vertebrates. The architecture of CCN proteins is multi-modular comprising four distinct modules. CCN Proteins achieve their primary functional activities by binding with several integrin7 receptors. The CCN family has been linked to cell adhesion, chemotaxis and migration, mitogenesis, cell survival, angiogenesis, differentiation, tumorigenesis, chondrogenesis, and wound healing, among other biological interactions. Breast cancer is the most commonly diagnosed cancer worldwide and CCN regulated breast cancer stands at the top. A favorable or unfavorable association between various CCNs has been reported in patients with breast carcinomas. The pro-tumorigenic CCN1, CCN2, CCN3, and CCN4 may lead to human breast cancer, although the anti-tumorigenic actions of CCN5 and CCN6 are also present. Several studies have been conducted on CCN proteins and cancer in recent years. CCN1 and CCN3 have been shown to exhibit a dual nature of tumor inhibition and tumor suppression to some extent in quiet recent time. Pharmacological advances in treating breast cancer by targeting CCN proteins are also reported. In our study, we intend to provide an overview of these research works while keeping breast cancer in focus. This information may facilitate early diagnosis, early prognosis and the development of new therapeutic strategies.

scholarly journals The Aspects of CCN Protein Family on Breast Cancer

2021 ◽  
Author(s):  
Abu Saim Mohammad Saikat ◽  
Kazi Ahsan Ahmed ◽  
Md. Saddam ◽  
Afsana Mimi ◽  
Tasnin Al Hasib ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Protein Family ◽  
Ccn Proteins ◽  
Biological Interactions ◽  
Immune Functions ◽  
Matricellular Proteins ◽  
Ccn Family ◽  
Aberrant Expression ◽  
And Migration

CCNs are specific type of matricellular proteins, which are essential signaling molecules, and play multiple roles in multicellular eukaryotes. This family of proteins consists of six separate members in mammals. The architecture of CCN proteins is multimodular and comprises four distinct motifs. CCN proteins achieve their specific physiological functions by binding to integrin receptors. The CCN family has been implicated in both cure and disease with impacts on biological interactions, such as cell adhesion, chemotaxis and migration, mitogenesis, cell survival, angiogenesis, differentiation, tumorigenesis, immune functions, chondrogenesis, and wound healing. Breast cancer is the most commonly diagnosed cancer worldwide and the leading cause of cancer mortality among women triggered by atypical expression of CCNs. A favorable or unfavorable association between various CCNs has been reported in patients with breast carcinomas. Aberrant expression of CCN1 intensifies the proliferation of epithelial cells that line the lobes and ducts of the breast. Evidence also shows that the expression of CCN2 can ameliorate tumor growth and metastasis. However, CCN3 (NOV), CCN5 (WISP-2), and CCN6 (WISP-3) are consistent with neoplastic development and metastasis repression. Particular CCN members can develop tumors and cancer progression, whereas others can competitively counter the processes. Several studies have been conducted on CCN proteins and cancer in recent years. In our study, we intend to provide an overview of those research works while keeping breast carcinoma on focus. We believe that the importance of the CCN protein family in breast cancer should be reconsidered.

scholarly journals The Potential Prognostic Role of Oligosaccharide-Binding Fold-Containing Protein 2A (OBFC2A) in Triple-Negative Breast Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Qianxue Wu ◽  
Xin Tang ◽  
Wenming Zhu ◽  
Qing Li ◽  
Xiang Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cancer Cells ◽  
Candidate Genes ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
G1 Phase ◽  
And Migration

BackgroundPatients with triple-negative breast cancer (TNBC) have poor overall survival. The present study aimed to investigate the potential prognostics of TNBC by analyzing breast cancer proteomic and transcriptomic datasets.MethodsCandidate proteins selected from CPTAC (the National Cancer Institute’s Clinical Proteomic Tumor Analysis Consortium) were validated using datasets from METABRIC (Molecular Taxonomy of Breast Cancer International Consortium). Kaplan-Meier analysis and ROC (receiver operating characteristic) curve analysis were performed to explore the prognosis of candidate genes. GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analysis were performed on the suspected candidate genes. Single-cell RNA-seq (scRNA-seq) data from GSE118389 were used to analyze the cell clusters in which OBFC2A (Oligosaccharide-Binding Fold-Containing Protein 2A) was mainly distributed. TIMER (Tumor Immune Estimation Resource) was used to verify the correlation between OBFC2A expression and immune infiltration. Clone formation assays and wound healing assays were used to detect the role of OBFC2A expression on the proliferation, invasion, and migration of breast cancer cells. Flow cytometry was used to analyze the effects of silencing OBFC2A on breast cancer cell cycle and apoptosis.ResultsSix candidate proteins were found to be differentially expressed in non-TNBC and TNBC groups from CPTAC. However, only OBFC2A was identified as an independently poor prognostic gene marker in METABRIC (HR=3.658, 1.881-7.114). And OBFC2A was associated with immune functions in breast cancer. Biological functional experiments showed that OBFC2A might promote the proliferation and migration of breast cancer cells. The inhibition of OBFC2A expression blocked the cell cycle in G1 phase and inhibited the transformation from G1 phase to S phase. Finally, downregulation of OBFC2A also increased the total apoptosis rate of cells.ConclusionOn this basis, OBFC2A may be a potential prognostic biomarker for TNBC.

scholarly journals Long non-coding RNA ARAP1-AS1 accelerates cell proliferation and migration in breast cancer through miR-2110/HDAC2/PLIN1 axis

2020 ◽  
Vol 40 (4) ◽  
Author(s):  
Chong Lu ◽  
Xiuhua Wang ◽  
Xiangwang Zhao ◽  
Yue Xin ◽  
Chunping Liu
Keyword(s):  
Breast Cancer ◽  
Normal Breast ◽  
Tumor Promoter ◽  
Women Health ◽  
Non Coding Rna ◽  
Non Coding Rnas ◽  
And Migration ◽  
Breast Tissues ◽  
Long Non Coding Rna

Abstract Breast cancer (BC) poses a great threaten to women health. Numerous evidences suggest the important role of long non-coding RNAs (lncRNAs) in BC development. In the present study, we intended to investigate the role of ARAP1-AS1 in BC progression. First of all, the GEPIA data suggested that ARAP1-AS1 was highly expressed in breast invasive carcinoma (BRAC) tissues compared with the normal breast tissues. Meanwhile, the expression of ARAP1-AS1 was greatly up-regulated in BC cell lines. ARAP1-AS1 knockdown led to repressed proliferation, strengthened apoptosis and blocked migration of BC cells. Moreover, ARAP1-AS1 could boost HDAC2 expression in BC through sponging miR-2110 via a ceRNA mechanism. Of note, the UCSC predicted that HDAC2 was a potential transcriptional regulator of PLIN1, an identified tumor suppressor in BC progression. Moreover, we explained that the repression of HDAC2 on PLIN1 was owing to its deacetylation on PLIN1 promoter. More importantly, depletion of PLIN1 attenuated the mitigation function of ARAP1-AS1 silence on the malignant phenotypes of BC cells. To sum up, ARAP1-AS1 serves a tumor-promoter in BC development through modulating miR-2110/HDAC2/PLIN1 axis, which may help to develop novel effective targets for BC treatment.

TIPE1 suppresses the invasion and migration of breast cancer cells and inhibits epithelial-to-mesenchymal transition primarily via the ERK signaling pathway

2019 ◽  
Vol 51 (10) ◽  
pp. 1008-1015 ◽  
Author(s):  
Shusheng Qiu ◽  
Wei Hu ◽  
Qiuhong Ma ◽  
Yi Zhao ◽  
Liang Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Western Blot ◽  
Cancer Cells ◽  
Blot Analysis ◽  
Western Blot Analysis ◽  
Breast Cancer Cells ◽  
Mesenchymal Transition ◽  
Invasion And Migration ◽  
And Migration

Abstract Tumor necrosis factor α-induced protein 8-like-1 (TIPE1) functions as an activator or a repressor in a tumor cell type-specific manner. However, the role of TIPE1 in breast cancer, especially regarding metastasis, is unknown. In this study, we aimed to investigate the TIPE1 expression in breast cancer tissues, the biological functions, and the underlying mechanisms of TIPE1 regarding the metastatic properties of breast cancer cells. The results of immunohistochemical staining and western blot analysis indicated that TIPE1 expression was associated with tumor size and lymph node metastasis, and the expression of TIPE1 was downregulated in the tissues of patients with lymph node metastasis. Transwell and wound healing assay results showed that TIPE1 inhibited the invasive and migratory capacities of breast cancer cells. Moreover, the epithelial-mesenchymal transition (EMT) was suppressed in TIPE1-overexpressing cells, as demonstrated by western blot analysis. In addition, western blot analysis also showed that TIPE1 reduced the expression levels of MMP2 and MMP9 and decreased the phosphorylation level of ERK. These results suggested that TIPE1 might suppress the invasion and migration of breast cancer cells and inhibit EMT primarily via the ERK signaling pathway. Our findings revealed the anti-tumor metastasis role of TIPE1 in breast cancer and TIPE1 might be a new candidate prognostic indicator and a potential molecular target for the treatment of breast cancer.

The role of circCNIH4 in the adipocyte's effects on metastasis of breast cancer cells.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e13086-e13086
Author(s):  
Xiu Chen ◽  
Jinhai Tang
Keyword(s):  
Breast Cancer ◽  
Wound Healing ◽  
Cell Invasion ◽  
Invasion And Migration ◽  
Non Invasive ◽  
In Vivo Experiments ◽  
And Migration ◽  
Mcf 7

e13086 Background: Obesity is associated with the risk of breast cancer(BCa) incidence and development. However, biological changes in obesity BCa individuals are still uncertain. Nowadays, circCNIH4, one of novel non-coding RNAs, was found to be a non-invasive biomarker in cancers. Methods: We verified the cancer-promoting role of obesity in BCa patients by comparing BMI indexes of 33 BCa and 44 benign tumor patients. Then we cocultured viscera adipose cells(HPA-v) and BCa cells(MCF-7/H and MDA-MB-231/H) to confirm the function of adipocytes on metastasis of BCa cells through wound healing, transwell assays. In vivo experiments were also performed. We analyzed the expression level of circCNIH4 in MCF-7/H, MDA-MB-231/H and different subtypes of BCa cells by quantitative polymerase chain reaction. Simultaneously, we identified inhibited effects of circCNIH4 on metastasis of BCa cells by wound healing, transwell assays and verified the location of circCNIH4 by FISH. Luciferase Assay was used to detect harbored miRNA. Rescue experiments were then applied. Results: We found the BMI of BCa patients(24.37±2.51) was much higher than benign patients(22.97±2.91). Metastasis of BCa cells were obviously promoted after in vitro and in vivo experiments. Then we found the expression of circCNIH4 in MCF-7/H and MDA-MB-231/H were down-regulated 0.71 and 0.52 than that in MCF-7 and MDA-MB-231. Also, circCNIH4 was positively correlated with less aggressive types of BCa cells. Overexpression of circCNIH4 in MDA-MB-231 could suppress cell invasion and migration, while silencing of it in MCF-7 promoted cell invasion and migration. The FISH assay demonstrated that circCNIH4 mainly located in the cytoplasm and might function as a “sponge” for miRNA. MiR-135b functioned as a tumor promoter gene from data of 93 BCa patients (HR = 2.27; 1.01 − 5.12), and it could be captured by circCNIH4 via luciferase and rescued assays. Conclusions: In this study, we revealed that BMI or viscera adipocytes could deteriorate prognosis of BCa and circCNIH4 could be a novel biomarker for non-invasive BCa. In details, circCNIH4 mainly suppressed the adipocyte's pro-metastasis effects on BCa by capturing miR-135b.

scholarly journals The CCN family: a new stimulus package

2003 ◽  
Vol 178 (2) ◽  
pp. 169-175 ◽  
Author(s):  
DR Brigstock
Keyword(s):  
Clinical Endocrinology ◽  
Cell Types ◽  
Tissue Growth ◽  
Ccn Proteins ◽  
Ccn Family ◽  
Igf Binding Proteins ◽  
Igf Binding ◽  
Multiple Cell ◽  
Activate Cell ◽  
And Migration

The CCN family comprises cysteine-rich 61 (CYR61/CCN1), connective tIssue growth factor (CTGF/CCN2), nephroblastoma overexpressed (NOV/CCN3), and Wnt-induced secreted proteins-1 (WISP-1/CCN4), -2 (WISP-2/CCN5) and -3 (WISP-3/CCN6). These proteins stimulate mitosis, adhesion, apoptosis, extracellular matrix production, growth arrest and migration of multiple cell types. Many of these activities probably occur through the ability of CCN proteins to bind and activate cell surface integrins. Accumulating evidence supports a role for these factors in endocrine pathways and endocrine-related processes. To illustrate the broad role played by the CCN family in basic and clinical endocrinology, this Article highlights the relationship between CCN proteins and hormone action, skeletal growth, placental angiogenesis, IGF-binding proteins and diabetes-induced fibrosis.

scholarly journals Restoring of miR-193a-5p Sensitizes Breast Cancer Cells to Paclitaxel through P53 Pathway

2020 ◽  
Vol 10 (4) ◽  
pp. 595-601 ◽  
Author(s):  
Monireh Khordadmehr ◽  
Roya Shahbazi ◽  
Behzad Baradaran ◽  
Sanam Sadreddini ◽  
Dariush Shanebandi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Expression Level ◽  
Dapi Staining ◽  
Scratch Wound ◽  
Effective Therapeutic Strategy ◽  
Health And Disease ◽  
And Migration ◽  
Induced Apoptosis

Purpose : Recent evidence presented the important role of microRNAs in health and disease particularly in human cancers. Among those, miR-193 family contributes as a tumor suppressor in different benign and malignant cancers like breast cancer (BC) via interaction with specific targets. On the other hand, it was stated that miR-193 is able to modulate some targets in chemoresistant cancer cells. Therefore, the aim of this study was to evaluate the potential function of miR-193a-5p and paclitaxel in the apoptosis induction by targeting P53 in BC cells. Methods: At first, miR-193a-5p mimics were transfected to MDA-MB-231 BC cell line which indicated the lower expression level of miR-193a-5p. Subsequently, the transfected cells were treated with paclitaxel. Then, cell viability, apoptosis, and migration were evaluated by MTT, flow cytometry and DAPI staining, and scratch-wound motility assays, respectively. Moreover, the expression levels of P53 was evaluated by qRT-PCR. Results: The expression level of miR-193a-5p was restored in MDA-MB-231 cells which profoundly inhibited the proliferation (P<0.0001), induced apoptosis (P<0.0001) and harnessed migration (P<0.0001) in the BC cells and more effectiveness was observed in combination with paclitaxel. Interestingly, increased miR-193a-5p expression led to a reduction in P53 mRNA, offering that it can be a potential target of miR-193a. Conclusion: Taken together, it is concluded that the combination of miR-193a-5p restoration and paclitaxel could be potentially considered as an effective therapeutic strategy to get over chemoresistance during paclitaxel chemotherapy

scholarly journals Brain and Breast Cancer Cells with PTEN Loss of Function Demonstrate Enhanced Durotaxis and RHOB Dependent Amoeboid Migration Using 3D Printed Scaffolds and Aligned Microfiber Tracts

2021 ◽  
Author(s):  
Annalena Wieland ◽  
Pamela L. Strissel ◽  
Hannah Schorle ◽  
Ezgi Bakirci ◽  
Dieter Janzen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Morphology ◽  
Live Cell Imaging ◽  
Essential Role ◽  
Cell Imaging ◽  
Loss Of Function ◽  
Pten Loss ◽  
3D Printed ◽  
And Migration

Abstract Background: Glioblastoma multiforme (GBM) and triple-negative breast cancer (TNBC) with PTEN mutations often lead to brain dissemination with very poor patient outcomes. GBM uses axons and vessels as migratory cues to disseminate, however it is not known, if TNBC shares the same behavior. There is a need to understand brain tumor cell spreading and if GBM and TNBC have similar migration properties involving the signaling pathway RHOB-ROCK-PTEN. We tested for durotaxis, adherence and migration of GBM and TNBC using live-cell imaging and performed molecular analyses on three-dimensional (3D) structures.Methods: Aligned 3D printed scaffolds and microfibers were designed to mimic brain axon tracts and vessels for migration. GBM and TNBC cell lines, each with opposing PTEN genotypes, were analysed with RHO, ROCK and PTEN inhibitors and rescuing PTEN function using live-cell imaging. RNA-sequencing and qPCR of tumor cells in 3D with microfibers were performed, while SEM, confocal microscopy and cell tracking addressed cell morphology. Results: GBM and TNBC with homozygote PTEN loss of function and RHOB high expression were amoeboid shaped and demonstrated enhanced durotaxis, adhesion and migration on 3D microfibers, in contrast to PTEN wildtype GBM and TNBC showing elongated cells and low RHOB. RNA-sequencing exhibited that RHOB was significantly the highest expressed gene in GBM PTEN loss of function cells. Pathway inhibitors and PTEN rescue of function verified an essential role of RHOB-ROCK-PTEN signaling for durotaxis, adhesion, migration, cell morphology and plasticity using 3D printed microfibers. Conclusions: This study validates a significant role of a PTEN genotype for cellular properties including durotaxis, adhesion and migration. GBM and TNBC cells with PTEN loss of function have a greater affinity for stiffer brain structures promoting metastasis. We propose the significance of PTEN and RHOB in cellular oncology not only for primary tumors, but also for metastasizing tumors, where RHOB inhibitors could play an essential role for improved therapy.

scholarly journals Thrombospondin module 1 domain (TSP1) of the matricellular protein CCN3 shows an atypical disulfide pattern and incomplete CWR layers

2019 ◽  
Author(s):  
Emma-Ruoqi Xu ◽  
Aleix Lafita ◽  
Alex Bateman ◽  
Marko Hyvönen
Keyword(s):  
Bone Development ◽  
Heparan Sulphate ◽  
Cell Signalling ◽  
Matricellular Protein ◽  
Ccn Proteins ◽  
Ccn Family ◽  
X Ray Crystallography ◽  
Extracellular Matrix Components ◽  
Wide Range ◽  
Definition Of

AbstractMembers of the CCN (Cyr61/CTGF/Nov) family are a group of matricellular regulatory proteins, essential to a wide range of functional pathways in cell signalling. Through interacting with extracellular matrix components and growth factors via one of its four domains, the CCN proteins are involved in critical biological processes such as angiogenesis, cell proliferation, bone development, fibrogenesis, and tumorigenesis. We present here the crystal structure of the thrombospondin module 1 (TSP1) domain of CCN3 (previously known as Nov), which shares a similar three-stranded fold with the thrombospondin type 1 repeats of thrombospondin-1 and Spondin-1, but with variations in the disulfide connectivity. Moreover, the CCN3 TSP1 lacks the typical pi-stacked ladder of charged and aromatic residues on one side of the domain, as seen in other TSP1 domains. Using conservation analysis among orthologous domains, we show that a charged cluster in the centre of the domain is the most conserved site and predict it to be a potential functional epitope for heparan sulphate binding. This variant TSP1 domain has also been used to revise the sequence determinants of TSP1 domains and derive improved Pfam sequence profiles for identification of novel TSP1 domains in more than 10,000 proteins across diverse phyla.SynopsisThe first structure of a thrombospondin module 1 domain (TSP1) from a CCN family matricellular protein has been determined by X-ray crystallography. The structure shows a typical three-stranded fold, but with an incomplete pi-stacked structure that is usually found in these domains. The structure reveals highest conservation in the positively charged central segment, which we predict to be a binding site for heparan sulphates. The atypical features of this domain have been used to revise the definition of the TSP1 domains and identify a number of new domains in sequence databases.

scholarly journals HER2-intronic miR-4728-5p facilitates HER2 expression and accelerates cell proliferation and migration by targeting EBP1 in breast cancer

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0245832
Author(s):  
Yu Zhou ◽  
Yuan Yuan ◽  
Liuyi Li ◽  
Xueliang Wang ◽  
Yimin Quan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Luciferase Reporter ◽  
Her2 Expression ◽  
Cell Proliferation And Migration ◽  
And Migration ◽  
Proliferation And Migration

HER2 amplification greatly contributes to the tumorigenesis of multiple cancers. Intronic miR-4728-5p is transcribed along with its host gene HER2. However, little is known about the role of miR-4728-5p in cancer. This study aims to elucidate the potential role of miR-4728-5p and the underlying mechanism in breast cancer. Kaplan-Meier analysis showed that higher expression of HER2 led to worse survival outcomes in breast cancer patients. The TCGA dataset revealed that compared to normal breast tissues, HER2 and miR-4728-5p levels were significantly upregulated in breast cancer tissues with a positive correlation. In functional assays, miR-4728-5p was confirmed to promote the proliferation and migration in breast cancer cell BT474. EBP1 was identified as a direct target of miR-4728-5p via bioinformatics and luciferase reporter assays. miR-4728-5p was further demonstrated to increase HER2 expression and promote cell proliferation and migration by directly inhibiting EBP1 in breast cancer. Taken together, the HER2-intronic miR-4728-5p/EBP1/HER2 feedback loop plays an important role in promoting breast cancer cell proliferation and migration. Our study provides novel insights for targeted therapies of breast cancer.

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