YWHAZ interacts with DAAM1 to promote cell migration in breast cancer

AbstractDishevelled-associated activator of morphogenesis 1 (DAAM1) is a critical driver in facilitating metastasis in breast cancer (BrCa). However, molecular mechanisms for the regulation of DAAM1 activation are only partially elucidated. In this research, the expression levels of YWHAZ and DAAM1 were examined by immunohistochemistry (IHC) staining in BrCa tissues. The functional roles of tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ)–DAAM1 axis and their regulator microRNA-613 (miR-613) in BrCa cells and associated molecular mechanisms were demonstrated in vitro. As results, the expression levels of DAAM1 and YWHAZ were significantly upregulated in BrCa tissues compared with normal tissues and remarkably associated with poor prognosis. Besides, DAAM1 and YWHAZ were positively correlated with each other in BrCa tissues. YWHAZ interacted and colocalized with DAAM1 in BrCa cells, which was essential for DAAM1-mediated microfilament remodeling and RhoA activation. Moreover, miR-613 directly targeted both YWHAZ and DAAM1, contributing to inhibiting BrCa cells migration via blocking the complex of YWHAZ–DAAM1. To sum up, these data reveal that YWHAZ regulates DAAM1 activation, and the YWHAZ–DAAM1 complex is directly targeted by the shared post-transcriptional regulator miR-613.

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The Effect of High CDC6 Levels on Predicting Poor Prognosis in Colorectal Cancer

Chemotherapy ◽

10.1159/000519913 ◽

2022 ◽

pp. 1-10

Author(s):

Cheng Yang ◽

Na Xie ◽

Zhifei Luo ◽

Xiling Ruan ◽

Yixin Zhang ◽

...

Keyword(s):

Colorectal Cancer ◽

Protein Expression ◽

Poor Prognosis ◽

Cancer Metastasis ◽

Mrna Level ◽

Normal Mucosa ◽

Tnm Stage ◽

Expression Levels ◽

Normal Tissues

Introduction: We investigated the function of cell division cycle 6 (CDC6) on the prognosis in colorectal carcinoma (CRC). Methods: CDC6 protein expression levels in 121 patients with colorectal cancer and adjacent normal mucosa were detected by immunohistochemistry. Results: Compared to adjacent normal tissues, CDC6 mRNA level was overexpressed in CRC tissues. Moreover, CDC6 protein levels were expressed up to 93.39% (113/121) in CRC tissues in the cell nucleus or cytoplasm. However, there were only 5.79% (7/121) in normal mucosal tissues with nuclear expression. CDC6 expression was significantly correlated with TNM stage and tumor metastasis. The 5-year survival rate was lower in the high CDC6 expression group than the low group. After silencing of CDC6 expression in SW620 cells, cell proliferation was slowed, the tumor clones were decreased, and the cell cycle was arrested in G1 phase. In multivariate analysis, increased CDC6 protein expression levels in colon cancer tissues were associated with cancer metastasis, TNM stage, and patient survival time. Conclusion: CDC6 is highly expressed in CRC, and downregulation of CDC6 can slow the growth of CRC cells in vitro. It is also an independent predictor for poor prognosis and may be a useful biomarker for targeted therapy and prognostic evaluation.

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GABRQ is Overexpressed and Correlated with Tumor Progression in Breast Cancer

10.21203/rs.3.rs-503791/v1 ◽

2021 ◽

Author(s):

Ran Mei ◽

Xichun Cui ◽

Lili Zheng ◽

Li Jingyi

Keyword(s):

Breast Cancer ◽

Molecular Mechanisms ◽

Tumor Development ◽

Bioinformatic Analysis ◽

Gamma Aminobutyric Acid ◽

Nude Mouse Model ◽

Expression Levels ◽

The Public

Abstract Background: Breast cancer (BRCA) is the most common type of women's cancer with a high incidence. The function of gamma-aminobutyric acid A receptor θ subunit (GABRQ) has been studied in other cancers. The results demonstrated that the expression levels of GABRQ were closely associated with tumor prognosis. However, the functions and mechanisms of GABRQ in BRCA remain unclear.Materials and methods: We used the public genome datasets and a tissue microarray (TMA) cohort to analyze the GABRQ expression levels. We performed Immunohistochemistry (IHC) and Western blot to determine GABRQ expression in BRCA cell lines and tissues. Cell proliferation was assessed by EDU assay and colony formation assay. Transwell assay was carried out to investigate the cell invasion ability in vitro and Xenograft nude mouse model was constructed to test the function of GABRQ on tumor growth in vivo. Moreover, we utilized bioinformatic analysis to identify the potential molecular mechanisms mediated by GABRQ modification in BRCA.Results: GABRQ was markedly up-regulated in BRCA tissues, and the expression levels of GABRQ were closely associated with BRCA prognosis. Functional analysis elucidated that knockdown of GABRQ could suppress BRCA cell growth and invasion in vitro, and inhibit tumor development in vivo. Moreover, we found that GABRQ overexpression activated the EMT signaling pathway.Conclusions: These results demonstrated that the function of GABRQ in BRCA progression provided potential prognostic predictors for BRCA patients.

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NcRNAs-mediated High Expression of TIMM8A Correlates with Poor Prognosis and Act as an Oncogene in Breast Cancer

10.21203/rs.3.rs-1079496/v1 ◽

2021 ◽

Author(s):

Zhonglin Wang ◽

Shuqin Li ◽

Feng Xu ◽

Jingyue Fu ◽

Jie Sun ◽

...

Keyword(s):

Breast Cancer ◽

Poor Prognosis ◽

Molecular Mechanisms ◽

Human Cancer ◽

Luciferase Reporter ◽

Inner Mitochondrial Membrane ◽

Cancer Proliferation ◽

Bioinformatics Analyses

Abstract Background: Breast cancer is notorious for its increasing incidence for decades. Ascending evidence has demonstrated that translocase of inner mitochondrial membrane (TIMM) proteins play vital roles in progression of several types of human cancer. However, the biological behaviors and molecular mechanisms of TIMM8A in breast cancer remain not fully illustrated.Methods: Pan-cancer analysis was firstly performed for TIMM8A’s expression and prognosis by Oncomine database. Subsequently, TIMM8A-related noncoding RNAs (ncRNAs) were identified by a series of bioinformatics analyses and dual-luciferase reporter assay, including expression analysis, correlation analysis, and survival analysis. Moreover, the effect of TIMM8A on breast cancer proliferation and apoptosis was evaluated in vitro by CCK-8 assays, colony formation assays and Western blot assays and the in vivo effect was revealed through a patient-derived xenograft mouse model.Results: We found that TIMM8A showed higher expression level in breast cancer and the higher TIMM8A mRNA expression group had a poorer prognosis than the lower TIMM8A group. hsa-circ-0107314/hsa-circ-0021867/hsa-circ-0122013 might be the three most potential upstream circRNAs of hsa-miR-34c-5p/hsa-miR-449a-TIMM8A axis in breast cancer. TIMM8A promotes proliferation of breast cancer cells in vitro and tumor growth in vivo.Conclusion: Our results confirmed that ncRNAs-mediated upregulation of TIMM8A correlated with poor prognosis and act as an oncogene in breast cancer.

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SOX8 acts as a prognostic factor and mediator to regulate the progression of triple-negative breast cancer

Carcinogenesis ◽

10.1093/carcin/bgz034 ◽

2019 ◽

Vol 40 (10) ◽

pp. 1278-1287 ◽

Cited By ~ 6

Author(s):

Hailin Tang ◽

Bo Chen ◽

Peng Liu ◽

Xinhua Xie ◽

Rongfang He ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Poor Prognosis ◽

Molecular Mechanisms ◽

Triple Negative ◽

Transcript Level ◽

Vital Role ◽

Data Sets ◽

Normal Tissues ◽

Chip Experiment

Abstract The molecular mechanisms underlying triple-negative breast cancer (TNBC) pathology are not fully understood. Here, we reviewed the SOX8 transcript level in 24 types of cancer and normal tissues and the SOX8 expression pattern in breast cancer from the TCGA and METABRIC data sets and found that SOX8 was highly expressed in TNBC. We investigated the effect of SOX8 on tumorigenicity, migration and apoptosis in TNBC cell lines and xenografts models. We identified SOX8 as a functional oncogene that involved in the maintenance of stem-like capacities in TNBC cells. Through a promoter truncation experiment and ChIP experiment, we verified zinc finger E-box binding homeobox 1 (ZEB1) as a transcriptional activator of SOX8 that enhanced SOX8 expression by binding to its promoter. We evaluated the ZEB1 and the SOX8 levels in 240 TNBC patients and high expression of ZEB1 and SOX8 were significantly associated with poor prognosis. We demonstrated the significance of the ZEB1–SOX8 axis in regulating TNBC cancer stem-like cells (CSCs) and its connection with poor prognosis. Due to its vital role in TNBC CSCs, the ZEB1–SOX8 regulatory axis could be a promising therapeutic target for TNBC.

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Targeting PKM2 promotes chemosensitivity of breast cancer cells in vitro and in vivo

Cancer Biomarkers ◽

10.3233/cbm-210111 ◽

2021 ◽

pp. 1-10

Author(s):

Yu Wang ◽

Han Zhao ◽

Ping Zhao ◽

Xingang Wang

Keyword(s):

Breast Cancer ◽

Neoadjuvant Chemotherapy ◽

Cancer Cells ◽

Cancer Patients ◽

Poor Prognosis ◽

Breast Cancer Cells ◽

Breast Cancer Patients ◽

Cancer Tissues

BACKGROUND: Pyruvate kinase M2 (PKM2) was overexpressed in many cancers, and high PKM2 expression was related with poor prognosis and chemoresistance. OBJECTIVE: We investigated the expression of PKM2 in breast cancer and analyzed the relation of PKM2 expression with chemotherapy resistance to the neoadjuvant chemotherapy (NAC). We also investigated whether PKM2 could reverse chemoresistance in breast cancer cells in vitro and in vivo. METHODS: Immunohistochemistry (IHC) was performed in 130 surgical resected breast cancer tissues. 78 core needle biopsies were collected from breast cancer patients before neoadjuvant chemotherapy. The relation of PKM2 expression and multi-drug resistance to NAC was compared. The effect of PKM2 silencing or overexpression on Doxorubicin (DOX) sensitivity in the MCF-7 cells in vitro and in vivo was compared. RESULTS: PKM2 was intensively expressed in breast cancer tissues compared to adjacent normal tissues. In addition, high expression of PKM2 was associated with poor prognosis in breast cancer patients. The NAC patients with high PKM2 expression had short survival. PKM2 was an independent prognostic predictor for surgical resected breast cancer and NAC patients. High PKM2 expression was correlated with neoadjuvant treatment resistance. High PKM2 expression significantly distinguished chemoresistant patients from chemosensitive patients. In vitro and in vivo knockdown of PKM2 expression decreases the resistance to DOX in breast cancer cells in vitro and tumors in vivo. CONCLUSION: PKM2 expression was associated with chemoresistance of breast cancers, and could be used to predict the chemosensitivity. Furthermore, targeting PKM2 could reverse chemoresistance, which provides an effective treatment methods for patients with breast cancer.

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FK506-binding protein 5 promotes the progression of papillary thyroid carcinoma

Journal of International Medical Research ◽

10.1177/03000605211008325 ◽

2021 ◽

Vol 49 (4) ◽

pp. 030006052110083

Author(s):

Zhenya Gao ◽

Fang Yu ◽

Huanxia Jia ◽

Zhuo Ye ◽

Shijie Yao

Keyword(s):

Papillary Thyroid Carcinoma ◽

Thyroid Carcinoma ◽

Binding Protein ◽

Progression Free Survival ◽

Papillary Thyroid ◽

Expression Levels ◽

Fk506 Binding Protein ◽

Normal Tissues ◽

Induced Apoptosis

Objective To detect the expression of FK506-binding protein 5 (FKBP5) in human papillary thyroid carcinoma (PTC) tissues, and explore its possible role in the progression of PTC. Methods FKBP5 expression levels were assessed in 115 PTC tissues and corresponding normal tissues by immunohistochemistry. We also examined the correlations between FKBP5 expression and clinicopathological factors and survival in 75 patients with PTC. The effects of FKBP5 on the proliferation and apoptosis of PTC cells were detected by colony-formation, MTT, and flow cytometry assays, respectively. We further investigated the effects of FKBP5 on tumor growth in mice. Results We revealed high expression levels of FKBP5 in human PTC tissues compared with normal tissues. Furthermore, high FKBP5 expression was associated with an increased incidence of intraglandular dissemination, and lower overall and progression-free survival. FKBP5 depletion remarkably suppressed the proliferation and induced apoptosis of PTC cells in vitro. FKBP5 further contributed to the growth of PTC tumors in mice. Conclusions The results of this study demonstrated the potential involvement of FKBP5 in the progression of PTC, and confirmed FKBP5 as a novel therapeutic target for PTC treatment.

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A prospective study revealing the role of an immune-related eRNA, WAKMAR2, in breast cancer

Scientific Reports ◽

10.1038/s41598-021-94784-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Linbang Wang ◽

Jingkun Liu ◽

Jiaojiao Tai ◽

Nian Zhou ◽

Tianji Huang ◽

...

Keyword(s):

Breast Cancer ◽

Target Genes ◽

Pearson Correlation ◽

Tumour Microenvironment ◽

The Cancer Genome Atlas ◽

Mcf7 Cells ◽

Tumour Immunity ◽

Immune Genes ◽

Normal Tissues

AbstractEnhancer RNAs (eRNAs) are a subclass of non-coding RNAs that are generated during the transcription of enhancer regions and play an important role in tumourigenesis. In this study, we focused on the crucial eRNAs that participate in immune responses in invasive breast cancer (IBC). We first used The Cancer Genome Atlas and Human enhancer RNA Atlas to screen for tissue-specific eRNAs and their target genes. Through Pearson correlation analysis with immune genes, the eRNA WAKMAR2 was identified as a key candidate involved in IBC. Our further research suggested that WAKMAR2 is crucial in regulating the tumour microenvironment and may function by regulating immune-related genes, including IL27RA, RAC2, FABP7, IGLV1-51, IGHA1, and IGHD. Quantitative reverse transcription-polymerase chain reaction was used to detect the expression of WAKMAR2 in IBC and normal tissues, and the effect of WAKMAR2 on the regulation of downstream genes in MB-231 and MCF7 cells was studied in vitro. WAKMAR2 was found to be highly involved in tumour immunity and was downregulated in IBC tissues. Furthermore, the expression of WAKMAR2 and its target genes was observed at the pan-cancer level. This study provides evidence to suggest new potential targets for the treatment of breast cancer.

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Cyclin-Dependent Kinase Regulatory Subunit 2 Indicated Poor Prognosis and Facilitated Aggressive Phenotype of Hepatocellular Carcinoma

Disease Markers ◽

10.1155/2019/8964015 ◽

2019 ◽

Vol 2019 ◽

pp. 1-13

Author(s):

Jie Zhang ◽

Qianqian Song ◽

Jinxia Liu ◽

Lina Lu ◽

Yuqing Xu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Poor Prognosis ◽

Disease Free Survival ◽

Normal Liver ◽

Regulatory Subunit ◽

Mrna Levels ◽

Cyclin Dependent Kinase ◽

Normal Tissues ◽

Hcc Cells

Cyclin-dependent kinase regulatory subunit 2 (CKS2) is a member of the cell cycle-dependent protein kinase subunit family, which is implicated as an oncogene in various malignancies. However, the clinical significance, oncogenic functions, and related mechanisms of CKS2 in hepatocellular carcinoma (HCC) remain largely unclear. In the present study, expression features and prognostic value of CKS2 were evaluated in the bioinformatic databases and HCC tissues. The effects of CKS2 on the malignant phenotypes of HCC cells were explored in vitro. According to the analyses of three bioinformatic databases, mRNA levels of CKS2 were elevated in HCC tissues compared with the normal tissues. Immunohistochemical assays found that high CKS2 expression was closely associated with liver cirrhosis (P=0.019), poor differentiation (P=0.02), portal vein invasion (P<0.001), TNM stage (P=0.019), tumor metastasis (P=0.008), and recurrence (P=0.003). The multivariate regression analyses suggested that CKS2 was an independent prognostic factor for overall survival (HR=2.088, P=0.014) and disease-free survival (HR=2.511, P=0.002) of HCC patients. Moreover, the bioinformatic analyses indicated that CKS2 might be associated with the malignant phenotypes in HCC progression. In addition, in vitro assays showed that CKS2 expression was higher in HCC cell lines than in normal liver cells. Knockdown of CKS2 remarkably repressed the proliferation, colony formation (P=0.0003), chemoresistance, migration (P=0.0047), and invasion (P=0.0012) of HCC cells. Taken together, overexpression of CKS2 was significantly correlated with poor prognosis of HCC patients and the malignant phenotypes of HCC cells, suggesting that it was a novel prognostic biomarker and potential target of HCC.

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Circular RNA hsa_circ_0005046 and hsa_circ_0001791 May Become Diagnostic Biomarkers for Breast Cancer Early Detection

Journal of Oncology ◽

10.1155/2021/2303946 ◽

2021 ◽

Vol 2021 ◽

pp. 1-7

Author(s):

Melika Ameli-Mojarad ◽

Mandana Ameli-Mojarad ◽

Mitra Nourbakhsh ◽

Ehsan Nazemalhosseini-Mojarad

Keyword(s):

Breast Cancer ◽

Roc Curve ◽

Expression Profiles ◽

Circular Rna ◽

Diagnostic Value ◽

High Expression ◽

Expression Level ◽

Diagnostic Biomarker ◽

Expression Levels ◽

Normal Tissues

Breast cancer (BC) is one of the most common lethal diseases in women worldwide. Recent evidence has shown that covalently closed Circular RNA (circRNA) deregulation is observed in different human malignancies and cancers. Lately, circRNAs are being considered as a new diagnostic biomarker; however, the mechanism and the correlation of action between circRNAs and BC are still unclear. In the present study, we try to investigate the expression level of hsa_circ_0005046 and hsa_circ_0001791 in BC. By using quantitative real-time polymerase chain reaction (qRT-PCR), expression profiles of candidate circRNAs were detected in 60 BC tissue and paired adjacent normal tissues. Furthermore, the clinicopathological relation and diagnostic value were estimated. Our results showed the higher expression levels of hsa_circ_0005046 and hsa_circ_0001791 in BC tissues compared to paired adjacent normal tissues with P value ( P < 0.0001 ) for both circRNAs, and the area under the receiver operating characteristic (ROC) curve was 0.857 and 1.0, respectively; in addition, a total 10 miRNAs that can be targeted by each candidate circRNAs was predicted base on bioinformatics databases. Taken together, for the first time, the results of our study presented high expression levels of hsa_circ_0005046 and hsa_circ_00017916 in BC; although there was no direct correlation between the high expression level of both circRNAs with clinic pathological factors, except hsa_circ_0001791 association with estrogen receptors (ER), high ROC curve in expressed samples indicated that both circRNAs could be used as a new diagnostic biomarker for BC. Moreover, miRNAs selection tools predicted that miR-215 and mir-383-5p which have a tumor suppressor role in BC can be targeted by our candidate circRNAs to affect the PI3K/AKT pathway; in conclusion, further studies are required to validate the oncogene role of our candidate circRNAs through the PI3k pathway.

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Patient-Derived Head and Neck Cancer Organoids Recapitulate EGFR Expression Levels of Respective Tissues and Are Responsive to EGFR-Targeted Photodynamic Therapy

Journal of Clinical Medicine ◽

10.3390/jcm8111880 ◽

2019 ◽

Vol 8 (11) ◽

pp. 1880 ◽

Cited By ~ 13

Author(s):

Else Driehuis ◽

Sacha Spelier ◽

Irati Beltrán Hernández ◽

Remco de Bree ◽

Stefan M. Willems ◽

...

Keyword(s):

Photodynamic Therapy ◽

Head And Neck ◽

Three Dimensional ◽

Growth Factor Receptor ◽

Therapeutic Interventions ◽

Expression Levels ◽

Tumor Patient ◽

Normal Tissues ◽

Egfr Expression

Patients diagnosed with head and neck squamous cell carcinoma (HNSCC) are currently treated with surgery and/or radio- and chemotherapy. Despite these therapeutic interventions, 40% of patients relapse, urging the need for more effective therapies. In photodynamic therapy (PDT), a light-activated photosensitizer produces reactive oxygen species that ultimately lead to cell death. Targeted PDT, using a photosensitizer conjugated to tumor-targeting molecules, has been explored as a more selective cancer therapy. Organoids are self-organizing three-dimensional structures that can be grown from both normal and tumor patient-material and have recently shown translational potential. Here, we explore the potential of a recently described HNSCC–organoid model to evaluate Epidermal Growth Factor Receptor (EGFR)-targeted PDT, through either antibody- or nanobody-photosensitizer conjugates. We find that EGFR expression levels differ between organoids derived from different donors, and recapitulate EGFR expression levels of patient material. EGFR expression levels were found to correlate with the response to EGFR-targeted PDT. Importantly, organoids grown from surrounding normal tissues showed lower EGFR expression levels than their tumor counterparts, and were not affected by the treatment. In general, nanobody-targeted PDT was more effective than antibody-targeted PDT. Taken together, patient-derived HNSCC organoids are a useful 3D model for testing in vitro targeted PDT.

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