scholarly journals TOP2A is overexpressed and is a therapeutic target for adrenocortical carcinoma

2013 ◽  
Vol 20 (3) ◽  
pp. 361-370 ◽  
Author(s):  
Meenu Jain ◽  
Lisa Zhang ◽  
Mei He ◽  
Ya-Qin Zhang ◽  
Min Shen ◽  
...  
Keyword(s):  
Protein Expression ◽  
Anticancer Activity ◽  
Cell Lines ◽  
Antiproliferative Activity ◽  
Adrenocortical Carcinoma ◽  
Cellular Proliferation ◽  
Locally Advanced ◽  
Tissue Samples ◽  
Anchorage Independent Growth ◽  
Mrna And Protein Expression

Adrenocortical carcinoma (ACC) is a rare but aggressive malignancy with no effective therapy for patients with unresectable disease. The aim of the current study was i) to evaluate TOP2A expression and function in human adrenocortical neoplasm and ACC cells and ii) to determine the anticancer activity of agents that target TOP2A. TOP2A mRNA and protein expression levels were evaluated in 112 adrenocortical tissue samples (21 normal adrenal cortex, 80 benign adrenocortical tumors, and 11 ACCs). In vitro siRNA knockdown of TOP2A in ACC cell lines (NCI-H295R and SW13) was used to determine its effect on cellular proliferation, cell cycle, anchorage-independent growth, and cellular invasion. We screened 14 TOP2A inhibitors for their anticancer activity in ACC cells. TOP2A mRNA and protein expression was significantly higher in ACC than in benign and normal adrenocortical tissue samples (P<0.05). Knockdown of TOP2A gene expression in ACC cell lines significantly decreased cell proliferation, anchorage-independent growth, and invasion (P<0.05). A screening assay in NCI-H295R cells showed that 11 of 14 TOP2A inhibitors had antiproliferative activity, 5 of the 14 TOP2A inhibitors had a higher antiproliferative activity than mitotane, and aclarubicin was the agent with the highest activity. Aclarubicin was validated to significantly decrease proliferation and tumor spheroid size in both NCI-H295R and SW13 ACC cell lines (P<0.05). Our results suggest that TOP2A is overexpressed in ACC, regulates cellular proliferation and invasion in ACC cells, and is an attractive target for ACC therapy. Of the TOP2A inhibitors screened, aclarubicin is a good candidate agent to test in future clinical trials for patients with locally advanced and metastatic ACC.

PS02.051: HMGB IS INVOLVED IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA PROGRESSION

2018 ◽  
Vol 31 (Supplement_1) ◽  
pp. 134-135
Author(s):  
Daiki Matsubara ◽  
Hirotaka Konishi ◽  
Katsutoshi Shoda ◽  
Tomohiro Arita ◽  
Toshiyuki Kosuga ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Esophageal Squamous Cell Carcinoma ◽  
Protein Expression ◽  
Healthy Volunteers ◽  
Cell Carcinoma ◽  
Cell Lines ◽  
Squamous Cell ◽  
Plasma Samples ◽  
Tissue Samples ◽  
Mrna And Protein Expression

Abstract Background High-mobility group box-1 (HMGB1), originally characterized as a non-histone, nuclear DNA-binding protein, acts as a crucial proinflammatory cytokine, mediating a broad range of inflammatory responses as a secretory form. Recently, it has been reported to be involved in the tumorigenesis and progression of various types of malignancies, but it is unclear whether HMGB1 plays an important role in the progression of esophageal squamous cell carcinoma (ESCC). The aim of this study was to investigate the significance of HMGB1 in ESCC. Methods The tissue and plasma samples were obtained from ESCC patients at before or after operative period and healthy volunteers. The ESCC cell lines and normal human cell lines, such as fibroblast (WI-38) or Human umbilical vein endothelial cell (HUVEC), were used in vitro analyses. The expression levels of HMGB1 in tissue samples were measured by quantitative RT-PCR. The protein levels of HMGB1 were measured using the HMGB1 enzyme-linked immunosorbent assay kit in plasma samples, and using immunohistochemical staining or western blotting in tissue samples or cell lines. The functions of HMGB1 on the ESCC cell lines were investigated by proliferation, invasion, or migration assays. Results The mRNA and protein expression of HMGB1 in ESCC tissue was significantly higher than that in paired non-cancerous esophageal mucosa tissue. Plasma HMGB1 level was slightly higher, but not significant, in ESCC patients than in healthy volunteers. However, it was significantly higher in ESCC patients with Neoadjuvant chemotherapy (NAC) than in those without NAC. The mRNA and protein expression of HMGB1 were higher in ESCC cell lines than in WI-38 or HUVEC. In ESCC cells with high HMGB1 expression, knockdown of HMGB1 using specific siRNAs inhibited the cell proliferation, migration and invasion. Conclusion These findings suggest that HMGB1 plays a crucial role in tumor malignant potential through its overexpression in esophageal squamous cell carcinoma. Disclosure All authors have declared no conflicts of interest.

Bone sialoprotein mRNA and protein expression in human multiple myeloma cell lines and patients

2000 ◽  
Vol 111 (4) ◽  
pp. 1118-1121 ◽  
Author(s):  
A. Bellahcene ◽  
I. Van Riet ◽  
C. de Greef ◽  
N. Antoine ◽  
M. F. Young ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Protein Expression ◽  
Cell Lines ◽  
Myeloma Cell ◽  
Bone Sialoprotein ◽  
Multiple Myeloma Cell ◽  
Human Multiple Myeloma ◽  
Mrna And Protein Expression

scholarly journals Extracellular matrix changes in colorectal carcinoma and correlation with lymph node metastasis

2021 ◽  
Author(s):  
Thérèse Rachell Theodoro ◽  
Rodrigo Lorenzetti Serrano ◽  
Karine Corcione Turke ◽  
Sarhan Sydney Saad ◽  
Marcelo Augusto Fontenelle Ribeiro Junior ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Lymph Node ◽  
Lymph Node Metastasis ◽  
Colorectal Carcinoma ◽  
Protein Expression ◽  
Cross Sectional ◽  
Tissue Samples ◽  
Node Metastasis ◽  
Mrna And Protein Expression ◽  
Neoplastic Tissues

AbstractThe process of proliferation and invasion of tumor cells depends on changes in the extracellular matrix (ECM) through the activation of enzymes and alterations in the profile of ECM components. We aimed to investigate the mRNA and protein expression of ECM components such as heparanase (HPSE), heparanase-2 (HPSE2), matrix metalloproteinase-9 (MMP-9), and syndecan-1 (SYND1) in neoplastic and non-neoplastic tissues of patients with colorectal carcinoma (CRC). It is a cross-sectional study in which twenty-four adult patients that had CRC were submitted to resection surgery. We analyzed the expression of HPSE, HPSE2, MMP-9, and SYND1 by quantitative RT-PCR and immunohistochemistry. Differing from most of the studies that compare the mRNA expression between tumor samples and non-neoplastic tissues, we decided to investigate whether variations exist in the expression of the ECM components between the affected tissue and nontumoral tissue collected from the same patient with CRC. We removed both tissue samples immediately after the surgical resection of CRC. The data showed higher mRNA and protein expression of HPSE2 (P = 0.0058), MMP-9 (P = 0.0268), and SYND1 (P = 0.0002) in tumor samples compared to the non-neoplastic tissues, while there was only an increase in the level of HPSE protein in tumor tissues. A greater expression of HPSE2 was observed in patients with lymph node metastasis (P = 0.048), suggesting that such protein can be a marker of lymph node metastasis in CRC.

scholarly journals ABCG2 expression, function, and promoter methylation in human multiple myeloma

Blood ◽  
2006 ◽  
Vol 108 (12) ◽  
pp. 3881-3889 ◽  
Author(s):  
Joel G. Turner ◽  
Jana L. Gump ◽  
Chunchun Zhang ◽  
James M. Cook ◽  
Douglas Marchion ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Flow Cytometry ◽  
Drug Resistance ◽  
Protein Expression ◽  
Cell Lines ◽  
Promoter Methylation ◽  
Plasma Cells ◽  
Cancer Resistance ◽  
Response To Chemotherapy ◽  
Mrna And Protein Expression

AbstractWe investigated the role of the breast cancer resistance protein (BCRP/ABCG2) in drug resistance in multiple myeloma (MM). Human MM cell lines, and MM patient plasma cells isolated from bone marrow, were evaluated for ABCG2 mRNA expression by quantitative polymerase chain reaction (PCR) and ABCG2 protein, by Western blot analysis, immunofluorescence microscopy, and flow cytometry. ABCG2 function was determined by measuring topotecan and doxorubicin efflux using flow cytometry, in the presence and absence of the specific ABCG2 inhibitor, tryprostatin A. The methylation of the ABCG2 promoter was determined using bisulfite sequencing. We found that ABCG2 expression in myeloma cell lines increased after exposure to topotecan and doxorubicin, and was greater in logphase cells when compared with quiescent cells. Myeloma patients treated with topotecan had an increase in ABCG2 mRNA and protein expression after treatment with topotecan, and at relapse. Expression of ABCG2 is regulated, at least in part, by promoter methylation both in cell lines and in patient plasma cells. Demethylation of the promoter increased ABCG2 mRNA and protein expression. These findings suggest that ABCG2 is expressed and functional in human myeloma cells, regulated by promoter methylation, affected by cell density, up-regulated in response to chemotherapy, and may contribute to intrinsic drug resistance.

scholarly journals Absence of MGST1 mRNA and protein expression in human neuroblastoma cell lines and primary tissue

2014 ◽  
Vol 69 ◽  
pp. 167-171 ◽  
Author(s):  
Michael J. Kelner ◽  
Mitchell B. Diccianni ◽  
Alice L. Yu ◽  
Mary R. Rutherford ◽  
Leita A. Estes ◽  
...  
Keyword(s):  
Protein Expression ◽  
Cell Lines ◽  
Neuroblastoma Cell ◽  
Human Neuroblastoma Cell ◽  
Human Neuroblastoma ◽  
Mrna And Protein Expression ◽  
Neuroblastoma Cell Lines ◽  
Primary Tissue

scholarly journals Eight-gene risk score predicts progression and prognosis in bladder cancer

2021 ◽  
Author(s):  
Ruiliang Wang ◽  
Zongtai Zheng ◽  
Shiyu Mao ◽  
Wentao Zhang ◽  
Ji Liu ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Protein Expression ◽  
Cell Lines ◽  
Risk Score ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Risk Of Death ◽  
Mrna And Protein Expression ◽  
Muscle Invasive ◽  
Prognostic Prediction

Abstract Background: The progression from non-muscle-invasive bladder cancer (NMIBC) to muscle-invasive bladder cancer (MIBC) increases the risk of death. It is therefore important to find new relevant molecular models that will allow for effective prediction of the progression and prognosis of bladder cancer (BC).Methods: Using RNA-Sequence data of 49 BC patients in our center and weighted gene co-expression network analysis methods, a co-expression network of genes was developed and three key modules associated with malignant progression were selected. Based on the genes in three key modules, an eight-gene risk score was established using univariate Cox regression and the Least absolute shrinkage and selection operator Cox model in The Cancer Genome Atlas Program (TCGA) and validated in validation sets. Subsequently, a nomogram based on the risk score was constructed for prognostic prediction. The mRNA and protein expression levels of eight genes in cell lines and tissues were further investigated.Results: A novel eight-gene risk score was closely related to the malignant clinical features of BC and could predict the prognosis of patients in the training dataset (TCGA) and three validation sets (GSE3289 , GSE13507 and IMvigor210 trial). The nomogram showed good prognostic prediction and calibration. The mRNA and protein expression level of the eight genes were differentially expressed in cell lines and tissues.Conclusions: In our study, we established a novel eight-gene risk score which could predict the progression and prognoses of BC patients.

Synthesis and Reactivity of 6,8-Dibromo-2-ethyl-4H-benzo[d][1,3]oxazin-4-one Towards Nucleophiles and Electrophiles and Their Anticancer Activity

2019 ◽  
Vol 19 (4) ◽  
pp. 538-545 ◽  
Author(s):  
Maher A. El-hashash ◽  
Amira T. Ali ◽  
Rasha A. Hussein ◽  
Wael M. El-Sayed
Keyword(s):  
Anticancer Activity ◽  
Cancer Cells ◽  
Cell Lines ◽  
Antiproliferative Activity ◽  
Repair Mechanisms ◽  
Breast Cells ◽  
Nitrogen Nucleophiles ◽  
Quinazolinone Derivatives ◽  
Benzaldehyde Derivatives ◽  
Mcf 7

Background: The genetic heterogeneity of tumor cells and the development of therapy-resistant cancer cells in addition to the high cost necessitate the continuous development of novel targeted therapies. Methods: In this regard, 14 novel benzoxazinone derivatives were synthesized and examined for anticancer activity against two human epithelial cancer cell lines; breast MCF-7 and liver HepG2 cells. 6,8-Dibromo-2- ethyl-4H-benzo[d][1,3]oxazin-4-one was subjected to react with nitrogen nucleophiles to afford quinazolinone derivatives and other related moieties (3-12). Benzoxazinone 2 responds to attack with oxygen nucleophile such as ethanol to give ethyl benzoate derivative 13. The reaction of benzoxazinone 2 with carbon electrophile such as benzaldehyde derivatives afforded benzoxazinone derivatives 14a and 14b.The structure of the prepared compounds was confirmed with spectroscopic tools including IR, 1H-NMR, and 13C-NMR. Results: Derivatives 3, 9, 12, 13, and 14b exhibited high antiproliferative activity and were selective against cancer cells showing no toxicity in normal fibroblasts. Derivative 3 with NH-CO group in quinazolinone ring was effective only against breast cells, while derivative 12 with NH-CO group in imidazole moiety was only effective against liver cells probably through arresting cell cycle and enabling repair mechanisms. The other derivatives (9, 13, and 14b) had broader antiproliferative activity against both cell lines. These derivatives enhance the expression of the p53 and caspases 9 and 3 to varying degrees in both cell lines. Derivative 14b caused the highest induction in the investigated genes and was the only derivative to inhibit the EGFR activity. Conclusions: The unique features about derivative 14b could be attributed to its high lipophilicity, high carbon content, or its extended conjugation through planar aromatic system. More investigations are required to identify the lead compound(s) in animal models.

The Expression of the ER Stress Sensor GRP78/Bip Is a Target of R-CHOP and Bortezomib Treatments in DLBCL with Prognostic Value. A Rationale for the Use of Proteasome Inhibitors in DLBCL Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3734-3734
Author(s):  
Ana Mozos ◽  
Gael Roue ◽  
Armando López-Guillermo ◽  
Pedro Jares ◽  
Dolors Colomer ◽  
...  
Keyword(s):  
Stress Response ◽  
Combination Therapy ◽  
Protein Expression ◽  
Cell Viability ◽  
Er Stress ◽  
Cell Lines ◽  
Standard Chemotherapy ◽  
Er Stress Response ◽  
Mrna And Protein Expression

Abstract Abstract 3734 Poster Board III-670 Introduction The endoplasmic reticulum (ER) stress response is an adaptive signaling pathway that controls cell survival. The activation of the transcription factor Xbp1 is a main event in this response and we have previously shown that Xbp1 activation in DLBCL is associated with aggressive clinical course (Balagué et al. Am J Pathol 2009, 174(6):2337-46). GRP78/Bip is a molecular chaperone that senses ER homeostasis and initiates the ER stress response. The expression of GRP78/Bip in DLBCL has never been addressed before. DLBCL patients are treated with standard doxorubicin-based chemotherapy such as CHOP. Since the introduction of rituximab, no other therapies have shown greater benefit in these patients. The ER stress response may be altered by conventional chemotherapy and it is well known that proteasome inhibition with bortezomib disrupts this response in myeloma. Whether Bip is affected in DLBCL treated with R-CHOP or bortezomib is unknown. Recent evidences suggest that the addition of bortezomib to standard chemotherapy would improve the survival of patients with the DLBCL preferentially of the ABC subtype (Duneleavy et al. Blood 2009, 113(24):6069-76) but the implication of the ER stress in this combination therapy remains unknown. Methods We analyze the mRNA and protein expression of Bip in DLBCL cell lines (OCI-Ly8, SUHDL4, SUDHL6 and SUDHL16) treated with Bortezomib, R-CHOP or their combination. Moreover, we also evaluated the effect of Bip silencing in the response to these treatments by using siRNA assay. Cell viability was analyzed by Annexin V. We also analyze the expression of Bip in 138 DLBCL patients by immunohistochemistry and in 63 of them by mRNA gene expression. Clinical data and follow up were available in 52 patients with a mean follow up of 2.9 years (range 0.02 to 6.7 years). Results All cell lines responded to R-CHOP treatment, with a decrease in cell viability ranging from 20% observed in OCI-LY8 cells to 45% in SUDHL6 cells. Moreover, in parallel with this response we detected a marked decrease in Bip expression both by protein and qPCR analysis. Bortezomib alone was less effective than R-CHOP, with 25% decrease in cell viability in the most sensitive SUDHL6 cells and less than 1% decrease in cell viability in the most resistant OCI-LY8 cells. Bortezomib increased both BiP mRNA and protein expression. The combination of bortezomib plus R-CHOP induces higher rates of cell death in all cell lines ranging between 35% decrease in cell viability in OCI-LY8 cells to 53.7% in SUDHL16 cells. This combination therapy led to an increase of Bip mRNA and protein expression but at much less extent than bortezomib alone. To confirm that BiP plays an antiapoptotic role in DLBCL we performed a siRNA assay for Bip in OCI-LY8 and SUDHL16 cell lines, corresponding to the most resistant and sensitive cell lines. After siRNA transfection, both cell lines reduced 60% to 80% Bip mRNA expression and became sensitive to bortezomib alone and more sensitive to the combination therapy. Bip expression was observed in 96 (69.5%) of newly diagnosed DLBCL tumors independently of Xbp1 activation and ABC subtype. Moreover high Bip mRNA expression (3-4 quartile) was predictive of worse survival (median overall survival 3.34 vs 1.9 years, p=0.048). Conclusions The ER-stress sensor Bip is expressed in DLBCL cell lines and primary tumors and it plays an important prosurvival role. Moreover Bip expression is a target of R-CHOP and bortezomib treatments being responsible for the primary resistance to bortezomib. In addition, the combination of R-CHOP plus bortezomib reduced Bip expression and decreased cell survival providing a rationale for the combination therapy in the clinical settings. Furthermore, high Bip expression is an adverse prognostic factor in newly diagnosed DLBCL patients treated with R-CHOP and may be used to select patients that would benefit from the addition of bortezomib to the standard chemotherapy. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Downregulation of long non-coding RNA MALAT1 induces tumor progression of human breast cancer through regulating CCND1 expression

2016 ◽  
Vol 11 (1) ◽  
pp. 232-236 ◽  
Author(s):  
Zhang Yang ◽  
Wang Lu ◽  
Li Ning ◽  
Dai Hao ◽  
Sun Jian ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Protein Expression ◽  
Cell Lines ◽  
Breast Cancer Cell ◽  
Colony Formation ◽  
Breast Cancer Cell Lines ◽  
Non Coding Rna ◽  
Mrna And Protein Expression ◽  
Long Non Coding Rna

AbstractObjectiveMetastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is already known to be involved in the development and progression of many types of tumors. In the present study, we set to seek the role of MALAT1and the molecular mechanisms in breast cancer.MethodsMALAT1 mRNA expression level was measured by real-time PCR in selected tissues and breast cancer cell lines. SiRNAs targeting MALAT1 were employed to knockdown the endogenous MALAT1. Then cell counting method and colony formation method were applied to reveal the proliferation changes after MALAT1 was suppressed. Afterwards, the mRNA and protein expression of growth related gene cyclinD1 (CCND1) were detected by RT-PCR and western blotting, respectively.ResultsWe found a downregulation of MALAT1 expression in breast cancer cell lines and tissues. Inhibition of its expression led to enhanced cell proliferation and colony formation. Importantly, the mRNA and protein expression of CCND1 was significantly increased in MALAT1-depleted cells.ConclusionMALAT1 is a potential tumor suppressive long non-coding RNA that negatively regulates cell proliferation in breast cancer progression, via suppressing CCND1 expression.

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