BCL2

Gene Summary

Gene:BCL2; BCL2, apoptosis regulator
Aliases: Bcl-2, PPP1R50
Location:18q21.33
Summary:This gene encodes an integral outer mitochondrial membrane protein that blocks the apoptotic death of some cells such as lymphocytes. Constitutive expression of BCL2, such as in the case of translocation of BCL2 to Ig heavy chain locus, is thought to be the cause of follicular lymphoma. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:apoptosis regulator Bcl-2
Source:NCBIAccessed: 11 March, 2017

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (12)

Latest Publications: BCL2 (cancer-related)

Zhou S, Zhang S, Shen H, et al.
Curcumin inhibits cancer progression through regulating expression of microRNAs.
Tumour Biol. 2017; 39(2):1010428317691680 [PubMed] Related Publications
Curcumin, a major yellow pigment and spice in turmeric and curry, is a powerful anti-cancer agent. The anti-tumor activities of curcumin include inhibition of tumor proliferation, angiogenesis, invasion and metastasis, induction of tumor apoptosis, increase of chemotherapy sensitivity, and regulation of cell cycle and cancer stem cell, indicating that curcumin maybe a strong therapeutic potential through modulating various cancer progression. It has been reported that microRNAs as small noncoding RNA molecules are related to cancer progression, which can be regulated by curcumin. Dysregulated microRNAs play vital roles in tumor biology via regulating expressions of target genes and then influencing multiple cancer-related signaling pathways. In this review, we focused on the inhibition effect of curcumin on various cancer progression by regulating expression of multiple microRNAs. Curcumin-induced dysregulation of microRNAs may activate or inactivate a set of signaling pathways, such as Akt, Bcl-2, PTEN, p53, Notch, and Erbb signaling pathways. A better understanding of the relation between curcumin and microRNAs may provide a potential therapeutic target for various cancers.

Zhao Y, Yang F, Li W, et al.
miR-29a suppresses MCF-7 cell growth by downregulating tumor necrosis factor receptor 1.
Tumour Biol. 2017; 39(2):1010428317692264 [PubMed] Related Publications
Tumor necrosis factor receptor 1 is the main receptor mediating many tumor necrosis factor-alpha-induced cellular events. Some studies have shown that tumor necrosis factor receptor 1 promotes tumorigenesis by activating nuclear factor-kappa B signaling pathway, while other studies have confirmed that tumor necrosis factor receptor 1 plays an inhibitory role in tumors growth by inducing apoptosis in breast cancer. Therefore, the function of tumor necrosis factor receptor 1 in breast cancer requires clarification. In this study, we first found that tumor necrosis factor receptor 1 was significantly increased in human breast cancer tissues and cell lines, and knockdown of tumor necrosis factor receptor 1 by small interfering RNA inhibited cell proliferation by arresting the cell cycle and inducing apoptosis. In addition, miR-29a was predicted as a regulator of tumor necrosis factor receptor 1 by TargetScan and was shown to be inversely correlated with tumor necrosis factor receptor 1 expression in human breast cancer tissues and cell lines. Luciferase reporter assay further confirmed that miR-29a negatively regulated tumor necrosis factor receptor 1 expression by binding to the 3' untranslated region. In our functional study, miR-29a overexpression remarkably suppressed cell proliferation and colony formation, arrested the cell cycle, and induced apoptosis in MCF-7 cell. Furthermore, in combination with tumor necrosis factor receptor 1 transfection, miR-29a significantly reversed the oncogenic role caused by tumor necrosis factor receptor 1 in MCF-7 cell. In addition, we demonstrated that miR-29a suppressed MCF-7 cell growth by inactivating the nuclear factor-kappa B signaling pathway and by decreasing cyclinD1 and Bcl-2/Bax protein levels. Taken together, our results suggest that miR-29a is an important regulator of tumor necrosis factor receptor 1 expression in breast cancer and functions as a tumor suppressor by targeting tumor necrosis factor receptor 1 to influence the growth of MCF-7 cell.

Dai L, Wang G, Pan W
Andrographolide Inhibits Proliferation and Metastasis of SGC7901 Gastric Cancer Cells.
Biomed Res Int. 2017; 2017:6242103 [PubMed] Free Access to Full Article Related Publications
To explore the mechanisms by which andrographolide inhibits gastric cancer cell proliferation and metastasis, we employed the gastric cell line SGC7901 to investigate the anticancer effects of andrographolide. The cell survival ratio, cell migration and invasion, cell cycle, apoptosis, and matrix metalloproteinase activity were assessed. Moreover, western blotting and real-time PCR were used to examine the protein expression levels and the mRNA expression levels, respectively. The survival ratio of cells decreased with an increasing concentration of andrographolide in a dose-dependent manner. Consistent results were also obtained using an apoptosis assay, as detected by flow cytometry. The cell cycle was blocked at the G2/M2 phase by andrographolide treatment, and the proportion of cells arrested at G1/M was enhanced as the dose increased. Similarly, wound healing and Transwell assays showed reduced migration and invasion of the gastric cancer cells at various concentrations of andrographolide. Andrographolide can inhibit cell proliferation, invasion, and migration, block the cell cycle, and promote apoptosis in SGC7901 cells. The mechanisms may include upregulated expression of Timp-1/2, cyclin B1, p-Cdc2, Bax, and Bik and downregulated expression of MMP-2/9 and antiapoptosis protein Bcl-2.

Cheng F, Pan Y, Lu YM, et al.
RNA-Binding Protein Dnd1 Promotes Breast Cancer Apoptosis by Stabilizing the Bim mRNA in a miR-221 Binding Site.
Biomed Res Int. 2017; 2017:9596152 [PubMed] Free Access to Full Article Related Publications
RNA-binding proteins (RBPs) and miRNAs are capable of controlling processes in normal development and cancer. Both of them could determine RNA transcripts fate from synthesis to decay. One such RBP, Dead end (Dnd1), is essential for regulating germ-cell viability and suppresses the germ-cell tumors development, yet how it exerts its functions in breast cancer has remained unresolved. The level of Dnd1 was detected in 21 cancerous tissues paired with neighboring normal tissues by qRT-PCR. We further annotated TCGA (The Cancer Genome Atlas) mRNA expression profiles and found that the expression of Dnd1 and Bim is positively correlated (p = 0.04). Patients with higher Dnd1 expression level had longer overall survival (p = 0.0014) by KM Plotter tool. Dnd1 knockdown in MCF-7 cells decreased Bim expression levels and inhibited apoptosis. While knockdown of Dnd1 promoted the decay of Bim mRNA 3'UTR, the stability of Bim-5'UTR was not affected. In addition, mutation of miR-221-binding site in Bim-3'UTR canceled the effect of Dnd1 on Bim mRNA. Knockdown of Dnd1 in MCF-7 cells confirmed that Dnd1 antagonized miR-221-inhibitory effects on Bim expression. Overall, our findings indicate that Dnd1 facilitates apoptosis by increasing the expression of Bim via its competitive combining with miR-221 in Bim-3'UTR. The new function of Dnd1 may contribute to a vital role in breast cancer development.

Shen L, Zhang G, Lou Z, et al.
Cryptotanshinone enhances the effect of Arsenic trioxide in treating liver cancer cell by inducing apoptosis through downregulating phosphorylated- STAT3 in vitro and in vivo.
BMC Complement Altern Med. 2017; 17(1):106 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Arsenic trioxide (ATO) is approved for treating terminal-stage liver cancer in China. Cryptotanshinone (CT), a STAT3 inhibitor, has exhibited certain anti-tumor potency; however, the use of CT enhanced ATO for treating liver cancer has not been reported. Here we try to elucidate how CT could enhance the efficacy of ATO for treating liver cancer and its correlation to STAT3 in vitro and in vivo.
METHODS: Cell viability of ATO combined with CT was assessed by (1)MTT assay. Cell apoptosis induced by ATO combined with CT was detected by Annexin V/PI staining and apoptosis-related proteins were detected by western blotting. STAT3-related proteins were analysis by western blotting analysis and Immunofluorescence assays. Efficacy evaluation of ATO combined with CT on xenograft was carried in nude mice and related proteins were analysis by Immunohistochemistry assays.
RESULTS: First we evaluated cell vitality, and our data indicated that the ATO combined with CT showed obvious growth inhibition of Bel-7404 cells compared to ATO or CT alone. Next we found that ATO combined with CT induced cell apoptosis in Bel-7404 cells and upregulated the activation of apoptosis-related proteins cleaved-caspase-3, cleaved-caspase-9, and cleaved-poly(ADP-ribose) polymerase in a time-dependent manner. Next, we found that ATO combined with CT not only inhibited the constitutive levels of phosphorylated-JAK2 and phosphorylated-STAT3(Tyr705) but did so in a time-dependent manner. We also found that ATO combined with CT reversed the upregulated expression of phosphorylated-STAT3(Tyr705) stimulated by interleukin-6 and downregulated STAT3 direct target genes and the anti-apoptotic proteins Bcl-2, XIAP, and survivin but obviously upregulated the promoting apoptosis proteins Bak,.In vivo studies showed that ATO combined with CT decreased tumor growth. Tumors from ATO combined with CT-treated mice showed decreased levels of phosphorylated-STAT3(Tyr705) and the anti-apoptotic protein Bcl-2 but an increased level of pro-apoptotic protein Bax.
CONCLUSIONS: Our study provides strong evidence that CT could enhance the efficacy of ATO in treating liver cancer both in vitro and in vivo. Downregulation of phosphorylated-STAT3 expression may play an important role in inducing apoptosis of Bel-7404 cells.

Murai S, Matuszkiewicz J, Okuzono Y, et al.
Aurora B Inhibitor TAK-901 Synergizes with BCL-xL Inhibition by Inducing Active BAX in Cancer Cells.
Anticancer Res. 2017; 37(2):437-444 [PubMed] Related Publications
BACKGROUND: Aurora B kinase plays an essential role in chromosome segregation and cytokinesis, and is dysregulated in many cancer types, making it an attractive therapeutic target. TAK-901 is a potent aurora B inhibitor that showed efficacy in both in vitro and in vivo oncology models.
MATERIALS AND METHODS: We conducted a synthetic lethal siRNA screening to identify the genes that, when silenced, can potentiate the cell growth-inhibitory effect of TAK-901.
RESULTS: B-cell lymphoma-extra large (BCL-xL) depletion by siRNA or chemical inhibition synergized with TAK-901 in cancer cell lines. As a mechanism of synthetic lethality, active BCL2 associated X, apoptosis regulator (BAX) was induced by TAK-901. BCL-xL protected cells from BAX-dependent apoptosis induction. Therefore, TAK-901 sensitizes cancer cells to BCL-xL inhibition.
CONCLUSION: Polyploid cells induced by TAK-901 are vulnerable to BCL-xL inhibition. Our findings may have an impact on combination strategies with aurora B inhibitors in clinical studies.

Bastos V, Ferreira-de-Oliveira JM, Carrola J, et al.
Coating independent cytotoxicity of citrate- and PEG-coated silver nanoparticles on a human hepatoma cell line.
J Environ Sci (China). 2017; 51:191-201 [PubMed] Related Publications
The antibacterial potential of silver nanoparticles (AgNPs) resulted in their increasing incorporation into consumer, industrial and biomedical products. Therefore, human and environmental exposure to AgNPs (either as an engineered product or a contaminant) supports the emergent research on the features conferring them different toxicity profiles. In this study, 30nm AgNPs coated with citrate or poly(ethylene glycol) (PEG) were used to assess the influence of coating on the effects produced on a human hepatoma cell line (HepG2), namely in terms of viability, apoptosis, apoptotic related genes, cell cycle and cyclins gene expression. Both types of coated AgNPs decreased cell proliferation and viability with a similar toxicity profile. At the concentrations used (11 and 5μg/mL corresponding to IC50 and ~IC10 levels, respectively) the amount of cells undergoing apoptosis was not significant and the apoptotic related genes BCL2 (anti-apoptotic gene) and BAX (pro-apoptotic gene) were both downregulated. Moreover, both AgNPs affected HepG2 cell cycle progression at the higher concentration (11μg/mL) by increasing the percentage of cells in S (synthesis phase) and G2 (Gap 2 phase) phases. Considering the cell-cycle related genes, the expression of cyclin B1 and cyclin E1 genes were decreased. Thus, this work has shown that citrate- and PEG-coated AgNPs impact on HepG2 apoptotic gene expression, cell cycle dynamics and cyclin regulation in a similar way. More research is needed to determine the properties that confer AgNPs at lower toxicity, since their use has proved helpful in several industrial and biomedical contexts.

Kumar Mongre R, Sharma N, Singh Sodhi S, et al.
Novel phyto-derivative BRM270 inhibits hepatocellular carcinoma cells proliferation by inducing G2/M phase cell cycle arrest and apoptosis in xenograft mice model.
Biomed Pharmacother. 2017; 87:741-754 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is a major threat to human health worldwide and development of novel antineoplastic drug is demanding task. BRM270 is a proprietary combination of traditional medicinal herbs, has been shown to be effective against a wide range of stem-like cancer initiating cells (SLCICs). However, the underlying mechanism and antitumor efficacy of BRM270 in human hepatocellular carcinoma (HCC) cells have not been well elucidated till date. Here we studied the tumoricidal effect of BRM270 on human-CD133(+) expressing stem-like HepG-2 and SNU-398 cells. Gene expression profiling by qPCR and specific cellular protein expressions was measured using immunocytochemistry/western blot analysis. In vivo efficacy of BRM270 has been elucidated in the SLCICs induced xenograft model. In addition, 2DG-(2-Deoxy-d-Glucose) optical-probe guided tumor monitoring was performed to delineate the size and extent of metastasized tumor. Significant (P<0.05) induction of Annexin-V positive cell population and dose-dependent upregulation of caspase-3 confirmed apoptotic cell death by pre/late apoptosis. In addition, bright field and fluorescence microscopy of treated cells revealed apoptotic morphology and DNA fragmentation in Hoechst33342 staining. Levels of c-Myc, Bcl-2 and c-Jun as invasive potential apoptotic marker were detected using qPCR/Western blot. Moreover, BRM270 significantly (P<0.05) increased survival rate that observed by Kaplan-Meier log rank test. In conclusion, these results indicate that BRM270 can effectively inhibit proliferation and induce apoptosis in hepatoma cells by down-regulating CyclinD1/Bcl2 mediated c-Jun apoptotic pathway.

Zhang H, Zhong J, Bian Z, et al.
Long non-coding RNA CCAT1 promotes human retinoblastoma SO-RB50 and Y79 cells through negative regulation of miR-218-5p.
Biomed Pharmacother. 2017; 87:683-691 [PubMed] Related Publications
OBJECTIVE: To investigate the regulatory role and potential mechanism of long non-coding RNAs (lncRNA) in human retinoblastoma (RB).
METHODS: The lncRNA profile in RB tissues were analyzed by microarray and quantitative reverse transcription PCR (qRT-PCR). One of the identified lncRNAs (LncRNA CCAT1) was selected for further experiments. SO-RB50 and Y79 cells were transfected with negative control, siRNA targeting lncRNA CCAT1 (si-CCAT1) and si-CCAT1+miR218-5p inhibitor, respectively. lncRNA CCAT1 expression was measured by qRT-PCR. Cell proliferation, migration and invasion were detected by CCK8, wound scratching, and transwell assay, respectively. Apoptosis and cell cycle distribution were assessed by flow cytometry. Apoptosis- (cle-caspase-3, cle-caspase-9, Bax and Bcl-2) and cell cycle-related protein expression (cyclin B1, CDC2 and p-CDC2 (Thr161)) were analyzed by Western blot.
RESULTS: lncRNA CCAT1 expression in SO-RB50 and Y79 cells was significantly inhibited after si-CCAT1 transfection (P<0.01). Both RB cells exhibited significantly reduced proliferation, migration and invasion abilities, but markedly increased apoptosis at 48h after si-CCAT1 transfection (P<0.05 or 0.01). RB cells in si-CCAT1+miR218-5p inhibitor group had significantly higher proliferation, migration and invasion, but notably lower apoptosis compared with si-CCAT1 group at 24 and 48h after transfection (all P<0.05 or 0.01). si-CCAT1 significantly increased the expression of cle-caspase-3, cle-caspase-9, Bax, but decreased Bcl-2 expression (P<0.01). The proportion of G2/M SO-RB50 and Y79 cells in siCCAT1 group was significantly increased compared with negative control group (P<0.01). LncRNA CCAT1 interference significantly reduced the expression of cyclin B1, CDC2 and p-CDC2 (Thr161) (P<0.01).
CONCLUSION: LncRNA CCAT1 promotes the proliferation migration and invasion, and reduces cell apoptosis of SO-RB50 and Y79 cells, probably through negative modulation of miR-218-5p. Our study suggested lncRNA CCAT1 as a potential biomarker and therapeutic target for RB.

Lu Y, Li Y, Chai X, et al.
Long noncoding RNA HULC promotes cell proliferation by regulating PI3K/AKT signaling pathway in chronic myeloid leukemia.
Gene. 2017; 607:41-46 [PubMed] Related Publications
Aberrant expression of long noncoding RNA (lncRNA) HULC is associated with various human cancers. However, the role of HULC in chronic myeloid leukemia (CML) is unknown. In this study, we found that HULC was remarkably overexpressed in both leukemia cell lines and primary hematopoietic cells derived from CML patients. The increase in HULC expression was positively correlated with clinical stages in CML. Moreover, the knockdown of HULC significantly inhibited CML cell proliferation and induced apoptosis by repressing c-Myc and Bcl-2. Furthermore, inhibition of HULC enhanced imatinib-induced apoptosis of CML cells. Further experiments demonstrated that HULC silencing markedly suppressed the phosphorylation of PI3K and AKT, indicating that enhancement of imatinib-induced apoptosis by HULC inhibition is related with the reduction of c-Myc expression and inhibition of PI3K/Akt pathway activity. Furthermore, HULC could modulate c-Myc and Bcl-2 by miR-200a as an endogenous sponge. Taken together, these results reveal that HULC promotes oncogenesis in CML and suggest a potential strategy for the CML treatment.

Subash-Babu P, Alshammari GM, Ignacimuthu S, Alshatwi AA
Epoxy clerodane diterpene inhibits MCF-7 human breast cancer cell growth by regulating the expression of the functional apoptotic genes Cdkn2A, Rb1, mdm2 and p53.
Biomed Pharmacother. 2017; 87:388-396 [PubMed] Related Publications
Systematic analyses of plants that are used in traditional medicine may lead to the discovery of novel cytotoxic secondary metabolites. Diterpene possesses multiple bioactivities; here, epoxy clerodane diterpene (ECD) was isolated from Tinospora cordifolia (Willd.) stem and shown potential antiproliferative effect in MCF-7 human breast cancer cells. The antiproliferative effect of ECD on MCF-7 cells was systematically analyzed by cell and nuclear morphology, alterations in oxidative stress, and the expression of tumor suppressor and mitochondria-mediated apoptosis-related genes. We found that the IC50 value of ECD was 3.2μM at 24h and 2.4μM at 48h. We observed that the cytotoxicity of ECD was specific to MCF-7 cells, whereas ECD was nontoxic to normal Vero and V79 cells. ECD significantly triggered intracellular ROS generation even from the lower doses of 0.6 and 1.2μM; and it is relative to higher dose of 2.4μM. Further, we used 0.6μM, 1.2μM and 2.4μM as experimental doses to analyze the relative dose-dependent effects. Nuclear staining revealed that cells treated with the 2.4μM dose exhibited characteristic apoptotic morphological changes and that 46% of the cells were apoptotic and 4% were necrotic after 48h. ECD significantly increased the expression of mitochondria-dependent apoptotic pathway-related genes after 48h; we observed significantly (p≤0.05) increased expression of CYP1A, GPX, GSK3β and TNF-α and downregulated expression of NF-κB. ECD also increased the expression of tumor suppressor genes such as Cdkn2A, Rb1 and p53. In addition, we observed that ECD treatment significantly (p≤0.001) upregulated the expression of apoptotic genes such as Bax, cas-3, cas-8, cas-9 and p21 and downregulated the expression of BCL-2, mdm2 and PCNA. In conclusion, ECD regulates the expression of Cdkn2A, p53 and mdm2 and induces apoptosis via the mitochondrial pathway in MCF-7 human breast cancer cells.

Shabestari RM, Safa M, Alikarami F, et al.
CREB knockdown inhibits growth and induces apoptosis in human pre-B acute lymphoblastic leukemia cells through inhibition of prosurvival signals.
Biomed Pharmacother. 2017; 87:274-279 [PubMed] Related Publications
A majority of acute lymphoblastic leukemia patients overexpress CREB in the bone marrow. However, the functional significance of this up-regulation and the detailed molecular mechanism behind the regulatory effect of CREB on the growth of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cells has not been elucidated. We demonstrated here that CREB knockdown induced apoptosis and impaired growth of BCP-ALL NALM-6 cells which was associated with caspase activation. The gene expression levels of prosurvival signals Bcl-2, Mcl-1, Bcl-xL, survivin and XIAP were down-regulated upon CREB suppression. These findings indicate a critical role for CREB in proliferation, survival, and apoptosis of BCP-ALL cells. The data also suggest that CREB could possibly serve as potential therapeutic target in BCP-ALL.

Oliveira CC, Maciel-Guerra H, Kucko L, et al.
Double-hit lymphomas: clinical, morphological, immunohistochemical and cytogenetic study in a series of Brazilian patients with high-grade non-Hodgkin lymphoma.
Diagn Pathol. 2017; 12(1):3 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Double-hit lymphomas (DHL) are rare high-grade neoplasms characterized by two translocations: one involving the gene MYC and another involving genes BCL2 or BCL6, whose diagnosis depends on cytogenetic examination. This research studied DHL and morphological and/or immunophenotypic factors associated with the detection of these translocations in a group of high-grade non-Hodgkin lymphoma cases.
METHOD: Clinical and morphological reviews of 120 cases diagnosed with diffuse large B-cell lymphoma and Burkitt lymphoma were conducted. Immunohistochemistry (CD20, CD79a, PAX5, CD10, Bcl6, Bcl2, MUM1, TDT and Myc) and fluorescence in situ hybridization for detection of MYC, BCL2 and BCL6 gene translocations were performed in a tissue microarray platform.
RESULTS: Three cases of DHL were detected: two with translocations of MYC and BCL2 and one with translocations of MYC and BCL6, all leading to death in less than six months. Among 90 cytogenetically evaluable biopsies, associations were determined between immunohistochemistry and fluorescence in situ hybridization for MYC (p = 0.036) and BCL2 (p = 0.001). However, these showed only regular agreement, indicated by Kappa values of 0.23 [0.0;0.49] and 0.35 [0.13;0.56], respectively. "Starry sky" morphology was strongly associated with MYC positivity (p = 0.01). The detection of three cases of DHL, all resulting in death, confirms the rarity and aggressiveness of this neoplasm.
CONCLUSIONS: The "starry sky" morphological pattern and immunohistochemical expression of Myc and Bcl2 represent possible selection factors for additional cytogenetic diagnostic testing.

Oliveira C, Lourenço GJ, Rinck-Junior JA, et al.
Polymorphisms in apoptosis-related genes in cutaneous melanoma prognosis: sex disparity.
Med Oncol. 2017; 34(2):19 [PubMed] Related Publications
Cutaneous melanoma (CM) cells are resistant to apoptosis, and steroid hormones are involved in this process through regulation of TP53, MDM2, BAX, and BCL2 expression. We analyzed herein sex differences in outcomes of CM patients associated with TP53 c.215G>C, MDM2 c.309T>G, BAX c.-248G>A, and BCL2 c.-717C>A polymorphisms. DNA from 121 men and 116 women patients was analyzed by polymerase chain reaction and enzymatic digestion assays. At 60 months of follow-up, shorter progression-free survival (PFS) was seen in males with MDM2 GG + BCL2 AA (20.0 vs. 62.6%, P = 0.0008) genotype. Men carriers of the genotype had poor PFS (HR 3.78, 95% CI 1.30-11.0) than others. For women, shorter PFS was associated with TP53 GC or CC (61.4 vs. 80.8%, P = 0.01) and TP53 GC or CC + MDM2 TG or GG (59.1 vs. 85.4%, P = 0.01) genotypes at the same time. Women carriers of the genotypes had poor PFS (HR 2.46, 95% CI 1.19-5.09; HR 9.49, 95% CI 1.14-78.50) than others, respectively. Our data present, for the first time, preliminary evidence that inherited abnormalities on TP53, MDM2 and BCL2 genes, enrolled in apoptosis pathways, have a pivotal role in differences of outcomes in women and men with CM.

Wang Y, Chen Y, Zhang X, et al.
Tricholoma matsutake Aqueous Extract Induces Hepatocellular Carcinoma Cell Apoptosis via Caspase-Dependent Mitochondrial Pathway.
Biomed Res Int. 2016; 2016:9014364 [PubMed] Free Access to Full Article Related Publications
Tricholoma matsutake, one of widely accepted functional mushrooms, possesses various pharmacological activities, and its antitumor effect has become an important research point. Our study aims to evaluate the cytotoxicity activities of T. matsutake aqueous extract (TM) in HepG2 and SMMC-7721 cells. In in vitro experiments, TM strikingly reduced cell viability, promoted cell apoptosis, inhibited cell migration ability, induced excessive generation of ROS, and caused caspases cascade and mitochondrial membrane potential dissipation in hepatocellular carcinoma cells. In in vivo experiments, 14-day TM treatment strongly suppressed tumor growth in HepG2 and SMMC-7721-xenografted nude mice without influence on their body weights and liver function. Furthermore, TM increased the levels of cleaved poly-ADP-ribose polymerase (PARP), Bad, and Bax and reduced the expressions of B-cell lymphoma 2 (Bcl-2) in treated cells and tumor tissues. All aforementioned results suggest that caspase-dependent mitochondrial apoptotic pathways are involved in TM-mediated antihepatocellular carcinoma.

Pronina IV, Loginov VI, Burdennyy AM, et al.
DNA methylation contributes to deregulation of 12 cancer-associated microRNAs and breast cancer progression.
Gene. 2017; 604:1-8 [PubMed] Related Publications
The methylation of promoter CpG islands and the interaction between microRNAs (miRNAs) and messenger RNAs (mRNAs) of target genes are considered two crucial mechanisms for gene and pathway deregulation in malignant tumors. The aim of this study was to analyze the role of promoter methylation in altering the expression of 13 miRNAs that are associated with breast cancer (BC): miR-124, -125b, -127, -132, -137, -148a, -191, -193a, -203, -212, -34b, -375, -9. The role of methylation in the deregulation of these miRNAs has not been previously assessed in the representative set of BC samples. We used a set of 58 paired (tumor/normal) breast tissue samples and methylation-specific PCR to demonstrate significant aberrations in the methylation patterns of 9 miRNA genes. In particular, we observed hypermethylation of MIR-127, -132, and -193a, and hypomethylation of MIR-191 for the first time. Using quantitative PCR, we established a strong correlation between promoter methylation and expression levels for 12 miRNA genes (all except MIR-212); this finding demonstrates the functional importance of altered methylation patterns. We also performed a correlation analysis between expression levels of the 13 miRNAs and 5 cancer-associated genes, namely RASSF1(A), CHL1, APAF1, DAPK1, and BCL2, which were predicted as targets for these miRNAs, to investigate the impact of these miRNAs on these genes with key cellular functions in BC. Significant negative correlation was revealed for the following miRNA-mRNA pairs: miR-127-5p and DAPK1, miR-375 and RASSF1(A), and miR-124-3p and BCL2. Additionally, we also found a strong association between hypermethylation of MIR-127 and MIR-125b-1 and BC progression, particularly metastasis. Thus, our findings provide evidence for the significant role of methylation in the deregulation of 12 miRNA genes in BC, identify putative novel functional miRNA-mRNA pairs, and suggest MIR-127 and MIR-125b-1 hypermethylation to be potential biomarkers of BC metastasis.

Tu L, Zhao E, Zhao W, et al.
hsa-miR-376c-3p Regulates Gastric Tumor Growth Both In Vitro and In Vivo.
Biomed Res Int. 2016; 2016:9604257 [PubMed] Free Access to Full Article Related Publications
Background. In recent studies, aberrant expression of various microRNAs (miRNAs) is reported to be associated with gastric cancer metastasis. Method. Overexpression construct and inhibitor of hsa-miR-376c-3p were expressed in human gastric adenocarcinoma cell line SGC-7901. The expression level of tumor related genes was detected by qPCR, western blot, and immunostaining. Cell apoptosis was determined by flow cytometry. Xenograft of SGC-7901 cells was used to elucidate the function of hsa-miR-376c-3p in gastric tumor growth in vivo. Result. Expression of hsa-miR-376c-3p was detected in SGC-7901 cells. Downregulation of hsa-miR-376c-3p increased the expression level of BCL-2 and decreased the expression of smad4 and BAD. On the contrary, overexpression of hsa-miR-376c-3p increased the expression of BAD and smad4, while it led to the decreasing expression level of BCL-2. Overexpression of hsa-miR-376c-3p also promoted cell apoptosis in vitro and inhibited gastric tumor growth in vivo. Furthermore, the expression of BCL-2 was higher and expression of smad4 and BAD was lower in tumor tissue than the tissue adjacent to tumor from gastric cancer patients. Conclusion. This study demonstrated that hsa-miR-376c-3p plays an important role in the inhibition of gastric tumor growth and tumor related gene expression both in vitro and in vivo.

Liu F, Wang B, Wang J, et al.
Oxymatrine Inhibits Proliferation and Migration While Inducing Apoptosis in Human Glioblastoma Cells.
Biomed Res Int. 2016; 2016:1784161 [PubMed] Free Access to Full Article Related Publications
Oxymatrine (OMT), an alkaloid derived from the traditional Chinese medicine herb Sophora flavescens Aiton, has been shown to exhibit anticancer properties on various types of cancer cells. In this study, we investigate the anticancer properties of OMT on human glioblastoma (GBM) cells and evaluate their underlying mechanisms. MTT assays were performed and demonstrated that OMT significantly inhibits the proliferation of GBM cells. Flow cytometry suggested that OMT at a concentration of 10(-5) M may induce apoptosis in U251 and A172 cells. Western blot analyses demonstrated a significant increase in the expression of Bax and caspase-3 and a significant decrease in expression of Bcl-2 in both U251 and A172 cells. Additionally, OMT was found by transwell and high-content screening assays to decrease the migratory ability of the evaluated GBM cells. These findings suggest that the antitumor effects of OMT may be the result of inhibition of cell proliferation and migration and the induction of apoptosis by regulating the expression of apoptosis-associated proteins. OMT may represent a novel anticancer therapy for the treatment of GBM.

Lu M, Miao Y, Qi L, et al.
RNAi-Mediated Downregulation of FKBP14 Suppresses the Growth of Human Ovarian Cancer Cells.
Oncol Res. 2016; 23(6):267-274 [PubMed] Related Publications
FKBP14 belongs to the family of FK506-binding proteins (FKBPs). Altered expression of FKBPs has been reported in several malignancies. This study aimed to reveal the expression profile of FKBP14 in ovarian cancer and evaluate whether FKBP14 is a molecular target for cancer therapy. We found that the FKBP14 mRNA level was significantly higher in ovarian cancer tissues than in normal tissues. FKBP14 expression was then knocked down in two ovarian cancer cell lines, SKOV3 and HO8910 cells, by a lentiviral short hairpin RNA (shRNA) delivery system. Reduced expression of FKBP14 markedly impaired the proliferative ability of ovarian cancer cells. Additionally, ovarian cancer cells infected with FKBP14 shRNA lentivirus tended to arrest in the G0/G1 phase and undergo apoptosis. Moreover, knockdown of FKBP14 induced cell apoptosis via increasing the ratio of Bax to Bcl-2. These results indicated that FKBP14 might be a diagnostic marker for ovarian cancer and could be a potential molecular target for the therapy of ovarian cancer.

Zhou G, Zhang F, Guo Y, et al.
miR-200c enhances sensitivity of drug-resistant non-small cell lung cancer to gefitinib by suppression of PI3K/Akt signaling pathway and inhibites cell migration via targeting ZEB1.
Biomed Pharmacother. 2017; 85:113-119 [PubMed] Related Publications
Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is a major obstacle in the treatment of non-small cell lung cancer (NSCLC) patients. We explored the role of miR-200c in modulating the sensitivity of gefitinib-resistant NSCLC cells and examined the underlying mechanism. The gefitinib-resistant cell line PC-9-ZD and its parental PC-9 cells were used. Growth inhibition was detected by MTT assay. The cell apoptosis was detected by Annexin V/PI assay. Cell migration was assessed by wound-healing assay. RT-PCR was used to detected levels of miR-200c and ZEB1. The PI3k, Bcl-2, Bax, caspase-3 and ZEB1 protein expression were detected using Western blot analysis, and TUNEL, Immunohistochemistry for xenograft model. PC-9-ZD cells had low level of miR-200c expression compared to its parental PC-9 cells. PC-9-ZD cells with miR-200c transfection were more sensitive to gefitinib treatment. Apoptosis induced by gefitinib was observed in PC-9-ZD cells with miR-200c transfection significantly. The levels of phosphorylated-Akt and Bcl-2 expression decreased and levels of Bax and Caspase-3 expression increased in PC-9-ZD cells with miR-200c transfection. Cell migration was inhibited and ZEB1 mRNA level and protein expression were significantly decreased in PC-9-ZD cells with miR-200c transfection. Further in gefitinib resistant xenograft model, miR-200c enhanced sensitivity of gefitinib and induced apoptosis significantly through PI3K/Akt signaling pathway and targeting ZEB1. These results provided insights into the functions of miR-200c and offered an alternate approach in treating gefitinib-resistance NSCLC.

Ramdani LH, Talhi O, Taibi N, et al.
Effects of Spiro-bisheterocycles on Proliferation and Apoptosis in Human Breast Cancer Cell Lines.
Anticancer Res. 2016; 36(12):6399-6408 [PubMed] Related Publications
Breast cancer is the leading cause of cancer-related death in women worldwide and a critical public health concern. Here we investigated the anticancer potential and effects of low-molecular-weight bridgehead oxygen and nitrogen-containing spiro-bisheterocycles on proliferation and apoptosis of the human breast cancer cell lines MCF-7 and MDA-MB-231. The compounds feature a hydantoin moiety attached to either diazole, isoxazole, diazepine, oxazepine or benzodiazepine via the privileged tetrahedral spiro-linkage. Treatment with compounds spiro [hydantoin-isoxazole] and spiro [hydantoin-oxazepine] resulted in a dose-dependent decrease of cell proliferation and induction of apoptosis in both breast cancer cell lines, whereas spiro [hydantoin-diazepine] was only active against MDA-MB 231. Quantitative reverse transcription polymerase chain reaction analysis showed up-regulation of murine double minute 2 (MDM2), strictly p53-dependent, and detected an increase in expression of pro-apoptotic caspase 3 and BCL2-associated X (BAX) genes in both breast cancer cell lines expressing wild-type and mutant p53. In summary, the results suggest that our compounds promote apoptosis of breast cancer cell lines via p53-dependent and -independent pathways.

Zhang L, Jia G, Shi B, et al.
PRSS8 is Downregulated and Suppresses Tumour Growth and Metastases in Hepatocellular Carcinoma.
Cell Physiol Biochem. 2016; 40(3-4):757-769 [PubMed] Related Publications
BACKGROUND: Protease serine 8 (PRSS8), a trypsin-like serine peptidase, has been shown to function as a tumour suppressor in various malignancies. The present study aimed to investigate the expression pattern, prognostic value and the biological role of PRSS8 in human hepatocellular carcinoma (HCC).
METHODS: PRSS8 expression in 106 HCC surgical specimens was examined by Real-time polymerase chain reaction (PCR) and immunohistochemistry, and its clinical significance was analysed. The role of PRSS8 in cell proliferation, apoptosis and invasion were examined in vitro and in vivo.
RESULTS: PRSS8 mRNA and protein expression were decreased in most HCC tumours from that in matched adjacent non-tumour tissues. Low intratumoral PRSS8 expression was significantly correlated with poor overall survival (OS) in patients with HCC (P = 0.001). PRSS8 expression was an independent prognostic factor for OS (hazard ratio [HR] = 1.704, P = 0.009). Furthermore, restoring PRSS8 expression in high metastatic HCCLM3 cells significantly inhibited cell proliferation and invasion. In contrast, silencing PRSS8 expression in non-metastatic HepG2 cells significantly enhanced cell growth and invasion. Moreover, our in vivo data revealed that attenuated PRSS8 expression in HepG2 cells greatly promoted tumour growth, while overexpression of PRSS8 remarkably inhibited tumour growth in an HCCLM3 xenograft model. Enhanced cell growth and invasion ability mediated by the loss of PRSS8 expression was associated with downregulation of PTEN, Bax and E-cadherin and an upregulation in Bcl-2, MMP9 and N-cadherin.
CONCLUSIONS: Our data demonstrate that PRSS8 may serve as a tumour suppressor in HCC progression, and represent a valuable prognostic marker and potential therapeutic target for HCC.

Bortolotto LF, Barbosa FR, Silva G, et al.
Cytotoxicity of trans-chalcone and licochalcone A against breast cancer cells is due to apoptosis induction and cell cycle arrest.
Biomed Pharmacother. 2017; 85:425-433 [PubMed] Related Publications
Chalcones are precursors of flavonoids that exhibit structural heterogeneity and potential antitumor activity. The objective of this study was to characterize the cytotoxicity of trans-chalcone and licochalcone A (LicoA(1)) against a breast cancer cell line (MCF-7) and normal murine fibroblasts (3T3). Also the mechanisms of the anti-cancer activity of these two compounds were studied. The alkaline comet assay revealed dose-dependent genotoxicity, which was more responsive against the tumor cell line, compared to the 3T3 mouse fibroblast cell line. Flow cytometry showed that the two chalcones caused the cell cycle arrest in the G1 phase and induced apoptosis in MCF-7 cells. Using PCR Array, we found that trans-chalcone and LicoA trigger apoptosis mediated by the intrinsic pathway as demonstrated by the inhibition of Bcl-2 and induction of Bax. In western blot assay, the two chalcones reduced the expression of cell death-related proteins such as Bcl-2 and cyclin D1 and promoted the cleavage of PARP. However, only trans-chalcone induced the expression of the CIDEA gene and protein in these two experiments. Furthermore, transient transfections of MCF-7 using a construction of a promoter-luciferase vector showed that trans-chalcone induced the expression of the CIDEA promoter activity in 24 and 48h. In conclusion, the results showed that trans-chalcone promoted high induction of the CIDEA promoter gene and protein, which is related to DNA fragmentation during apoptosis.

Wang D, Wang D, Wang N, et al.
Long Non-Coding RNA BANCR Promotes Endometrial Cancer Cell Proliferation and Invasion by Regulating MMP2 and MMP1 via ERK/MAPK Signaling Pathway.
Cell Physiol Biochem. 2016; 40(3-4):644-656 [PubMed] Related Publications
BACKGROUND/AIMS: Microarray screening had found BRAF-activated non-coding RNA (BANCR) was significantly upregulated in type 1 endometrial cancer (EC). This study aimed to assess the potential role of long non-coding RNA (lncRNA) BANCR in the pathogenesis and progression of type 1 EC.
METHODS: Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to confirm the expression of BANCR in type 1 EC tissue, and analyze its clinical significance. In vitro, RNA interference (siRNA) was used to investigate the biological role of BANCR in type 1 EC.
RESULTS: qRT-PCR revealed that the expression of lncRNA BANCR was higher in type 1 EC (P<0.01). BANCR expression was significantly correlated with FIGO stage, pathological grade, myometrial invasion, and lymph node metastasis. The expression of BANCR was significantly correlated with that of MMP2/MMP1. In vitro, knockdown of BANCR significantly suppressed proliferation, migration, and invasion of Ishikawa and HEC-1A cells, and significantly inhibited the ERK/MAPK signaling pathway that decreased MMP2 and MMP1 expression.
CONCLUSION: BANCR is highly expressed in type 1 EC tissue and promotes EC-cell proliferation, migration, and invasion by activating ERK/MAPK signaling pathway that regulates MMP2/MMP1 expression. BANCR is expected to become a prognostic marker and therapeutic target in type 1 EC.

Sufi SA, Adigopula LN, Syed SB, et al.
In-silico and in-vitro anti-cancer potential of a curcumin analogue (1E, 6E)-1, 7-di (1H-indol-3-yl) hepta-1, 6-diene-3, 5-dione.
Biomed Pharmacother. 2017; 85:389-398 [PubMed] Related Publications
PURPOSE: Previously we showed that BDMC, an analogue of curcumin suppresses growth of human breast and laryngeal cancer cell line by causing apoptosis. Here, we demonstrate the enhanced anti-cancer activity of a heterocyclic ring (indole) incorporated curcumin analogue ((1E, 6E)-1, 7-di (1H-indol-3-yl) hepta-1, 6-diene-3, 5-Dione), ICA in short, in comparison to curcumin.
METHOD: ICA was synthesized by a one pot condensation reaction. Anti-cancer potential of ICA was assessed in three human cancer cell lines of different origin (Lung adenocarcinoma (A549), leukemia (K562) and colon cancer (SW480)) by MTT assay. Mode of cell death was determined by acridine orange-ethidium bromide (Ao-Eb) staining. Putative cellular targets of ICA were investigated by molecular docking studies. Cell cycle analysis following curcumin or ICA treatment in SW480 cell line was carried out by flow cytometry. Expression levels of Cyclin D1 and apoptotic markers, such as Caspase 3, 8 and 9 were studied by western blot analysis in SW480 cell line treated with or without ICA and curcumin.
RESULTS: The yield of ICA synthesis was found to be 69% with a purity of 98%. ICA demonstrated promising anti-cancer activity compared to curcumin alone, as discerned by MTT assay. ICA was non-toxic to the cell line of normal origin. We further observed that ICA is ∼2 fold more potent than curcumin in inhibiting the growth of SW480 cells. Ao-Eb staining revealed that ICA could induce apoptosis in all the cell lines tested. Molecular docking studies suggest that ICA may possibly exhibit its anticancer effect by inhibiting EGFR in A549, Bcr-Abl in K562 and GSK-3β kinase in SW480 cell line. Moreover, ICA showed strong binding avidity for Bcl-2 protein in silico, which could result in induction of apoptosis. Cell cycle analysis revealed that both curcumin and ICA induced concomitant cell cycle arrest at G0/G1 and G2/M phase. Western blot shows that ICA could effectively down regulate the expression of cell cycle protein cyclin D1, while promoting the activation of Caspase 3, 8 and 9 when compared to curcumin in human colon cancer cell line SW480.
CONCLUSION: The result of this study indicates that ICA could hold promise to be a potential anti-cancer agent. Since ICA has shown encouraging results in terms of its anti-cancer activity compared to curcumin, further research is necessary to fully delineate the underlying molecular mechanism of its anticancer potential.

Shafi O
Inverse relationship between Alzheimer's disease and cancer, and other factors contributing to Alzheimer's disease: a systematic review.
BMC Neurol. 2016; 16(1):236 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The AD etiology is yet not properly known. Interactions among environmental factors, multiple susceptibility genes and aging, contribute to AD. This study investigates the factors that play role in causing AD and how changes in cellular pathways contribute to AD.
METHODS: PUBMED database, MEDLINE database and Google Scholar were searched with no date restrictions for published articles involving cellular pathways with roles in cancers, cell survival, growth, proliferation, development, aging, and also contributing to Alzheimer's disease. This research explores inverse relationship between AD and cancer, also investigates other factors behind AD using several already published research literature to find the etiology of AD.
RESULTS: Cancer and Alzheimer's disease have inverse relationship in many aspects such as P53, estrogen, neurotrophins and growth factors, growth and proliferation, cAMP, EGFR, Bcl-2, apoptosis pathways, IGF-1, HSV, TDP-43, APOE variants, notch signals and presenilins, NCAM, TNF alpha, PI3K/AKT/MTOR pathway, telomerase, ROS, ACE levels. AD occurs when brain neurons have weakened growth, cell survival responses, maintenance mechanisms, weakened anti-stress responses such as Vimentin, Carbonic anhydrases, HSPs, SAPK. In cancer, these responses are upregulated and maintained. Evolutionarily conserved responses and maintenance mechanisms such as FOXO are impaired in AD. Countermeasures or compensatory mechanisms by AD affected neurons such as Tau, Beta Amyloid, S100, are last attempts for survival which may be protective for certain time, or can speed up AD in Alzheimer's microenvironment via C-ABL activation, GSK3, neuro-inflammation.
CONCLUSIONS: Alzheimer's disease and Cancer have inverse relationship; many factors that are upregulated in any cancer to sustain growth and survival are downregulated in Alzheimer's disease contributing to neuro-degeneration. When aged neurons or genetically susceptible neurons have weakened growth, cell survival and anti-stress responses, age related gene expression changes, altered regulation of cell death and maintenance mechanisms, they contribute to Alzheimer's disease. Countermeasures by AD neurons such as Beta Amyloid Plaques, NFTs, S100, are last attempts for survival and this provides neuroprotection for certain time and ultimately may become pathological and speed up AD. This study may contribute in developing new potential diagnostic tests, interventions and treatments.

Ejima-Yamada K, Oshiro Y, Okamura S, et al.
Epstein-Barr virus infection and gene promoter hypermethylation in rheumatoid arthritis patients with methotrexate-associated B cell lymphoproliferative disorders.
Virchows Arch. 2017; 470(2):205-215 [PubMed] Related Publications
We analyzed CpG-island hypermethylation status in 12 genes of paraffin-embedded tissues from 38 rheumatoid arthritis (RA) patients with methotrexate (MTX)-associated large B cell lymphoproliferative disorder (BLPD), 11 RA patients with non-MTX-associated BLPD (non-MTX-BLPD), 22 controls with diffuse large B cell lymphoma (DLBCL), and 10 controls with Epstein-Barr virus (EBV)(+) DLBCL. Among them, tumor cells from EBV(+) MTX-BLPD patients and control EBV(+) DLBCL patients had significantly lower median incidence of CpG island methylator phenotype (CIMP) than those from non-MTX-BLPD and control DLBCL groups (2.3 and 1.7 vs. 4.3 and 4.4; P < 0.01 for each). In the MTX-BLPD group, EBV(+) patients showed lower median CIMP than EBV(-) patients (2.3 vs. 3.2); they also had significantly lower hypermethylation incidence in four apoptosis-related genes, especially death-associated protein kinase (14 vs. 55 %), higher incidence of massive tumor necrosis (86 vs. 27 %), and lower BCL2 protein expression (19 vs. 86 %) than did the control DLBCL group (P < 0.01 for all). In all clinical stages, EBV(+) MTX-BLPD patients had better prognoses than the EBV(-) MTX-BLPD (P = 0.011), non-MTX-BLPD (P = 0.002), and control DLBCL groups (P = 0.015). MTX-BLPD patients without hypermethylated RAS-associated domain family-1A (RASSF1A) or O (6) -methyl guanine-DNA methyltransferase (MGMT) had significantly better prognosis than those with hypermethylation of those genes (P = 0.033). We conclude that in RA patients with MTX-BLPD, EBV infection is associated with a lower incidence of CIMP, apoptosis-related gene hypermethylation, and BCL2 expression, which can induce tumor regression by MTX withdrawal and lead to better prognoses.

Wyrwas M, Michel J, Guibaud I, et al.
Burkitt cells on a peripheral blood smear: how to deal with?
Ann Biol Clin (Paris). 2016; 74(6):697-703 [PubMed] Related Publications
The diagnosis of double hit lymphoma remains a challenge for the biologist for a good management of the patient. This new category of lymphoma "double hit" (DH) is part of a new entity of the WHO classification 2008: « Unclassifiable B lymphoma with features intermediate between diffuse large cell B lymphoma and Burkitt's lymphoma ». It is defined by the presence of a breakpoint at the locus 8q24 of the c-MYC gene associated with a recurrent translocation involving BCL2 genes primarily BCL6 or more rarely CCDN1 or BCL3 genes. These chromosomal alterations are not systematically screened at diagnosis, which can cause misdiagnosis and poor therapy management. These lymphomas DH have variable cytology and may be confused with Burkitt lymphoma (BL) or with diffuse large B-cell lymphoma (DLBCL). They have a very poor prognosis and are often resistant to chemotherapy. Their therapy and their prognosis are different from those of the BL or the DLBCL. This entity and its morphology as well as histology either immunophenotypic or cytogenetic characteristics must therefore be known to biologists, pathologists, and clinicians. Cooperation between the various actors in these disciplines is essential in case of atypical BL or DLBCL to lead to a precise classification of the pathology.

Demiroglu-Zergeroglu A, Candemir G, Turhanlar E, et al.
EGFR-dependent signalling reduced and p38 dependent apoptosis required by Gallic acid in Malignant Mesothelioma cells.
Biomed Pharmacother. 2016; 84:2000-2007 [PubMed] Related Publications
The unrestrained EGFR signalling contributes to malignant phenotype in a number of cancers including Malignant Mesotheliomas. Present study was designed to evaluate EGFR-dependent anti-proliferative and apoptotic effects of Gallic acid in transformed Mesothelial (MeT-5A) and Malignant Mesothelioma (SPC212) cells. Gallic acid reduced the viability of Malignant Mesothelioma cells in a concentration and time-dependent manner. However, viability of mesothelial cells reduced only at high concentration and longer time periods. Gallic acid restrained the activation of EGFR, ERK1/2 and AKT proteins and down regulated expression of Cyclin D and Bcl-2 genes, but upregulated the expression of p21 gene in EGF-induced SPC212 cells. GA-induced transitory G1 arrest and triggered mitochondrial and death receptor mediated apoptosis, which requires p38MAPK activation. The data provided here indicate that GA is able to inhibit EGFR dependent proliferation and survival signals and induces p38 pathway dependent apoptosis in Malignant Mesothelioma cells. On the basis of these experimental findings it is worthwhile to investigate further the biological activity of Gallic acid on other Mesothelioma cell lines harbouring aberrant EGFR signals.

Yao J, Huang A, Zheng X, et al.
53BP1 loss induces chemoresistance of colorectal cancer cells to 5-fluorouracil by inhibiting the ATM-CHK2-P53 pathway.
J Cancer Res Clin Oncol. 2017; 143(3):419-431 [PubMed] Related Publications
PURPOSE: Loss of P53 binding protein 1 (53BP1) is considered a poor prognostic factor for colorectal cancer. However, its effect on chemosensitivity of colorectal cancer to 5-fluorouracil (5-FU) remains elusive. This study aimed to examine the association of 53BP1 expression with chemosensitivity of colorectal cancer cells to 5-FU.
METHODS: Immunohistochemistry was performed on 30 metastatic colorectal cancer samples to assess the associations of 53BP1 levels with clinical therapeutic effects. In vitro, IC50 values for 5-FU and 53BP1 levels were determined by MTT assay and Western blot in 5 colorectal cancer cell lines. Then, 53BP1 was silenced in HCT116 and HT29 cells, and cell proliferation, apoptosis and cell cycle distribution were evaluated. Relative protein levels of ATM-CHK2-P53 pathway effectors and Bcl-2 family members were measured by Western blot. Finally, the effects of 53BP1 knockdown on tumor growth and 5-FU chemoresistance were investigated in vivo.
RESULTS: 53BP1 expression was closely related to time to progression (TTP) after first-line chemotherapy. Namely, 53BP1 downregulation resulted in reduced TTP. In addition, 53BP1 silencing increased proliferation, inhibited apoptosis and induced S phase arrest in HCT116 and HT29 cells after 5-FU treatment. Moreover, 53BP1 knockdown also reduced the protein levels of ATM-CHK2-P53 apoptotic pathway effectors, caspase9 and caspase3, while increasing Bcl-2 expression. In vivo, 53BP1 silencing accelerated tumor proliferation in nude mice and enhanced resistance to 5-FU.
CONCLUSIONS: These findings confirmed that 53BP1 loss might be a negative factor for chemotherapy efficacy, promoting cell proliferation and inhibiting apoptosis by suppressing ATM-CHK2-P53 signaling, and finally inducing 5-FU resistance.

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