Gene Summary

Gene:FH; fumarate hydratase
Summary:The protein encoded by this gene is an enzymatic component of the tricarboxylic acid (TCA) cycle, or Krebs cycle, and catalyzes the formation of L-malate from fumarate. It exists in both a cytosolic form and an N-terminal extended form, differing only in the translation start site used. The N-terminal extended form is targeted to the mitochondrion, where the removal of the extension generates the same form as in the cytoplasm. It is similar to some thermostable class II fumarases and functions as a homotetramer. Mutations in this gene can cause fumarase deficiency and lead to progressive encephalopathy. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:fumarate hydratase, mitochondrial
Source:NCBIAccessed: 01 September, 2019


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 (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Latest Publications: FH (cancer-related)

Romanchikova N, Trapencieris P
Wedelolactone Targets EZH2-mediated Histone H3K27 Methylation in Mantle Cell Lymphoma.
Anticancer Res. 2019; 39(8):4179-4184 [PubMed] Related Publications
BACKGROUND/AIM: Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of polycomb repressive complex 2 (PRC2), possesses histone N-methyltransferase (HMT) activity and plays an essential role in cancer initiation and development. The aim of the present study was to investigate the potential of Wedelolactone (WL) to inhibit the methylation activity of EZH2.
MATERIALS AND METHODS: The mantle cell lymphoma (MCL) cell line, Mino, was treated with WL, while untreated cells were used as control. HMT activity and EZH2 amount were measured in nuclear extracts from WL-treated and control Mino cells.
RESULTS: WL was found to target EZH2-mediated histone H3K27 methylation. Along with the inhibition of H3K27 methylation in vitro (IC50=0.3 μM), WL suppressed HMT activity in Mino cells with an IC50 value of 3.2 μM. We detected a reduced amount of EZH2 in Mino cells treated with WL, compared to untreated control cells.
CONCLUSION: This is the first study to show that WL induces inhibition of H3K27 methylation via EZH2 modulation and decreases cell proliferation in MCL, in vitro. WL is proposed as a promising agent and a novel epigenetic approach in MCL investigation and treatment.

Li X, Wu N, Li B
A high mutation rate of immunoglobulin heavy chain variable region gene associates with a poor survival and chemotherapy response of mantle cell lymphoma patients.
Medicine (Baltimore). 2019; 98(22):e15811 [PubMed] Related Publications
Immunoglobulin heavy chain variable region (IGHV) gene mutation status is a biomarker for the prognosis of chronic lymphocytic leukemia, whether it is associated with the diagnosis, staging, and prognosis of patients with mantle cell lymphoma (MCL) remains to be determined.The IGHV gene mutations of 52 MCL patients were determined by DNA sequencing and compared with published IGHV germline sequences.DNA sequence alignment of IGHV variable regions with published IGHV germline sequences showed that the coincidence rate was 94% to 100%. Ten cases (21%) were significantly mutated with the rate of 96.9% to 94.0%. The overall survival time of patients was negatively correlated with the degree of IGHV gene mutation. Further survival analysis with log-rank test demonstrated that the patients with significant IGHV gene mutations showed a trend towards poor survival.The mutation rate of the IGHV variant region may be determined to assess the prognosis and overall survival time of MCL patients.

Pei M, Zhao C, Gao F, Zhang M
Bilateral mantle cell lymphoma of the ciliary body that responded to a combined local radiotherapy and chemotherapy regimen: a case report.
BMC Cancer. 2019; 19(1):355 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) that often affects men over the age of 60. Systemic metastasis of MCL to eyes is rare and intraocular involvement is even rarer, which usually affects the choroid and iris. To the best of our knowledge, ciliary body metastasis of systemic MCL has not been reported.
CASE PRESENTATION: A 59-year-old Han Chinese male with past-history of systemic MCL complained of redness, pain and blurred vision in the left eye. Ocular examination revealed a normal appearance in the right eye, and conjunctival injection, pseudohypopyon and anterior protrusion of peripheral iris in the left eye, all of which were unresponsive to corticosteroid treatments. Ultrasound biomicroscopy (UBM) and B-scan were then performed which detected ciliary body masses in both eyes with no vitreous and retino-choroidal anomalies. Combined liquid-based cytology tests and gene rearrangement assays of the aqueous humor specimen confirmed this to be a B-cell malignancy. Then both eyes were treated with external beam irradiation (40 Gy, delivered evenly in twenty fractions) over a course of one month. Additionally, the left eye received intravitreal methotrexate (MTX) (weekly for the first month, every two weeks for the second month, and monthly thereafter) over a course of twelve months. This therapy eventually led to complete remission of all symptoms in one month and disappearance of the ciliary body masses in twelve months.
CONCLUSION: Here we first reported a case of bilateral ciliary body MCL infiltration which was diagnosed by combined liguid-based cytology and gene rearrangement of aqueous humor cells. UBM may serve as a valuable tool in the diagnosis and serial assessments of anterior segment tumors.

Zhang W, Liang X, Gong Y, et al.
The Signal Transducer and Activator of Transcription 5B (STAT5B) Gene Promotes Proliferation and Drug Resistance of Human Mantle Cell Lymphoma Cells by Activating the Akt Signaling Pathway.
Med Sci Monit. 2019; 25:2599-2608 [PubMed] Free Access to Full Article Related Publications
BACKGROUND Mantle cell lymphoma (MCL) is a high-grade B-cell lymphoma with poor prognosis. Fludarabine is used alone or in combination for relapsed and advanced-stage MCL. The expression of the signal transducer and activator of transcription 5B (STAT5B) gene is associated with tumorigenesis in solid tumors, but its role in MCL remains unknown. The aims of this study were to investigate the role of STAT5B in GRANTA-519 human mantle cell lymphoma cells and drug resistance. MATERIAL AND METHODS GRANTA-519 human mantle cell lymphoma cells were cultured with and without 10 μM fludarabine dephosphorylated 9-ß-D-arabinofuranosyl-2-fluoroadenine, (2-F-araA) or 10 μM 4-hydroperoxycyclophosphamide (4-HC). The MTT assay assessed cell proliferation. Flow cytometry was used to investigate the cell cycle in MCL cells treated with the specific inhibitor of the Akt pathway, LY294002, and assessed cell cycle and cell apoptosis. Western blot was used to detect the expression levels of p-Akt/Akt and STAT5B/p-STAT5B. The gene expression profiles of lymph node (LN)-derived MCL cells were compared with peripheral blood (PB)-derived lymphocytes using bioinformatics and hierarchical cluster analysis. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) was performed to determine the expression of the marker of proliferation Ki-67 (MKI67) gene. RESULTS STAT5B was significantly upregulated in LN-derived MCL cells compared with PB lymphocytes. Increased expression of STAT5B was associated with increased MCL cell proliferation and reduced cell apoptosis and was associated with drug resistance and activation of Akt. CONCLUSIONS STAT5B promoted cell proliferation and drug resistance in human MCL cells by activating the Akt signaling pathway.

Klenke S, Akdeli N, Stelmach P, et al.
The small molecule Bcl-2/Mcl-1 inhibitor TW-37 shows single-agent cytotoxicity in neuroblastoma cell lines.
BMC Cancer. 2019; 19(1):243 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: High-risk neuroblastoma with N-Myc amplification remains a therapeutic challenge in paediatric oncology. Antagonism of pro-death Bcl-2 homology (BH) proteins to pro-survival BH members such as Mcl-1 and Bcl-2 has become a treatment approach, but previous studies suggest that a combined inhibition of Bcl-2 and Mcl-1 is necessary. TW-37 inhibits Mcl-1 and Bcl-2 with almost the same affinity. However, single-agent cytotoxicity of TW-37 in neuroblastoma cell lines has not been investigated.
METHODS: Cell viability, apoptosis, proliferation and changes in growth properties were determined in SKNAS, IMR-5, SY5Y and Kelly cells after treatment with TW-37. After transfection with Mcl-1 or Bcl-2 siRNA, apoptosis and proliferation were investigated in Kelly cells. Mice with Kelly cell line xenografts were treated with TW-37 and tumor growth, survival and apoptosis were determined.
RESULTS: Cell lines with N-Myc amplification were more sensitive to TW-37 treatment, IC50 values for IMR-5 and Kelly cells being 0.28 μM and 0.22 μM, compared to SY5Y cells and SKNAS cells (IC50 0.96 μM and 0.83 μM). Treatment with TW-37 resulted in increased apoptosis and reduced proliferation rates, especially in IMR5 and Kelly cells. Bcl-2 as well as Mcl-1 knockdown induced apoptosis in Kelly cells. TW-37 led to a decrease in tumor growth and a favorable survival (p = 0.0379) in a Kelly neuroblastoma xenografts mouse model.
CONCLUSION: TW-37 has strong single-agent cytotoxicity in vitro and in vivo. Therefore, combined inhibition of Bcl-2/Mcl-1 by TW-37 in N-Myc amplified neuroblastoma may represent an interesting therapeutic strategy.

Zhang Y, Xiao Y, Dong Q, et al.
Neferine in the Lotus Plumule Potentiates the Antitumor Effect of Imatinib in Primary Chronic Myeloid Leukemia Cells In Vitro.
J Food Sci. 2019; 84(4):904-910 [PubMed] Related Publications
Imatinib, the prototype BCR-ABL tyrosine kinase inhibitor (TKI), is the first-line treatment for Philadelphia chromosome-positive chronic myeloid leukemia (CML) in the chronic phase. However, a subgroup of patients exhibit poor response or experience relapse. This issue may be overcome by combination therapy using natural compounds. Neferine, a major bisbenzylisoquinoline alkaloid extracted from "lotus plumule" (seed embryo of lotus) commonly used in traditional Chinese medicine and tea, was used herein in the combination treatment of CML. The MTT assay showed that neferine exerted cytotoxicity in primary CML cells in a dose-dependent manner. Moreover, low concentrations of neferine (4 and 8 µM) sensitized primary CML cells to imatinib (CI < 1), and significantly decreased its IC

Ko YC, Hu CY, Liu ZH, et al.
Int J Mol Sci. 2019; 20(5) [PubMed] Free Access to Full Article Related Publications
Internal tandem duplication of FLT3 juxtamembrane domain (FLT3-ITD)-positive acute myeloid leukemia (AML) leads to poor clinical outcomes after chemotherapy. We aimed to establish a cytarabine-resistant line from

Kinslechner K, Schütz B, Pistek M, et al.
Loss of SR-BI Down-Regulates MITF and Suppresses Extracellular Vesicle Release in Human Melanoma.
Int J Mol Sci. 2019; 20(5) [PubMed] Free Access to Full Article Related Publications
Melanoma is a skin tumor with a high tendency for metastasis and thus is one of the deadliest cancers worldwide. Here, we investigated the expression of the scavenger receptor class B type 1 (SR-BI), a high-density lipoprotein (HDL) receptor, and tested for its role in melanoma pigmentation as well as extracellular vesicle release. We first analyzed the expression of

Pott C, Brüggemann M, Ritgen M, et al.
MRD Detection in B-Cell Non-Hodgkin Lymphomas Using Ig Gene Rearrangements and Chromosomal Translocations as Targets for Real-Time Quantitative PCR.
Methods Mol Biol. 2019; 1956:199-228 [PubMed] Related Publications
Minimal residual disease (MRD) diagnostics is of high clinical relevance in patients with indolent B-cell non-Hodgkin lymphomas (B-NHL) and serves as a surrogate parameter to evaluate treatment effectiveness and long-term prognosis. MRD diagnostics performed by real-time quantitative PCR (RQ-PCR) is still the gold standard and currently the most sensitive and the most broadly applied method in follicular lymphoma (FL) and mantle cell lymphoma (MCL). Alternatively, droplet digital PCR (ddPCR) can be used for MRD monitoring in multiple myeloma, mantle cell lymphoma, and follicular lymphoma with comparable sensitivity, accuracy, and reproducibility.The most broadly applicable MRD target in B-NHL is the junctional regions of the rearranged immunoglobulin heavy chain gene (IGHV). Chromosomal translocations like the t(14;18) translocation in FL and t(11;14) translocation in MCL can be used as MRD target in selected lymphoma subtypes. In patients with B-cell chronic lymphocytic leukemia, both flow-cytometry and RQ-PCR are equally suited for MRD assessment as long as a sensitivity of 10

Agathangelidis A, Psomopoulos F, Stamatopoulos K
Stereotyped B Cell Receptor Immunoglobulins in B Cell Lymphomas.
Methods Mol Biol. 2019; 1956:139-155 [PubMed] Related Publications
Comprehensive analysis of the clonotypic B cell receptor immunoglobulin (BcR IG) gene rearrangement sequences in patients with mature B cell neoplasms has led to the identification of significant repertoire restrictions, culminating in the discovery of subsets of patients expressing highly similar, stereotyped BcR IG. This finding strongly supports selection by common epitopes or classes of structurally similar epitopes in the ontogeny of these tumors. BcR IG stereotypy was initially described in chronic lymphocytic leukemia (CLL), where the stereotyped fraction of the disease accounts for a remarkable one-third of patients. However, subsequent studies showed that stereotyped BcR IG are also present in other neoplasms of mature B cells, including mantle cell lymphoma (MCL) and splenic marginal zone lymphoma (SMZL). Subsequent cross-entity comparisons led to the conclusion that stereotyped IG are mostly "disease-specific," implicating distinct immunopathogenetic processes. Interestingly, mounting evidence suggests that a molecular subclassification of lymphomas based on BcR IG stereotypy is biologically and clinically relevant. Indeed, particularly in CLL, patients assigned to the same subset due to expressing a particular stereotyped BcR IG display remarkably consistent biological background and clinical course, at least for major and well-studied subsets. Thus, the robust assignment to stereotyped subsets may assist in the identification of mechanisms underlying disease onset and progression, while also refining risk stratification. In this book chapter, we provide an overview of the recent BcR IG stereotypy studies in mature B cell malignancies and outline previous and current methodological approaches used for the identification of stereotyped IG.

Manchanda R, Gaba F
A commentary on population genetic testing for primary prevention: changing landscape and the need to change paradigm.
BJOG. 2019; 126(6):686-689 [PubMed] Related Publications
BRCA1/BRCA2 genes were discovered in early 1990s and clinical testing for these has been available since the mid-1990s. National Institute of Health and Care Excellence (NICE) and other international guidelines recommend genetic-testing at a ~10% probability threshold of carrying a BRCA-mutation. A detailed three generation family-history (FH) of cancer is used within complex mathematical models (e.g. BOADICEA, BRCAPRO, Manchester-Scoring-System) or through standardized clinical-criteria to identify individuals who fulfil this probability threshold and can be offered genetic-testing. Identification of unaffected carriers is important given the high risk of cancer in these women and the effective options available for clinical management which can reduce cancer risk, improve outcomes and minimise burden of disease. This article is protected by copyright. All rights reserved.

Seeboeck R, Sarne V, Haybaeck J
Current Coverage of the mTOR Pathway by Next-Generation Sequencing Oncology Panels.
Int J Mol Sci. 2019; 20(3) [PubMed] Free Access to Full Article Related Publications
The mTOR pathway is in the process of establishing itself as a key access-point of novel oncological drugs and targeted therapies. This is also reflected by the growing number of mTOR pathway genes included in commercially available next-generation sequencing (NGS) oncology panels. This review summarizes the portfolio of medium sized diagnostic, as well as research destined NGS panels and their coverage of the mTOR pathway, including 16 DNA-based panels and the current gene list of Foundation One as a major reference entity. In addition, we give an overview of interesting, mTOR-associated somatic mutations that are not yet incorporated. Especially eukaryotic translation initiation factors (eIFs), a group of mTOR downstream proteins, are on the rise as far as diagnostics and drug targeting in precision medicine are concerned. This review aims to raise awareness for the true coverage of NGS panels, which should be valuable in selecting the ideal platform for diagnostics and research.

Chen WT, Hsu FT, Liu YC, et al.
Fluoxetine Induces Apoptosis through Extrinsic/Intrinsic Pathways and Inhibits ERK/NF-κB-Modulated Anti-Apoptotic and Invasive Potential in Hepatocellular Carcinoma Cells In Vitro.
Int J Mol Sci. 2019; 20(3) [PubMed] Free Access to Full Article Related Publications
The aim of the present study was to verify the effects of fluoxetine on dysregulation of apoptosis and invasive potential in human hepatocellular carcinoma (HCC) SK-Hep1 and Hep3B cells. Cells were treated with different concentrations of fluoxetine for different times. MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) assays were used for testing the effects of fluoxetine on cell viability. The regulation of apoptosis signaling, and anti-apoptotic, proliferation, and metastasis-associated proteins after fluoxetine treatment were assayed by flow cytometry and Western blotting assay. The detection of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation after fluoxetine treatment was performed by NF-κB reporter gene assay. The results demonstrated that fluoxetine significantly reduced cell viability, cell migration/invasion, NF-κB, extracellular signal-regulated kinases (ERK) activation, and expression of anti-apoptotic (Cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein (C-FLIP), Myeloid cell leukemia-1 (MCL-1), X-Linked inhibitor of apoptosis protein (XAIP), and Survivin), proliferation (Cyclin-D1), angiogenesis (vascular endothelial growth factor (VEGF)), and metastasis-associated proteins (matrix metalloproteinase-9 (MMP-9)). Fluoxetine also significantly induced apoptosis, unregulated extrinsic (activation of first apoptosis signal protein and ligand (Fas/FasL), and caspase-8) and intrinsic (loss of mitochondrial membrane potential (ΔΨm) pathways and increased Bcl-2 homologous antagonist killer (BAK) apoptosis signaling. Taken together, these results demonstrated that fluoxetine induced apoptosis through extrinsic/intrinsic pathways and diminished ERK/NF-κB-modulated anti-apoptotic and invasive potential in HCC cells in vitro.

Xie L, Li M, Liu D, et al.
Secalonic Acid-F, a Novel Mycotoxin, Represses the Progression of Hepatocellular Carcinoma via MARCH1 Regulation of the PI3K/AKT/β-catenin Signaling Pathway.
Molecules. 2019; 24(3) [PubMed] Free Access to Full Article Related Publications
Liver cancer is a very common and significant health problem. Therefore, powerful molecular targeting agents are urgently needed. Previously, we demonstrated that secalonic acid-F (SAF) suppresses the growth of hepatocellular carcinoma (HCC) cells (HepG2), but the other anticancer biological functions and the underlying mechanism of SAF on HCC are unknown. In this study, we found that SAF, which was isolated from a fungal strain in our lab identified as Aspergillus aculeatus, could inhibit the progression of hepatocellular carcinoma by targeting MARCH1, which regulates the PI3K/AKT/β-catenin and antiapoptotic Mcl-1/Bcl-2 signaling cascades. First, we confirmed that SAF reduced the proliferation and colony formation of HCC cell lines (HepG2 and Hep3B), promoted cell apoptosis, and inhibited the cell cycle in HepG2 and Hep3B cells in a dose-dependent manner. In addition, the migration and invasion of HepG2 and Hep3B cells treated with SAF were significantly suppressed. Western blot analysis showed that the level of MARCH1 was downregulated by pretreatment with SAF through the regulation of the PI3K/AKT/β-catenin signaling pathways. Moreover, knockdown of MARCH1 by small interfering RNAs (siRNAs) targeting MARCH1 also suppressed the proliferation, colony formation, migration, and invasion as well as increased the apoptotic rate of HepG2 and Hep3B cells. These data confirmed that the downregulation of MARCH1 could inhibit the progression of hepatocellular carcinoma and that the mechanism may be via PI3K/AKT/β-catenin inactivation as well as the downregulation of the antiapoptotic Mcl-1/Bcl-2. In vivo, the downregulation of MARCH1 by treatment with SAF markedly inhibited tumor growth, suggesting that SAF partly blocks MARCH1 and further regulates the PI3K/AKT/β-catenin and antiapoptosis Mcl-1/Bcl-2 signaling cascade in the HCC nude mouse model. Additionally, the apparent diffusion coefficient (ADC) values, derived from magnetic resonance imaging (MRI), were increased in tumors after SAF treatment in a mouse model. Taken together, our findings suggest that MARCH1 is a potential molecular target for HCC treatment and that SAF is a promising agent targeting MARCH1 to treat liver cancer patients.

Liu Y, Ide Y, Inuzuka M, et al.
BRCA1/BRCA2 mutations in Japanese women with ductal carcinoma in situ.
Mol Genet Genomic Med. 2019; 7(3):e493 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Ductal carcinoma in situ (DCIS) is considered a component of the clinical spectrum of breast cancer even in those with BRCA1/2 mutation. The aim of this study was to report the feature of DCIS raised in Japanese women with BRCA1/2 mutations.
METHODS: A total of 325 Japanese women with breast cancer (BC) (with or without invasive cancer) were referred for genetic counseling and underwent genetic testing for mutations in the BRCA1 and BRCA2 genes in Showa University Hospital between December 2011 and August 2016. And 49 of them who were pathologically diagnosed as DCIS were included in this study. Logistic regression models were fit to determine the associations between potential predictive factors and BRCA status. A Cox proportional hazards model is used to predictive value of parameters for Ipsilateral breast tumor recurrence (IBTR) and contralateral breast tumor recurrence (CBTR).
RESULTS: (a) Of 325 patients (with or without invasive cancer), 19.1% (62/325) tested positive for BRCA1/BRCA2 mutations. And 18.4% (9/49) was positive for BRCA1/BRCA2 mutations in DCIS, compared with 19.2% (53/276) in IDC (p = 1.000). Among BRCA mutations, 14.5% (9/62) had DCIS compared with nonmutations (15.2%, 40/263). Incidence of DCIS was 3.0% (1/33) of BRCA1 mutations and 27.5% (8/29) of BRCA2 mutation (p = 0.009). (b) Median age of diagnosis in BRCA mutation carriers was 39 years, compared with 46 years in noncarriers. Age, Family history (FH) of BC, FH of first or second BC and total number of relatives with BC diagnosis (DX) has significant difference between BRCA mutation carriers and noncarriers in univariate analysis. In a multivariate logistic model, total relatives with BC DX ≥ 2 (odds ratio [OR], 5.128; 95% confidence interval [CI], 1.266-20.763; p = 0.022), age at diagnosis ≤35 years (OR 0.149, 95% CI 0.023-0.954, p = 0.045) and ER+/HER2+ status (OR 5.034, 95% CI 1.092-23.210, p = 0.038) remained as independent significant predictors for BRCA mutation. Ki67 index (cut off by 14% or 30%) did not differ between BRCA mutation carriers and noncarriers (p = 0.459 and p = 0.651). (c) There was a significant difference in ER-positive tumors among BRCA2 carriers and noncarriers (p = 0.042). Subgroup analysis showed BRCA2 carriers tend to be of higher grade (Grade 2 and 3), more frequently ER+/PR+ (p = 0.041) and lower proliferation (Ki67 index) than noncarriers, whereas differences in nuclear grade and ki67 index were not found significantly in our study. (d) BRCA mutation was not associated with an increased risk of IBTR and CBTR.
CONCLUSION: DCIS is equally as prevalent in patients who were BRCA mutation carriers as in high familial-risk women who were noncarriers, but occurs at earlier age. BRCA2 carriers have higher incidence in DCIS than that of BRCA1 carriers, and tend to be higher grade and more frequently ER positive and lower proliferation. Total relatives with BC DX ≥2, age at diagnosis ≤35 years and ER+/HER2+ might be independent predictors for BRCA mutation in Japanese women with DCIS and patients of these risk factors should be recommended to receive genetic counseling and BRCA testing.

Hahn EC, Bittar CM, Vianna FSL, et al.
TP53 p.Arg337His germline mutation prevalence in Southern Brazil: Further evidence for mutation testing in young breast cancer patients.
PLoS One. 2018; 13(12):e0209934 [PubMed] Free Access to Full Article Related Publications
Premenopausal breast cancer (BC) is a core tumor of Li-Fraumeni (LFS) and Li-Fraumeni-like (LFL) Syndromes, predisposition disorders caused by germline mutations in TP53 gene. In the Southern and Southeastern regions of Brazil, a specific TP53 germline mutation, c.1010G>A (p.Arg337His), was identified at a population frequency of 0.3%, the highest value ever described for a TP53 germline variation. In Brazilian BC patients, carrier frequency can vary from 0.5% to 8.7%. The current study assessed carrier frequency by genotyping TP53 c.1010G>A in 2 BC groups: 1) 315 patients unselected for age of diagnosis and family history (FH) and 2) 239 patients diagnosed before 46 years and without Chompret criteria for LFS or LFL. One carrier was identified in group 1 (0.3%; CI 95% 0.1-1.76%) and six carriers in group 2 (2.5%; CI 95% 0.93-5.39%). The frequencies differed significantly between groups (p = 0.04). The mutation carrier frequency observed in group 2 could justify mutation testing in BC patients diagnosed before 46 years and without Chompret criteria for LFS or LFL. Further studies in larger samples of BC patients of different ages and regions of the country are necessary to provide more definitive TP53 p.Arg337His carrier frequencies in different scenarios.

Ma Z, Bao X, Gu J
Furowanin A-induced autophagy alleviates apoptosis and promotes cell cycle arrest via inactivation STAT3/Mcl-1 axis in colorectal cancer.
Life Sci. 2019; 218:47-57 [PubMed] Related Publications
Aim Furowanin A (Fur A) is a flavonoid isolated from Millettia pachycarpa Benth. Studies show its potent anti-neoplastic effects against leukemia cells. The aim of the present study was to determine the potential therapeutic effect of Fur A against colorectal cancer (CRC), and elucidate the underlying mechanism.
MATERIAL AND METHODS: Cell Counting Kit-8 (CCK-8) assay was used to determine cell, and TUNEL and Annexin-V/PI staining was used to detect apoptosis and the cell cycle distribution. The expression levels of specific proteins in the CRC cells were analyzed by Western blotting. A xenograft model was also established to evaluate the therapeutic effect of Fur A in vivo.
KEY FINDINGS: Fur A suppressed proliferation, blocked cell cycle progression, induced apoptosis and promoted autophagy in CRC cells. Interestingly, Fur A-induced autophagy functioned not only as a survival mechanism against apoptosis but also intensified the cell cycle arrest in CRC cells. In addition, Fur A mediated its effects via the inactivation of the STAT3/Mcl-1 axis.
SIGNIFICANCE: Fur A is a promising drug candidate for the treatment and prevention of CRC.

Tan ZB, Fan HJ, Wu YT, et al.
Rheum palmatum extract exerts anti-hepatocellular carcinoma effects by inhibiting signal transducer and activator of transcription 3 signaling.
J Ethnopharmacol. 2019; 232:62-72 [PubMed] Related Publications
ETHNOPHARMACOLOGICAL RELEVANCE: Hepatocellular carcinoma (HCC) is among the most common malignancies. Signal transducer and activator of transcription 3 (STAT3), with abnormal expression and constitutive activation, has been reported to promote proliferation, metastasis, survival and angiogenesis of HCC cells. Rheum palmatum (RP), a traditional Chinese medicinal herb, exhibited tumor-suppressing effects in multiple human cancers, but its potential functions in HCC remain unexplored.
AIM OF THE STUDY: This study aimed to examine the involvement of STAT3 signaling in the anti-HCC effects of RP extract.
MATERIALS AND METHODS: SMMC-7721 and HepG2 HCC cell lines were treated with RP extract for 24 h, and then viability, migration, and invasion of HCC cells and angiogenesis of human umbilical vein endothelial cells (HUVECs) were analyzed using MTS, wound-healing, Transwell invasion and tube formation assays, respectively. Western blotting and immunohistochemistry (IHC) were used to examine the activation of key molecules in STAT3 signaling, including STAT3, JAK2, and Src. Additionally, we explored the in vivo antitumor effects of RP extract in a xenograft tumor nude mouse model of HCC.
RESULTS: The result showed that RP extract reduced viability, migration, and invasion of SMMC-7721 and HepG2 cells and angiogenesis of HUVECs. It suppressed the phosphorylation of STAT3 and its upstream kinases including JAK2 and Src. In addition, RP extract treatment downregulated STAT3 target genes, including survivin, Bcl-xL, Mcl-1, Bcl-2, MMP-2, MMP-9, Cyclin D1, CDK4, c-Myc, and VEGF-C. Furthermore, RP extract suppressed the xenograft tumor growth and activation of STAT3 in xenograft tumor mice.
CONCLUSION: Collectively, the results showed that RP extract prevented HCC progression by inhibiting STAT3, and might be useful for the treatment of HCC.

Augello G, Emma MR, Cusimano A, et al.
Targeting HSP90 with the small molecule inhibitor AUY922 (luminespib) as a treatment strategy against hepatocellular carcinoma.
Int J Cancer. 2019; 144(10):2613-2624 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is a highly malignant tumor that responds very poorly to existing therapies, most probably due to its extraordinary inter- and intra-tumor molecular heterogeneity. The modest therapeutic response to molecular targeted agents underlines the need for new therapeutic approaches for HCC. In our study, we took advantage of well-characterized human HCC cell lines, differing in transcriptomic subtypes, DNA mutation and amplification alterations, reflecting the heterogeneity of primary HCCs, to provide a preclinical evaluation of the specific heat shock protein 90 (HSP90) inhibitor AUY922 (luminespib). Indeed, HSP90 is highly expressed in different tumor types, but its role in hepatocarcinogenesis remains unclear. Here, we analyzed HSP90 expression in primary human HCC tissues and evaluated the antitumor effects of AUY922 in vitro as well as in vivo. HSP90 expression was significantly higher in HCC tissues than in cirrhotic peritumoral liver tissues. AUY922 treatment reduced the cell proliferation and viability of HCC cells in a dose-dependent manner, but did not do so for normal human primary hepatocytes. AUY922 treatment led to the upregulation of HSP70 and the simultaneous depletion of HSP90 client proteins. In addition, in a cell type-dependent manner, treatment induced either both caspase-dependent β-catenin cleavage and the upregulation of p53, or Mcl-1 expression, or NUPR1 expression, which contributed to the increased efficacy of, or resistance to, treatment. Finally, in vivo AUY922 inhibited tumor growth in a xenograft model. In conclusion, HSP90 is a promising therapeutic target in HCC, and AUY922 could be a drug candidate for its treatment.

Jeon MY, Min KJ, Woo SM, et al.
Maritoclax Enhances TRAIL-Induced Apoptosis via CHOP-Mediated Upregulation of DR5 and miR-708-Mediated Downregulation of cFLIP.
Molecules. 2018; 23(11) [PubMed] Free Access to Full Article Related Publications
Maritoclax, an active constituent isolated from marine bacteria, has been known to induce Mcl-1 downregulation through proteasomal degradation. In this study, we investigated the sensitizing effect of maritoclax on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human renal carcinoma cells. We found that combined treatment with maritoclax and TRAIL markedly induced apoptosis in renal carcinoma (Caki, ACHN and A498), lung cancer (A549) and hepatocellular carcinoma (SK-Hep1) cells. The upregulation of death receptor 5 (DR5) and downregulation of cellular FLICE-inhibitory protein (cFLIP) were involved in maritoclax plus TRAIL-induced apoptosis. Maritoclax-induced DR5 upregulation was regulated by induction of C/EBP homologous protein (CHOP) expression. Interestingly, maritoclax induced cFLIP downregulation through the increased expression of miR-708. Ectopic expression of cFLIP prevented combined maritoclax and TRAIL-induced apoptosis. Taken together, maritoclax sensitized TRAIL-induced apoptosis through CHOP-mediated DR5 upregulation and miR-708-mediated cFLIP downregulation.

Yu JG, Ji CH, Shi MH
MicroRNA-26b suppresses tumorigenicity and promotes apoptosis in small cell lung cancer cells by targeting myeloid cell leukemia 1 protein.
Kaohsiung J Med Sci. 2018; 34(11):593-605 [PubMed] Related Publications
The aim of this study was to investigate the role of microRNA-26b (miR-26b) in regulating the proliferation, migration, and apoptosis of small cell lung cancer (SCLC) cells. First, we examined the expression level of miR-26b in human normal fetal lung fibroblasts (NFLFs) and three SCLC cell lines NCI-H466, NCI-H1688, and NCI-H196. In the following experiments, the three SCLC cell lines were transfected with miR-26b mimic and inhibitor. Cell growth and survival, as well as migration and invasion capacities were determined by MTT, colony formation, Transwell migration and invasion, and wound healing assays. Cell apoptosis, production of reactive oxygen species, and mitochondrial membrane potential were also measured in the three cell lines following various treatments. As a result, we found that the level of miR-26b was significantly lower in SCLC cells than in NFLFs. Additionally, transfection with miR-26b mimic could inhibit proliferation, colony formation, and migration, as well as induce apoptosis in these SCLC cell lines; while miR-26b inhibitor showed the opposite effects. Further mechanistic experiment revealed that miR-26b could suppress the expression of myeloid cell leukemia 1 protein (Mcl-1) and the 3'-untranslated region (3'-UTR) of Mcl-1 may be the direct binding site of miR-26b, suggesting that the effect of miR-26b may be mediated by targeting Mcl-1. Collectively, our findings offer a new insight into the role of miR-26b in the pathogenesis of SCLC, and provide primary evidence supporting the potential of miR-26b-based therapy for the treatment of SCLC.

Mello JBH, Barros-Filho MC, Abreu FB, et al.
MicroRNAs involved in the HMGA2 deregulation and its co-occurrence with MED12 mutation in uterine leiomyoma.
Mol Hum Reprod. 2018; 24(11):556-563 [PubMed] Related Publications
STUDY QUESTION: Can the mediator complex subunit 12 (MED12) mutation and high mobility group AT-hook 2 (HMGA2) overexpression co-occurrence be explained by the alternative mechanism of HMGA2 dysregulation in uterine leiomyomas (UL)?
SUMMARY ANSWER: The co-occurrence of MED12 mutation and HMGA2 overexpression, and a negative correlation of five validated or predicted microRNAs that target HMGA2 were reported.
WHAT IS KNOWN ALREADY: The recent stratification of UL, according to recurrent and mutually exclusive genomic alterations affecting HMGA2, MED12, fumarate hydratase (FH) and collagen type IV alpha 5-alpha 6 (COL4A5-COL4A6) pointed out the involvement of distinct molecular pathways. However, the mechanisms of regulation involving these drivers are poorly explored.
STUDY DESIGN, SIZE, DURATION: A total of 78 UL and 34 adjacent normal myometrium (NM) tissues was collected from 56 patients who underwent hysterectomies at a single institution. The patients were treated at the Department of Gynecology and Obstetrics, School of Medicine, Sao Paulo State University, Botucatu, SP, Brazil, from October 1995 to February 2004.
PARTICIPANTS/MATERIALS, SETTING, METHODS: Gene expression profiling was evaluated from fresh frozen tissues and compared with MED12 mutations at exon 2. In addition, RT-qPCR was applied to evaluate the expression levels of HMGA2 and their predictive miRNA regulators: hsa-let-7a, miR-26a, miR-26b, mir-93 and mir-106b.
MAIN RESULTS AND THE ROLE OF CHANCE: An unsupervised hierarchical clustering analysis revealed two main clusters with one of them (26 of 42 UL) showing an enrichment of MED12 mutated cases (18 of 26 UL). Increased expression levels of HMGA2 were observed in both clusters, including cases with MED12 mutation (cluster 1:18 UL). A significant HMGA2 overexpression (P < 0.001) in UL in comparison with NM was found. Five miRNAs predicted to regulate HMGA2 were significantly downregulated (P < 0.001) and negatively correlated to HMGA2 expression levels (P < 0.05) in UL.
LIMITATIONS REASONS FOR CAUTION: An in vivo functional study was not performed to validate the microRNAs and HMGA2 interaction due to technical limitations.
WIDER IMPLICATIONS OF THE FINDINGS: HMGA2 overexpression was detected in a significant number of MED12 mutated ULs, suggesting that these alterations coexist. Furthermore, five miRNAs were described as potential regulators of HMGA2 expression in UL.
LARGE-SCALE DATA: Data available in the Gene Expression Omnibus GSE42939.
STUDY FUNDING AND COMPETING INTEREST(S): This study was supported by grants from Fundação de Amparo a Pesquisa do Estado de São Paulo (# 2008/58835-2) and Conselho Nacional de Pesquisa (# 485032/2007-4), Brazil. The authors declared having no conflicts of interest.

Vallet S, Fan F, Malvestiti S, et al.
Rationally derived drug combinations with the novel Mcl-1 inhibitor EU-5346 in breast cancer.
Breast Cancer Res Treat. 2019; 173(3):585-596 [PubMed] Related Publications
PURPOSE: Recent studies have emphasized a key role for the anti-apoptotic Bcl-2 family member Mcl-1 in conferring tumor cell survival and drug resistance in breast cancer (BC). Mcl-1 inhibitors, such as the BH3-mimetic EU-5346, therefore represent an exciting new class of targeting agents and are a current focus of widespread cancer-drug development efforts.
METHODS: ONCOMINE analysis was utilized to compare expression profiles of Bcl-2 family members across all major BC subgroups. Potential toxicities of EU-5346 were evaluated using iPS-generated cardiomyocytes, blood cells and astrocytes. The anti-BC cell activity of EU-5346-based therapies was evaluated using [
RESULTS: We previously demonstrated significant anti-tumor activity of EU-5346 in all BC subtypes. Our present results go further and suggest that EU-5346 may induce limited adverse events such as cardiotoxicity, hematotoxicity, and neurotoxicity, frequently observed with other BH3 mimetics. As demonstrated by our mathematical scoring model, the prediction of EU-5643-induced IC
CONCLUSION: These data strongly support the further clinical development of EU-5346 to improve BC patient survival.

Wei N, Li J, Fang C, et al.
Targeting colon cancer with the novel STAT3 inhibitor bruceantinol.
Oncogene. 2019; 38(10):1676-1687 [PubMed] Related Publications
STAT3, a transcriptional mediator of oncogenic signaling, is constitutively active in ~70% of human cancers. The development of STAT3 inhibitors remains an active area of research as no inhibitors have yet to be approved for the treatment of human cancer. Herein, we revealed that bruceantinol (BOL) is a novel STAT3 inhibitor demonstrating potent antitumor activity in in vitro and in vivo human colorectal cancer (CRC) models. BOL strongly inhibited STAT3 DNA-binding ability (IC

Eustace AJ, Conlon NT, McDermott MSJ, et al.
Development of acquired resistance to lapatinib may sensitise HER2-positive breast cancer cells to apoptosis induction by obatoclax and TRAIL.
BMC Cancer. 2018; 18(1):965 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Lapatinib has clinical efficacy in the treatment of trastuzumab-refractory HER2-positive breast cancer. However, a significant proportion of patients develop progressive disease due to acquired resistance to the drug. Induction of apoptotic cell death is a key mechanism of action of lapatinib in HER2-positive breast cancer cells.
METHODS: We examined alterations in regulation of the intrinsic and extrinsic apoptosis pathways in cell line models of acquired lapatinib resistance both in vitro and in patient samples from the NCT01485926 clinical trial, and investigated potential strategies to exploit alterations in apoptosis signalling to overcome lapatinib resistance in HER2-positive breast cancer.
RESULTS: In this study, we examined two cell lines models of acquired lapatinib resistance (SKBR3-L and HCC1954-L) and showed that lapatinib does not induce apoptosis in these cells. We identified alterations in members of the BCL-2 family of proteins, in particular MCL-1 and BAX, which may play a role in resistance to lapatinib. We tested the therapeutic inhibitor obatoclax, which targets MCL-1. Both SKBR3-L and HCC1954-L cells showed greater sensitivity to obatoclax-induced apoptosis than parental cells. Interestingly, we also found that the development of acquired resistance to lapatinib resulted in acquired sensitivity to TRAIL in SKBR3-L cells. Sensitivity to TRAIL in the SKBR3-L cells was associated with reduced phosphorylation of AKT, increased expression of FOXO3a and decreased expression of c-FLIP. In SKBR3-L cells, TRAIL treatment caused activation of caspase 8, caspase 9 and caspase 3/7. In a second resistant model, HCC1954-L cells, p-AKT levels were not decreased and these cells did not show enhanced sensitivity to TRAIL. Furthermore, combining obatoclax with TRAIL improved response in SKBR3-L cells but not in HCC1954-L cells.
CONCLUSIONS: Our findings highlight the possibility of targeting altered apoptotic signalling to overcome acquired lapatinib resistance, and identify potential novel treatment strategies, with potential biomarkers, for HER2-positive breast cancer that is resistant to HER2 targeted therapies.

Skala SL, Dhanasekaran SM, Mehra R
Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome (HLRCC): A Contemporary Review and Practical Discussion of the Differential Diagnosis for HLRCC-Associated Renal Cell Carcinoma.
Arch Pathol Lab Med. 2018; 142(10):1202-1215 [PubMed] Related Publications

Samadi P, Saki S, Dermani FK, et al.
Emerging ways to treat breast cancer: will promises be met?
Cell Oncol (Dordr). 2018; 41(6):605-621 [PubMed] Related Publications
BACKGROUND: Breast cancer (BC) is the most common cancer among women and it is responsible for more than 40,000 deaths in the United States and more than 500,000 deaths worldwide each year. In previous decades, the development of improved screening, diagnosis and treatment methods has led to decreases in BC mortality rates. More recently, novel targeted therapeutic options, such as the use of monoclonal antibodies and small molecule inhibitors that target specific cancer cell-related components, have been developed. These components include ErbB family members (HER1, HER2, HER3 and HER4), Ras/MAPK pathway components (Ras, Raf, MEK and ERK), VEGF family members (VEGFA, VEGFB, VEGFC, VEGF and PGF), apoptosis and cell cycle regulators (BAK, BAX, BCL-2, BCL-X, MCL-1 and BCL-W, p53 and PI3K/Akt/mTOR pathway components) and DNA repair pathway components such as BRCA1. In addition, long noncoding RNA inhibitor-, microRNA inhibitor/mimic- and immunotherapy-based approaches are being developed for the treatment of BC. Finally, a novel powerful technique called CRISPR-Cas9-based gene editing is emerging as a precise tool for the targeted treatment of cancer, including BC.
CONCLUSIONS: Potential new strategies that are designed to specifically target BC are presented. Several clinical trials using these strategies are already in progress and have shown promising results, but inherent limitations such as off-target effects and low delivery efficiencies still have to be resolved. By improving the clinical efficacy of current therapies and exploring new ones, it is anticipated that novel ways to overcome BC may become attainable.

Luanpitpong S, Poohadsuan J, Samart P, et al.
Reactive oxygen species mediate cancer stem-like cells and determine bortezomib sensitivity via Mcl-1 and Zeb-1 in mantle cell lymphoma.
Biochim Biophys Acta Mol Basis Dis. 2018; 1864(11):3739-3753 [PubMed] Related Publications
Mantle cell lymphoma (MCL) is an aggressive, incurable non-Hodgkin B-cell lymphoma with good initial response to therapy then subsequently relapse. Cancer stem cells (CSCs) are considered to be an underlying cause of these inevitable drug resistance and tumor regrowth, but how CSCs are regulated is largely unknown. We demonstrate here for the first time the existence of CSC-like subpopulations that are modulated by reactive oxygen species (ROS) in MCL cell lines and patient-derived primary cells in an inverse correlation with bortezomib (BTZ) sensitivity. Using various known donors and inhibitors of cellular superoxide (O

Yan W, Li SX, Wei M, Gao H
Identification of MMP9 as a novel key gene in mantle cell lymphoma based on bioinformatic analysis and design of cyclic peptides as MMP9 inhibitors based on molecular docking.
Oncol Rep. 2018; 40(5):2515-2524 [PubMed] Free Access to Full Article Related Publications
Mantle cell lymphoma (MCL) is an aggressive disease. MCL is associated with poor patient prognosis and limited survival. To identify key genes and explore targeting cyclic peptide inhibitors for the treatment of MCL, we downloaded two gene expression profiles (GSE32018 and GSE9327) from the Gene Expression Omnibus (GEO) database. We screened 84 differentially expressed genes (DEGs). Pathway analysis showed that DEMs were mainly enriched in the 'Pathway in cancer', 'PI3K‑Akt signaling pathway', 'Cytokine‑cytokine receptor interaction', 'Rap1 signaling pathway', 'NF‑κB signaling pathway' and 'Leukocyte trans‑endothelial migration'. We subsequently constructed a protein‑protein interaction (PPI) network of DEGs. In addition, matrix metalloproteinase 9 (MMP9) with a high degree in the PPI network was identified as a hub gene in MCL. Meanwhile in the Molecular Complex Detection (MCODE) analysis, MMP9 was located in the important cluster. Thus, MMP9 can be used as a therapeutic target for MCL and we designed cyclic peptides as MMP9 inhibitors. MMP9 protein structure was gathered from the Protein Data Bank (PDB), with a PDB ID: 1L6J. MMP9 and cyclic peptides were docked using Molecular Operating Environment (MOE) software after structural optimization. It was revealed that cyclic peptide 2 bound deeply in the binding pocket of MMP9 and had interaction with the active‑site Zn2+ ion in the catalytic domain. Cyclic peptides 1, 2, 4‑6 also displayed potential interaction with active residues of MMP9; thus, these cyclic peptides can serve as potential drug candidates to block MMP9 activity and future studies are warranted to confirm their efficacy.

Chou YC, Chang MY, Lee HT, et al.
Phenethyl Isothiocyanate Inhibits In Vivo Growth of Xenograft Tumors of Human Glioblastoma Cells.
Molecules. 2018; 23(9) [PubMed] Free Access to Full Article Related Publications
Phenethyl isothiocyanate (PEITC) from cruciferous vegetables can inhibit the growth of various human cancer cells. In previous studies, we determined that PEITC inhibited the in vitro growth of human glioblastoma GBM 8401 cells by inducing apoptosis, inhibiting migration and invasion, and altering gene expression. Nevertheless, there are no further in vivo reports disclosing whether PEITC can suppress the growth of glioblastoma. Therefore, in this study we investigate the anti-tumor effects of PEITC in a xenograft model of glioblastoma in nude mice. Thirty nude mice were inoculated subcutaneously with GBM 8401 cells. Mice with one palpable tumor were divided randomly into three groups: control, PEITC-10, and PEITC-20 groups treated with 0.1% dimethyl sulfoxide (DMSO), and 10 and 20 μmole PEITC/100 μL PBS daily by oral gavage, respectively. PEITC significantly decreased tumor weights and volumes of GBM 8401 cells in mice, but did not affect the total body weights of mice. PEITC diminished the levels of anti-apoptotic proteins MCL-1 (myeloid cell leukemia 1) and XIAP (X-linked inhibitor of apoptosis protein) in GBM 8401 cells. PEITC enhanced the levels of caspase-3 and Bax in GBM 8401 cells. The growth of glioblastoma can be suppressed by the biological properties of PEITC in vivo. These effects might support further investigations into the potential use of PEITC as an anticancer drug for glioblastoma.

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