Research IndicatorsGraph generated 29 August 2019 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (8)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: MKL1 (cancer-related)
Fiano V, Trevisan M, Fasanelli F, et al.Methylation in host and viral genes as marker of aggressiveness in cervical lesions: Analysis in 543 unscreened women.
Gynecol Oncol. 2018; 151(2):319-326 [PubMed
] Related Publications
OBJECTIVE: The present study aimed to evaluate the association between altered methylation and histologically confirmed high grade cervical intraepithelial neoplasia (hgCIN).
METHODS: Methylation levels in selected host (CADM1, MAL, DAPK1) and HPV (L1_I, L1_II, L2) genes were measured by pyrosequencing in DNA samples obtained from 543 women recruited in Curitiba (Brazil), 249 with hgCIN and 294 without cervical lesions. Association of methylation status with hgCIN was estimated by Odds Ratio (OR) with 95% confidence interval (CI).
RESULTS: The mean methylation level increased with severity of the lesion in the host and viral genes (p-trend < 0.05), with the exception of L1_II region (p-trend = 0.075). Positive association was found between methylation levels for host genes and CIN2 and CIN3 lesions respectively [CADM1: OR 4.17 (95%CI 2.03-8.56) and OR 9.54 (95%CI 4.80-18.97); MAL: OR 5.98 (95%CI 2.26-15.78) and OR 22.66 (95%CI 9.21-55.76); DAPK1: OR 3.37 (95%CI 0.93-12.13) and OR 6.74 (95%CI 1.92-23.64)]. Stronger risk estimates were found for viral genes [L1_I: OR 10.74 (95%CI 2.66-43.31) and OR 15.00 (95%CI 3.00-74.98); L1_II: OR 73.18 (95%CI 4.07-1315.94) and OR 32.50 (95%CI 3.86-273.65); L2: OR 4.73 (95%CI 1.55-14.44) and OR 10.62 (95%CI 2.60-43.39)]. The cumulative effect of the increasing number of host and viral methylated genes was associated with the risk of CIN2 and CIN3 lesions (p-trend < 0.001).
CONCLUSIONS: Our results, empowered by a wide cervical sample series with a large number of hgCIN, supported the role of methylation as marker of aggressiveness.
As a strong transactivator of promoters containing CarG boxes, myocardin‑related transcription factor A (MRTF‑A) is critical for the process of metastasis in tumor cells. Nuclear factor erythroid 2‑like 1 (Nrf1) is well known as an important regulator of oxidative stress, which exists in multiple splicing forms with many unknown functions. The present study demonstrated a novel regulation loop between Nrf1α (the longest splicing form of Nrf1) and MRTF‑A that regulated the migration and invasion of breast cancer MDA‑MB‑231 cells. The underlying mechanism of this regulation look was further investigated. In particular, Nrf1α inhibited migration and invasion of breast cancer cells through inhibiting the expression of MRTF‑A via miR‑219. The current results revealed that miR‑219 could bind to the MRTF‑A 3'‑UTR to directly regulate its expression. However, MRTF‑A could reverse activate the Nrf1α expression through binding to the CarG box in the Nrf1α promoter. It can be speculated that this regulation loop may be a homeostasis mechanism in cells against tumorigenesis.
Chen B, Li Z, Feng Y, et al.Myocardin-related transcription factor A (MRTF-A) mediates doxorubicin-induced PERP transcription in colon cancer cells.
Biochem Biophys Res Commun. 2018; 503(3):1732-1739 [PubMed
] Related Publications
Doxorubicin (DOX) is a cytotoxic compound capable of instigating apoptosis in cancer cells. TP53 apoptosis effector (PERP) is a key mediator of apoptosis in multiple cell types. PERP transcription is activated by a range of pro-apoptotic stimuli. In the present study, we investigated the regulation of DOX-induced PERP transcription in colon cancer cells (SW480) by the transcriptional modulator myocardin-related transcription factor A (MRTF-A). We report that DOX treatment up-regulated MRTF-A expression paralleling PERP activation. DOX also promoted nuclear translocation of MRTF-A. On the contrary, MRTF-A depletion or inhibition attenuated DOX-induced apoptosis as evidenced by the MTT assay and caspase 3 cleavage. In accordance, MRTF-A depletion or inhibition dampened PERP transcription. Chromatin immunoprecipitation (ChIP) assay showed that DOX treatment promoted the binding of MRTF-A on the PERP promoter. Mechanistically, MRTF-A was recruited to the PERP promoter by activator protein 1 (AP-1). AP-1 interacted and cooperated with MRTF-A to activate PERP transcription. AP-1 silencing weakened PERP trans-activation by DOX presumably by compromising MRTF-A recruitment to the PERP promoter. In conclusion, our data suggest that MRTF-A might be a key regulator of DOX-induced PERP transcription in colon cancer cells.
Gao X, Chen Z, Li A, et al.MiR-129 regulates growth and invasion by targeting MAL2 in papillary thyroid carcinoma.
Biomed Pharmacother. 2018; 105:1072-1078 [PubMed
] Related Publications
MAL2, a member of the MAL proteolipid family, is essential for raft-mediated transport. In this study, we investigated the roles and underlying mechanism of MAL2 in the development of papillary thyroid carcinoma (PTC). Up-regulation of MAL2 was found in human PTC tissues and significantly correlated with poor overall survival (OS). Knockdown of MAL2 dramatically suppressed PTC cell proliferation and invasion in vitro and inhibited tumor growth in vivo. We further found that miR-129 suppressed the expression of MLA through directly binding to the 3' untranslated region (3' UTR). While forced miR-129 expression suppressed growth and invasion of PTC cells, re-expression of MAL2 rescued these effects. Taken together, our data indicated that MAL2 acted as an oncogene and was negatively regulated by miR-129, supporting the potential therapeutic strategy against PTC by targeting miR-129-MAL2 axis.
Motivation: Identifying molecular mechanisms that drive cancers from early to late stages is highly important to develop new preventive and therapeutic strategies. Standard machine learning algorithms could be used to discriminate early- and late-stage cancers from each other using their genomic characterizations. Even though these algorithms would get satisfactory predictive performance, their knowledge extraction capability would be quite restricted due to highly correlated nature of genomic data. That is why we need algorithms that can also extract relevant information about these biological mechanisms using our prior knowledge about pathways/gene sets.
Results: In this study, we addressed the problem of separating early- and late-stage cancers from each other using their gene expression profiles. We proposed to use a multiple kernel learning (MKL) formulation that makes use of pathways/gene sets (i) to obtain satisfactory/improved predictive performance and (ii) to identify biological mechanisms that might have an effect in cancer progression. We extensively compared our proposed MKL on gene sets algorithm against two standard machine learning algorithms, namely, random forests and support vector machines, on 20 diseases from the Cancer Genome Atlas cohorts for two different sets of experiments. Our method obtained statistically significantly better or comparable predictive performance on most of the datasets using significantly fewer gene expression features. We also showed that our algorithm was able to extract meaningful and disease-specific information that gives clues about the progression mechanism.
Availability and implementation: Our implementations of support vector machine and multiple kernel learning algorithms in R are available at https://github.com/mehmetgonen/gsbc together with the scripts that replicate the reported experiments.
We demonstrated previously that the splicing of the actin regulator, hMENA, generates two alternatively expressed isoforms, hMENA
The role of YAP (Yes-associated protein 1) and MRTF-A (myocardin-related transcription factor A), two transcriptional co-activators regulated downstream of GPCRs (G protein-coupled receptors) and RhoA, in the growth of glioblastoma cells and in vivo glioblastoma multiforme (GBM) tumor development was explored using human glioblastoma cell lines and tumor-initiating cells derived from patient-derived xenografts (PDX). Knockdown of these co-activators in GSC-23 PDX cells using short hairpin RNA significantly attenuated in vitro self-renewal capability assessed by limiting dilution, oncogene expression, and neurosphere formation. Orthotopic xenografts of the MRTF-A and YAP knockdown PDX cells formed significantly smaller tumors and were of lower morbidity than wild-type cells. In vitro studies used PDX and 1321N1 glioblastoma cells to examine functional responses to sphingosine 1-phosphate (S1P), a GPCR agonist that activates RhoA signaling, demonstrated that YAP signaling was required for cell migration and invasion, whereas MRTF-A was required for cell adhesion; both YAP and MRTF-A were required for proliferation. Gene expression analysis by RNA-sequencing of S1P-treated MRTF-A or YAP knockout cells identified 44 genes that were induced through RhoA and highly dependent on YAP, MRTF-A, or both. Knockdown of F3 (tissue factor (TF)), a target gene regulated selectively through YAP, blocked cell invasion and migration, whereas knockdown of HBEGF (heparin-binding epidermal growth factor-like growth factor), a gene selectively induced through MRTF-A, prevented cell adhesion in response to S1P. Proliferation was sensitive to knockdown of target genes regulated through either or both YAP and MRTF-A. Expression of TF and HBEGF was also selectively decreased in tumors from PDX cells lacking YAP or MRTF-A, indicating that these transcriptional pathways are regulated in preclinical GBM models and suggesting that their activation through GPCRs and RhoA contributes to growth and maintenance of human GBM.
Sun D, Li A, Tang B, Wang MIntegrating genomic data and pathological images to effectively predict breast cancer clinical outcome.
Comput Methods Programs Biomed. 2018; 161:45-53 [PubMed
] Related Publications
BACKGROUND AND OBJECTIVE: Breast cancer is a leading cause of death from cancer for females. The high mortality rate of breast cancer is largely due to the complexity among invasive breast cancer and its significantly varied clinical outcomes. Therefore, improving the accuracy of breast cancer survival prediction has important significance and becomes one of the major research areas. Nowadays many computational models have been proposed for breast cancer survival prediction, however, most of them generate the predictive models by employing only the genomic data information and few of them consider the complementary information from pathological images.
METHODS: In our study, we introduce a novel method called GPMKL based on multiple kernel learning (MKL), which efficiently employs heterogeneous information containing genomic data (gene expression, copy number alteration, gene methylation, protein expression) and pathological images. With above heterogeneous features, GPMKL is proposed to execute feature fusion which is embedded in breast cancer classification.
RESULTS: Performance analysis of the GPMKL model indicates that the pathological image information plays a critical part in accurately predicting the survival time of breast cancer patients. Furthermore, the proposed method is compared with other existing breast cancer survival prediction methods, and the results demonstrate that the proposed framework with pathological images performs remarkably better than the existing survival prediction methods.
CONCLUSIONS: All results performed in our study suggest that the usefulness and superiority of GPMKL in predicting human breast cancer survival.
Meng C, He Y, Wei Z, et al.MRTF-A mediates the activation of COL1A1 expression stimulated by multiple signaling pathways in human breast cancer cells.
Biomed Pharmacother. 2018; 104:718-728 [PubMed
] Related Publications
Deposition of type I collage in ECM is an important property of various fibrotic diseases including breast cancer. The excessive expression of type I collagen contributes to the rigidity of cancer tissue and increases the mechanical stresses which facilitate metastasis and proliferation of cancer cells via the activation of TGF-β signaling pathway. The increased mechanical stresses also cause the compression of blood vessels and result in hypoperfusion and impaired drug delivery in cancer tissue. Additionally, type I collage functions as the ligand of α2β1-integrin and DDR1/2 receptors on the membrane of cancer cells to initiate signal transduction leading to metastasis. The expression of type I collage in cancer cells is previously shown to be inducible by TGF-β however the detailed mechanism by which the synthesis of type I collagen is regulated in breast cancer cells remains unclear. Herein, we report that MRTF-A, a co-activator of SRF, is important for the regulation of type I collagen gene COL1A1 in breast cancer cells. MRTF-A physically interacted with the promoter of COL1A1 to facilitate histone acetylation and RNA polymerase II recruitment. The RhoC-ROCK signaling pathway which controls the nuclear localization of MRTF-A regulated the transcription of COL1A1 in human breast cancer cells. TGF-β and Wnt signaling increased the expression of both MRTF-A and COL1A1. Furthermore, depletion of MRTF-A abolished the upregulation of COL1A1 in response to the TGF-β or Wnt signaling, indicating the importance of MRTF-A in the synthesis of type I collagen in breast cancer. Given the crucial roles of type I collagen in the formation of metastasis-prone and hypoperfusion microenvironment, MRTF-A would be a potential target for the development of anti-breast cancer activities.
Neonatal leukaemia is defined as occurring within the first 28 days of life and most, if not all, cases are congenital. With the exception of Down syndrome-associated transient abnormal myelopoiesis, which is not considered here, neonatal leukaemias are rare. In two-thirds of patients the disease manifests as an acute myeloid leukaemia, frequently with monocytic/monoblastic characteristics. Most other cases are acute lymphoblastic leukaemia, particularly B lineage, but some are mixed phenotype or blastic plasmacytoid dendritic cell neoplasms. The most frequently observed cytogenetic/molecular abnormality is t(4;11)(q21.3;q23.3)/KMT2A-AFF1 followed by t(1;22)(p13.3;q13.1)/RBM15-MKL1 and t(8;16)(p11.2;p13.3)/KAT6A-CREBBP. Common clinical features include prominent hepatosplenomegaly and a high incidence of skin involvement, sometimes in the absence of bone marrow disease. A distinctive feature is the occurrence of spontaneous remission in some cases, particularly in association with t(8;16). In this review, we summarise current knowledge of the clinical, cytogenetic and molecular features of neonatal leukaemia and discuss clinical management of these cases.
Roussy M, Bilodeau M, Jouan L, et al.NUP98-BPTF gene fusion identified in primary refractory acute megakaryoblastic leukemia of infancy.
Genes Chromosomes Cancer. 2018; 57(6):311-319 [PubMed
] Related Publications
The advent of large scale genomic sequencing technologies significantly improved the molecular classification of acute megakaryoblastic leukaemia (AMKL). AMKL represents a subset (∼10%) of high fatality pediatric acute myeloid leukemia (AML). Recurrent and mutually exclusive chimeric gene fusions associated with pediatric AMKL are found in 60%-70% of cases and include RBM15-MKL1, CBFA2T3-GLIS2, NUP98-KDM5A and MLL rearrangements. In addition, another 4% of AMKL harbor NUP98 rearrangements (NUP98r), with yet undetermined fusion partners. We report a novel NUP98-BPTF fusion in an infant presenting with primary refractory AMKL. In this NUP98r, the C-terminal chromatin recognition modules of BPTF, a core subunit of the NURF (nucleosome remodeling factor) ATP-dependent chromatin-remodeling complex, are fused to the N-terminal moiety of NUP98, creating an in frame NUP98-BPTF fusion, with structural homology to NUP98-KDM5A. The leukemic blasts expressed two NUP98-BPTF splicing variants, containing one or two tandemly spaced PHD chromatin reader domains. Our study also identified an unreported wild type BPTF splicing variant encoding for 2 PHD domains, detected both in normal cord blood CD34
Hedgehog pathway-dependent cancers can escape Smoothened (SMO) inhibition through mutations in genes encoding canonical hedgehog pathway components; however, around 50% of drug-resistant basal cell carcinomas (BCCs) lack additional variants of these genes. Here we use multidimensional genomics analysis of human and mouse drug-resistant BCCs to identify a noncanonical hedgehog activation pathway driven by the transcription factor serum response factor (SRF). Active SRF along with its coactivator megakaryoblastic leukemia 1 (MKL1) binds DNA near hedgehog target genes and forms a previously unknown protein complex with the hedgehog transcription factor glioma-associated oncogene family zinc finger-1 (GLI1), causing amplification of GLI1 transcriptional activity. We show that cytoskeletal activation through Rho and the formin family member Diaphanous (mDia) is required for SRF-MKL-driven GLI1 activation and for tumor cell viability. Remarkably, nuclear MKL1 staining served as a biomarker in tumors from mice and human subjects to predict tumor responsiveness to MKL inhibitors, highlighting the therapeutic potential of targeting this pathway. Thus, our study illuminates, for the first time, cytoskeletal-activation-driven transcription as a personalized therapeutic target for combatting drug-resistant malignancies.
BACKGROUND: Long non-coding RNAs (lncRNAs) have emerged as a new and crucial layer of gene regulation in recent years and regulate various biological processes such as carcinogenesis and metastasis. LncRNA HOTAIR, an oncogenic lncRNA, is involved in human tumorigenesis and dysregulated in cervical cancer. Megakaryoblastic leukemia 1 (MKL1), as a transcription coactivity factor, involved in cancer metastasis and cell differentiation. However, the precise mechanism of biological roles of HOTAIR and MKL1 in cancer cells remain unclear.
METHODS: The expression levels of HOTAIR and MKL1 were measured by quantitative PCR (qPCR), immunoblotting, in situ hybridization (ISH) and immunohistochemistry (IHC). Wound-healing and transwell assays were used to examine the invasive abilities of HeLa cells. Luciferase reporter assays and CHIP were used to determine how MKL1 regulates HOTAIR. Tissue microarray and immunohistochemical staining were used to assess the correlation between HOTAIR and MKL1 in Cervical cancer tissues in vivo.
RESULT: In this study, we have identified that MKL1 had a role in the induction of migration and invasion in cervical cancer cells. Moreover, the expression level of MKL1, as the targeting gene of miR206, was decreased after HOTAIR inhibition in HeLa cells. Agreement with it, Highly level of MKL1 correlation with HOTAIR is validated in cervical cancer tissues. Importantly, HOTAIR is observed to participate in the silencing of miR206 expression. Interestingly, HOTAIR inhibition could also accelerate the expression of MKL1 in cytoplasm. What is more, MKL1 can activate the transcription of HOTAIR through binding the CArG box in the promoter of HOTAIR.
CONCLUSION: These elucidates that the phenotypic effects of migration and invasion observed after HOTAIR inhibition, at least in part, through the regulation of MKL1 via inhibition of miR206 expression in HeLa cells. These data indicate the existence of a positive feedback loop between HOTAIR and MKL1. Together, these findings suggest that MKL1 is an important player in the functions of HOTAIR in the migration and invasion of cancer cells.
Morita T, Hayashi KTumor Progression Is Mediated by Thymosin-β4 through a TGFβ/MRTF Signaling Axis.
Mol Cancer Res. 2018; 16(5):880-893 [PubMed
] Related Publications
Although enhanced thymosin β4 (TMSB4X/Tβ4) expression is associated with tumor progression and metastasis, its tumor-promoting functions remain largely unknown. Here, it is demonstrated that TGFβ facilitates Tβ4 expression and leads to the activation of myocardin-related transcription factors (MRTF), which are coactivators of serum response factor (SRF) and regulate the expression of genes critical for the epithelial-mesenchymal transition (EMT) and tumor metastasis. In murine mammary gland cells (NMuMG), Tβ4 upregulation is required for full induction of a MRTF-regulated EMT gene expression program after TGFβ stimulation. Tβ4 levels are transcriptionally regulated via the novel
Foster CT, Gualdrini F, Treisman RMutual dependence of the MRTF-SRF and YAP-TEAD pathways in cancer-associated fibroblasts is indirect and mediated by cytoskeletal dynamics.
Genes Dev. 2017; 31(23-24):2361-2375 [PubMed
] Free Access to Full Article Related Publications
Both the MRTF-SRF and the YAP-TEAD transcriptional regulatory networks respond to extracellular signals and mechanical stimuli. We show that the MRTF-SRF pathway is activated in cancer-associated fibroblasts (CAFs). The MRTFs are required in addition to the YAP pathway for CAF contractile and proinvasive properties. We compared MRTF-SRF and YAP-TEAD target gene sets and identified genes directly regulated by one pathway, the other, or both. Nevertheless, the two pathways exhibit mutual dependence. In CAFs, expression of direct MRTF-SRF genomic targets is also dependent on YAP-TEAD activity, and, conversely, YAP-TEAD target gene expression is also dependent on MRTF-SRF signaling. In normal fibroblasts, expression of activated MRTF derivatives activates YAP, while activated YAP derivatives activate MRTF. Cross-talk between the pathways requires recruitment of MRTF and YAP to DNA via their respective DNA-binding partners (SRF and TEAD) and is therefore indirect, arising as a consequence of activation of their target genes. In both CAFs and normal fibroblasts, we found that YAP-TEAD activity is sensitive to MRTF-SRF-induced contractility, while MRTF-SRF signaling responds to YAP-TEAD-dependent TGFβ signaling. Thus, the MRF-SRF and YAP-TEAD pathways interact indirectly through their ability to control cytoskeletal dynamics.
Bergqvist C, Kadara H, Hamie L, et al.SLURP-1 is mutated in Mal de Meleda, a potential molecular signature for melanoma and a putative squamous lineage tumor suppressor gene.
Int J Dermatol. 2018; 57(2):162-170 [PubMed
] Related Publications
BACKGROUND: Mal de Meleda (MDM) is a rare inherited autosomal recessive genodermatosis characterized by palmoplantar keratoderma (PPK) with transgrediens and caused by mutations in the SLURP1 gene. Uncommonly, cutaneous tumors have been found at PPK sites in MDM patients.
OBJECTIVE: To study a Middle Eastern family with MDM with both PPK and skin tumors.
METHODS: We studied a Middle Eastern (Palestinian) family with clinical features of MDM and cutaneous tumors. Histopathological analysis was performed on biopsies from skin lesions found in the affected individuals. Direct sequencing of SLURP1 was performed in MDM affected members. In silico analysis of publicly available datasets was used to survey SLURP1 mRNA levels in normal and malignant tissues. Statistical analysis was performed in the R statistical language.
RESULTS: Affected members from the Middle Eastern family displayed severe forms of PPK consistent with MDM. Histopathological analysis of the skin lesions revealed that the examined affected members exhibited skin squamous cell carcinomas (SCCs) and melanoma. Sequence analysis revealed homozygous SLURP1 mutations (c.82delT) in the affected members. Following analysis of various publicly available expression datasets, SLURP1 mRNA levels were found to be markedly elevated in tissues of epithelial lineage, relative to tissues of other lineages, and significantly suppressed in malignant tumors of epithelial lineage relative to normal or their premalignant counterparts. There was significant decrease in SLURP-1 expression in melanomas versus melanocytic nevi as well as a highly significant decrease in SLURP-1 expression in metastatic melanomas as compared to primary melanoma.
CONCLUSION: Our study underscores cases of Middle Eastern MDM with SLURP1 mutations and skin malignancies at PPK sites. Our findings also highlight a plausible epithelial lineage-specific tumor suppressor role for the SLURP1 gene, as well as a role in the development and metastasis of melanoma and thus a potential molecular signature for melanoma.
Zhuang C, Yuan Y, Song T, et al.miR-219a-5p inhibits breast cancer cell migration and epithelial-mesenchymal transition by targeting myocardin-related transcription factor A.
Acta Biochim Biophys Sin (Shanghai). 2017; 49(12):1112-1121 [PubMed
] Related Publications
Although many miRNAs are reported to be involved in tumor formation and progression, the effect of miR-219a-5p on breast cancer metastasis is not well-known. The aim of this study is to investigate the effect of miR-219a-5p on the migratory ability and epithelial-mesenchymal transition (EMT) of breast cancer cells. First, miR-219a-5p was found to be highly expressed in low-invasive breast cancer MCF-7 cells, but lowly expressed in high-invasive breast cancer MDA-MB-231 cells. Wound scratch assay and transwell assay showed that miR-219a-5p inhibited the migratory ability of MDA-MB-231 cells. miR-219a-5p also suppressed the cellular EMT, confirmed by suppressing the expression of mesenchymal markers vimentin and N-cadherin and increasing the expression of epithelial marker E-cadherin. Using the epithelial-mesenchymal-epithelial model in MCF-7 cells, we confirmed that the level of miR-219a-5p was highly expressed in epithelial-type cells and lowly expressed in mesenchymal-type cells. Importantly, we identified myocardin-related transcription factor A (MRTF-A) as a novel potential target gene of miR-219a-5p. Overexpression of miR-219a-5p in MDA-MB-231 cells could inhibit the expression of MRTF-A as revealed by real-time PCR and western blot analysis. miR-219a-5p inhibited the transcription of MRTF-A by targeting the 3'UTR of MRTF-A, which was confirmed by wild-type or mutant MRTF-A 3'UTR luciferase reporter system. Furthermore, knockdown of MRTF-A using siRNA for MRTF-A could depress breast cell migration. In conclusion, our present study revealed the tumor suppressive role of miR-219a-5p in regulating breast cancer migration by targeting MRTF-A, suggesting that miR-219a-5p might be a therapeutic target in breast cancer through regulating EMT.
Wang J, Wu Z, Pan G, et al.Enhanced doxorubicin delivery to hepatocellular carcinoma cells via CD147 antibody-conjugated immunoliposomes.
Nanomedicine. 2018; 14(6):1949-1961 [PubMed
] Related Publications
HAb18G/CD147, an important marker in the progression of hepatocellular carcinoma (HCC), is highly expressed on the surface of HCC cells. To increase the therapeutic efficacy of Doxil (PEGylated liposomal doxorubicin) against HCC, we constructed CD147-targeted doxorubicin-loaded immunoliposomes (Anti-CD147 ILs-DOX) by conjugating F(ab')2 of a CD147-specific monoclonal antibody to DSPE-PEG-MAL, and then inserted the antibody-conjugated polymer to Doxil. Anti-CD147 ILs-DOX delivered DOX to CD147-overexpressing HCC cells specifically and efficiently in vitro and in vivo, resulting in enhanced therapeutic effects than non-targeted controls. Strikingly, Anti-CD147 ILs-DOX reduced the CD133-positive fraction of HCC cells, suggesting its potential in reducing the number of HCC stem cells. Pharmacokinetic and biodistribution studies of Anti-CD147 ILs-DOX confirmed its long circulation time and efficient accumulation in tumors. The superior antitumor effects of Anti-CD147 ILs-DOX than other treatments were demonstrated in both HCC cells and patient-derived HCC xenograft models. Anti-CD147 ILs-DOX represent a novel approach for targeted HCC therapy.
Farid S, AbuSaleh O, Liesman R, Sohail MRIsolated cerebral mucormycosis caused by
BMJ Case Rep. 2017; 2017 [PubMed
] Related Publications
A 61-year-old man with relapsing chronic lymphocytic leukaemia, status post allogeneic stem cell transplant and multiple chemotherapy regimens presented to the emergency room after suffering a grand mal seizure. His evaluation revealed a 1.5-2 cm ring-enhancing left temporal lobe brain lesion on the CT scan. This brain lesion was resected and the histopathology revealed an invasive fungal organism resembling mucormycosis. Amplification and sequencing of the 28S ribosomal RNA gene identified the organism as
BACKGROUND: Male breast cancer (MBC) represents a poorly characterised group of tumours, the management of which is largely based on practices established for female breast cancer. However, recent studies demonstrate biological and molecular differences likely to impact on tumour behaviour and therefore patient outcome. The aim of this study was to investigate methylation of a panel of commonly methylated breast cancer genes in familial MBCs.
METHODS: 60 tumours from 3 BRCA1 and 25 BRCA2 male mutation carriers and 32 males from BRCAX families were assessed for promoter methylation by methylation-sensitive high resolution melting in a panel of 10 genes (RASSF1A, TWIST1, APC, WIF1, MAL, RARβ, CDH1, RUNX3, FOXC1 and GSTP1). An average methylation index (AMI) was calculated for each case comprising the average of the methylation of the 10 genes tested as an indicator of overall tumour promoter region methylation. Promoter hypermethylation and AMI were correlated with BRCA carrier mutation status and clinicopathological parameters including tumour stage, grade, histological subtype and disease specific survival.
RESULTS: Tumours arising in BRCA2 mutation carriers showed significantly higher methylation of candidate genes, than those arising in non-BRCA2 familial MBCs (average AMI 23.6 vs 16.6, p = 0.01, 45% of genes hypermethylated vs 34%, p < 0.01). RARβ methylation and AMI-high status were significantly associated with tumour size (p = 0.01 and p = 0.02 respectively), RUNX3 methylation with invasive carcinoma of no special type (94% vs 69%, p = 0.046) and RASSF1A methylation with coexistence of high grade ductal carcinoma in situ (33% vs 6%, p = 0.02). Cluster analysis showed MBCs arising in BRCA2 mutation carriers were characterised by RASSF1A, WIF1, RARβ and GTSP1 methylation (p = 0.02) whereas methylation in BRCAX tumours showed no clear clustering to particular genes. TWIST1 methylation (p = 0.001) and AMI (p = 0.01) were prognostic for disease specific survival.
CONCLUSIONS: Increased methylation defines a subset of familial MBC and with AMI may be a useful prognostic marker. Methylation might be predictive of response to novel therapeutics that are currently under investigation in other cancer types.
Wang Z, Cheng Y, Abraham JM, et al.RNA sequencing of esophageal adenocarcinomas identifies novel fusion transcripts, including NPC1-MELK, arising from a complex chromosomal rearrangement.
Cancer. 2017; 123(20):3916-3924 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: Studies of chromosomal rearrangements and fusion transcripts have elucidated mechanisms of tumorigenesis and led to targeted cancer therapies. This study was aimed at identifying novel fusion transcripts in esophageal adenocarcinoma (EAC).
METHODS: To identify new fusion transcripts associated with EAC, targeted RNA sequencing and polymerase chain reaction (PCR) verification were performed in 40 EACs and matched nonmalignant specimens from the same patients. Genomic PCR and Sanger sequencing were performed to find the breakpoint of fusion genes.
RESULTS: Five novel in-frame fusion transcripts were identified and verified in 40 EACs and in a validation cohort of 15 additional EACs (55 patients in all): fibroblast growth factor receptor 2 (FGFR2)-GRB2-associated binding protein 2 (GAB2) in 2 of 55 or 3.6%, Niemann-Pick C1 (NPC1)-maternal embryonic leucine zipper kinase (MELK) in 2 of 55 or 3.6%, ubiquitin-specific peptidase 54 (USP54)-calcium/calmodulin dependent protein kinase II γ (CAMK2G) in 2 of 55 or 3.6%, megakaryoblastic leukemia (translocation) 1 (MKL1)-fibulin 1 (FBLN1) in 1 of 55 or 1.8%, and CCR4-NOT transcription complex subunit 2 (CNOT2)-chromosome 12 open reading frame 49 (C12orf49) in 1 of 55 or 1.8%. A genomic analysis indicated that NPC1-MELK arose from a complex interchromosomal translocation event involving chromosomes 18, 3, and 9 with 3 rearrangement points, and this was consistent with chromoplexy.
CONCLUSIONS: These data indicate that fusion transcripts occur at a stable frequency in EAC. Furthermore, our results indicate that chromoplexy is an underlying mechanism that generates fusion transcripts in EAC. These and other fusion transcripts merit further study as diagnostic markers and potential therapeutic targets in EAC. Cancer 2017;123:3916-24. © 2017 American Cancer Society.
BACKGROUND: Myocardin-related transcription factors (MRTF) A and B link actin dynamics and mechanotransduction to gene expression. In mice, MRTF-A is involved in mammary gland differentiation, but its role in human mammary epithelial cells remains unclear.
METHODS: Three-dimensional cultures of human mammary epithelial MCF10A cells were used to model acinar morphogenesis. Stable MRTF-A knockdown, MRTF-A/B rescue and MRTF-A/B overexpression was established to characterize the functional role during morphogenesis using confocal microscopy and expression analysis. Breast cancer patient databases were analyzed for MRTF-A expression.
RESULTS: We showed that a precise temporal control of MRTFs is required for normal morphogenesis of MCF10A mammary acini. MRTF transcriptional activity, but not their protein amounts, is transiently induced during 3D acini formation. MRTF-A knockdown dramatically reduces acini size and prevents lumen formation. These effects are rescued by re-expression of MRTF-A, and partially by MRTF-B. Conversely, overexpression of MRTF-A and MRTF-B increases acini size, resulting in irregular spheroids without lumen and defective apico-basal polarity. These phenotypes correlate with deregulated expression of cell cycle inhibitors p21/Waf1, p27/Kip1 and altered phosphorylation of retinoblastoma protein. In MRTF overexpressing spheroids, proliferation and apoptosis are simultaneously increased at late stages, whilst neither occurs in control acini. MRTFs interfere with anoikis of the inner cells and cause an integrin switch from α6 to α5, repression of E-cadherin and induction of mesenchymal markers vimentin, Snai2 and Zeb1. Moreover, MRTF-overexpressing spheroids are insensitive to alteration in matrix stiffness. In two breast cancer cohorts, high expression of MRTF-A and known target genes was associated with decreased patient survival.
CONCLUSION: MRTF-A is required for proliferation and formation of mammary acini from luminal epithelial cells. Conversely, elevated MRTF activity results in pre-malignant spheroid formation due to defective proliferation, polarity loss and epithelial-mesenchymal transition.
BACKGROUND: The existence of cancer stem cells (CSCs) within a tumor bulk has been demonstrated for many solid tumors including epithelial ovarian carcinoma (EOC). CSCs have been associated to tumor invasion, metastasis and development of chemoresistant recurrences. In this context, we aim to characterize EOC CSCs from the molecular point of view in order to identify potential biomarkers associated with chemoresistance.
METHODS: We isolated a population of cells with stem-like characteristics (OVA-BS4 spheroids) from a primary human EOC cell line under selective conditions. OVA-BS4 spheroids were characterized for drug response by cytotoxicity assays and their molecular profile was investigated by microarray and RT-qPCR. Finally, we performed a gene expression study in a cohort of 74 high-grade serous EOC (HGSOC) patients by RT-qPCR.
RESULTS: Spheroids exhibited properties of self-renewal and a pronounced expression of well-known stem cell genes. Moreover, they demonstrated greater resistance towards several anticancer drugs compared to parent cell line, consistent with their higher ABCG2 gene expression. From microarray studies MAL (T-cell differentiation protein) emerged as the most up-regulated gene in spheroids, compared to parent cell line. In HGSOC patients, MAL was significantly overexpressed in platinum-resistant compared to platinum-sensitive patients and resulted as an independent prognostic marker of survival.
CONCLUSIONS: This investigation provides an important contribution to the identification of molecular markers of ovarian CSCs and chemoresistance. Successful translation of molecular findings would lead to a better comprehension of the mechanisms triggering chemoresistant recurrences, to the individuation of novel therapeutic targets and to the personalization of treatment regimens.
PURPOSE: The molecular nature and the rate-limiting step of epigenetic field defects in the evolution of left-sided colorectal cancer (LCA) remain uncertain.
MATERIALS AND METHODS: The methylation status of 27 candidate field defect markers, six classic CpG island methylator phenotype (CIMP) markers, and LINE-1 were determined in LCA and adjacent normal mucosas (ADJs) from 33 LCA patients and in left normal colorectal mucosa (LNM) from 33 age- and sex-matched controls. Hotspot mutation analyses in KRAS codons 12 and 13 and BRAF V600E were performed by genomic PCR and pyrosequencing using DNA extracted from endoscopically biopsied tissues.
RESULTS: Among the 27 candidate genes tested, we confirmed 15 differentially methylated genes in cancer (15 DMGs; ER, SFRP1, MYOD1, MGMT, CD8a, SPOCK2, ABHD9, BNIP3, IGFBP3, WIF1, MAL, GDNF, ALX4, DOK5, and SLC16A12) in comparison to ADJ samples. We further compared the methylation status of 15 DMGs of ADJs to LNM and found only methylation levels of SLC16A12 in ADJs of LCA patients to be significantly higher than that in LNM (17.3% vs. 11.5%, p=0.002). Based on the CIMP, no significant differences in methylation levels of the 15 DMGs were found between ADJs in CIMP positive LCA cases and those without CIMP. In mutation analyses, no mutation was found in ADJs, while significant KRAS mutations (6/33, 18%) were noted in LCA samples.
CONCLUSION: Epigenetic field defect marked by aberrant methylation is uncommon in normal-appearing ADJs of LCA, indicating the critical rate-limiting change of methylation is likely to occur with morphological alterations in the evolution of LCA.
Clarke MA, Luhn P, Gage JC, et al.Discovery and validation of candidate host DNA methylation markers for detection of cervical precancer and cancer.
Int J Cancer. 2017; 141(4):701-710 [PubMed
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Human papillomavirus (HPV) testing has been recently introduced as an alternative to cytology for cervical cancer screening. However, since most HPV infections clear without causing clinically relevant lesions, additional triage tests are required to identify women who are at high risk of developing cancer. We performed DNA methylation profiling on formalin-fixed, paraffin-embedded tissue specimens from women with benign HPV16 infection and histologically confirmed cervical intraepithelial neoplasia grade 3, and cancer using a bead-based microarray covering 1,500 CpG sites in over 800 genes. Methylation levels in individual CpG sites were compared using a t-test, and results were summarized by computing p-values. A total of 12 candidate genes (ADCYAP1, ASCL1, ATP10, CADM1, DCC, DBC1, HS3ST2, MOS, MYOD1, SOX1, SOX17 and TMEFF2) identified by DNA methylation profiling, plus an additional three genes identified from the literature (EPB41L3, MAL and miR-124) were chosen for validation in an independent set of 167 liquid-based cytology specimens using pyrosequencing and targeted, next-generation bisulfite sequencing. Of the 15 candidate gene markers, 10 had an area under the curve (AUC) of ≥ 0.75 for discrimination of high grade squamous intraepithelial lesions or worse (HSIL+) from
Xiang Y, Liao XH, Yu CX, et al.MiR-93-5p inhibits the EMT of breast cancer cells via targeting MKL-1 and STAT3.
Exp Cell Res. 2017; 357(1):135-144 [PubMed
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Epithelial-mesenchymal transition (EMT) plays an important role in breast cancer cell metastasis. Both (megakaryoblastic leukemia)/myocardin-like 1 (MKL-1) and Signal transducer and activator of transcription 3 (STAT3) have been implicated in the control of cellular metabolism, survival and growth. Our previous study has shown that cooperativity of MKL-1 and STAT3 promoted breast cancer cell migration. Herein, we demonstrate a requirement for MKL-1 and STAT3 in miRNA-mediated cellular EMT to affect breast cancer cell migration. Here we show that cooperativity of MKL-1 and STAT3 promoted the EMT of MCF-7 cells. Importantly, MKL-1 and STAT3 promoted the expression of Vimentin via its promoter CArG box. Interestingly, miR-93-5p inhibits the EMT of breast cancer cells through suppressing the expression of MKL-1 and STAT3 via targeted their 3'UTR. These results demonstrated a novel pathway through which miR-93-5p regulates MKL-1 and STAT3 to affect EMT controlling breast cancer cell migration.
BACKGROUND The reciprocal translocation t(1;22)(p13;q13) involving the RBM15 and MKL1 genes is an uncommon abnormality that occurs in a subset of acute myeloid leukemia with megakaryocytic differentiation (AMKL). Variant translocations have been infrequently described in this subtype of leukemia. CASE REPORT We describe the case of a 3-month-old girl who presented with progressive abdominal distension, vomiting, and fever. Although there was no morphologic evidence of leukemia in the bone marrow, cytogenetic and metaphase fluorescence in situ hybridization analysis identified an insertion of p13p31 bands of chromosome 1 onto the long arm of chromosome 22, resulting in the karyotype: 46,XX,ins(22;1)(q13;p13p31). Subsequent liver biopsy demonstrated extensive involvement by AMKL. CONCLUSIONS AMKL can present with fewer than 20% blasts in the peripheral blood or bone marrow, necessitating careful evaluation for extramedullary disease. In other situations, bone marrow fibrosis can result in difficult marrow aspirations and a falsely decreased blast count. This case report highlights the critical role of careful cytogenetic and FISH testing in the diagnosis of AMKL.
Ayllón V, Vogel-González M, González-Pozas F, et al.New hPSC-based human models to study pediatric Acute Megakaryoblastic Leukemia harboring the fusion oncogene RBM15-MKL1.
Stem Cell Res. 2017; 19:1-5 [PubMed
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Pediatric Acute Megakaryoblastic Leukemia not associated to Down Syndrome (non-DS AMKL) is a rare disease with a dismal prognosis. Around 15% of patients carry the chromosomal translocation t(1;22) that originates the fusion oncogene RBM15-MKL1, which is linked to an earlier disease onset (median of 6months of age) and arises in utero. Here we report the generation of two hPSC cell lines constitutively expressing the oncogene RBM15-MKL1, resulting in an increased expression of known RBM15-MKL1 gene targets. These cell lines represent new disease models of pediatric AMKL to study the impact of the RBM15-MKL1 oncogene on human embryonic hematopoietic development.
Knips J, Czech-Sioli M, Spohn M, et al.Spontaneous lung metastasis formation of human Merkel cell carcinoma cell lines transplanted into scid mice.
Int J Cancer. 2017; 141(1):160-171 [PubMed
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Merkel cell carcinoma (MCC) is an aggressive skin cancer entity that frequently leads to rapid death due to its high propensity to metastasize. The etiology of most MCC cases is linked to Merkel cell polyomavirus (MCPyV), a virus which is monoclonally integrated in up to 95% of tumors. While there are presently no animal models to study the role of authentic MCPyV infection on transformation, tumorigenesis or metastasis formation, xenograft mouse models employing engrafted MCC-derived cell lines (MCCL) represent a promising approach to study certain aspects of MCC pathogenesis. Here, the two MCPyV-positive MCC cell lines WaGa and MKL-1 were subcutaneously engrafted in scid mice. Engraftment of both MCC cell lines resulted in the appearance of circulating tumor cells and metastasis formation, with WaGa-engrafted mice showing a significantly shorter survival time as well as increased numbers of spontaneous lung metastases compared to MKL-1 mice. Interestingly, explanted tumors compared to parental cell lines exhibit an upregulation of MCPyV sT-Antigen expression in all tumors, with WaGa tumors showing significantly higher sT-Antigen expression than MKL-1 tumors. RNA-Seq analysis of explanted tumors and parental cell lines furthermore revealed that in the more aggressive WaGa tumors, genes involved in inflammatory response, growth factor activity and Wnt signalling pathway are significantly upregulated, suggesting that sT-Antigen is the driver of the observed differences in metastasis formation.
The Mig10/RIAM/Lpd (MRL) adapter protein Lpd regulates actin dynamics through interactions with Scar/WAVE and Ena/VASP proteins to promote the formation of cellular protrusions and to stimulate invasive migration. However, the ability of MRL proteins to interact with multiple actin regulators and to promote serum response factor (SRF) signalling has raised the question of whether MRL proteins employ alternative downstream mechanisms to drive oncogenic processes in a context-dependent manner. Here, using a Drosophila model, we show that overexpression of either human Lpd or its Drosophila orthologue Pico can promote growth and invasion of Ras
Mercher T, Courtois G, Berger R, Bernard OA[Molecular basis of the t(1;22)(p13;q13) specific for human acute megakaryoblastic leukemia].
Pathol Biol (Paris). 2003; 51(1):27-32 [PubMed
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The t(1;22)(p13;q13) translocation is specifically associated with infant acute megakaryoblastic leukemia (M7). We have recently characterized the two genes involved in this translocation: OTT (One Two Two) and MAL (Megakaryoblastic Acute Leukemia) respectively located on chromosome 1 and 22. The t(1;22) translocation results in the fusion of these genes in all the cases studied to date. We summarize here present knowledge regarding this translocation.