KRIT1

Gene Summary

Gene:KRIT1; KRIT1 ankyrin repeat containing
Aliases: CAM, CCM1
Location:7q21.2
Summary:This gene encodes a protein containing four ankyrin repeats, a band 4.1/ezrin/radixin/moesin (FERM) domain, and multiple NPXY sequences. The encoded protein is localized in the nucleus and cytoplasm. It binds to integrin cytoplasmic domain-associated protein-1 alpha (ICAP1alpha), and plays a critical role in beta1-integrin-mediated cell proliferation. It associates with junction proteins and RAS-related protein 1A (Rap1A), which requires the encoded protein for maintaining the integrity of endothelial junctions. It is also a microtubule-associated protein and may play a role in microtubule targeting. Mutations in this gene result in cerebral cavernous malformations. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2009]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:krev interaction trapped protein 1
Source:NCBIAccessed: 31 August, 2019

Ontology:

What does this gene/protein do?
Show (16)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Mutation
  • Hemangioma, Cavernous, Central Nervous System
  • Magnetic Resonance Imaging
  • Siblings
  • Skin Diseases, Vascular
  • Adolescents
  • KRIT1 Protein
  • RTPCR
  • Severity of Illness Index
  • Genetic Predisposition
  • RNA Splicing
  • Childhood Cancer
  • Veins
  • Carrier Proteins
  • Vestibulocochlear Nerve
  • Apoptosis Regulatory Proteins
  • Two-Hybrid System Techniques
  • Subcellular Fractions
  • Sex Factors
  • DNA Mutational Analysis
  • Brain Tumours
  • Sequence Deletion
  • Brain and CNS Tumours
  • X-Ray Computed Tomography
  • Chromosome 7
  • Seizures
  • Brain Tumours
  • Spain
  • Pedigree
  • Switzerland
  • Brain
  • Signal Transduction
  • Risk Assessment
  • Skin Abnormalities
  • Skin Cancer
  • Risk Factors
  • Pyramidal Cells
  • Microtubule-Associated Proteins
  • Retinal Neoplasms
  • Membrane Proteins
  • Hemangioma, Cavernous
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

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).

Latest Publications: KRIT1 (cancer-related)

Böhm J, Muenzner JK, Caliskan A, et al.
Loss of enhancer of zeste homologue 2 (EZH2) at tumor invasion front is correlated with higher aggressiveness in colorectal cancer cells.
J Cancer Res Clin Oncol. 2019; 145(9):2227-2240 [PubMed] Related Publications
PURPOSE: Enhancer of zeste homolog 2 (EZH2) is associated with epigenetic gene silencing and aggressiveness in many tumor types. However, the prognostic impact of high EZH2 expression is controversially discussed for colorectal cancer. For this reason, we immunohistochemically analyzed EZH2 expression in 105 specimens from colon cancer patients separately for tumor center and invasion front.
METHODS: All sections from tissue microarrays were evaluated manually and digitally using Definiens Tissue Studio software (TSS). To mirror-image the EZH2 status at the tumor invasion front, we treated HCT116 colon cancer cells with the EZH2 inhibitor 3-Deazaneplanocin A (DZNep) and studied the growth of in ovo xenografts in the chorioallantoic membrane (CAM) assay.
RESULTS: We showed a significant decrease in EZH2 expression and the repressive H3K27me3 code at the tumor invasion front as supported by the TSS-constructed heatmaps. Loss of EZH2 at tumor invasion front, but not in tumor center was correlated with unfavorable prognosis and more advanced tumor stages. The observed cell cycle arrest in vitro and in vivo was associated with higher tumor aggressiveness. Xenografts formed by DZNep-treated HCT116 cells showed loosely packed tumor masses, infiltrative growth into the CAM, and high vessel density.
CONCLUSION: The differences in EZH2 expression between tumor center and invasion front as well as different scoring and cutoff values can most likely explain controversial literature data concerning the prognostic value of EZH2. Epigenetic therapies using EZH2 inhibitors have to be carefully evaluated for each specific tumor type, since alterations in cell differentiation might lead to unfavorable results.

Holding AN, Giorgi FM, Donnelly A, et al.
VULCAN integrates ChIP-seq with patient-derived co-expression networks to identify GRHL2 as a key co-regulator of ERa at enhancers in breast cancer.
Genome Biol. 2019; 20(1):91 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: VirtUaL ChIP-seq Analysis through Networks (VULCAN) infers regulatory interactions of transcription factors by overlaying networks generated from publicly available tumor expression data onto ChIP-seq data. We apply our method to dissect the regulation of estrogen receptor-alpha activation in breast cancer to identify potential co-regulators of the estrogen receptor's transcriptional response.
RESULTS: VULCAN analysis of estrogen receptor activation in breast cancer highlights the key components of the estrogen receptor complex alongside a novel interaction with GRHL2. We demonstrate that GRHL2 is recruited to a subset of estrogen receptor binding sites and regulates transcriptional output, as evidenced by changes in estrogen receptor-associated eRNA expression and stronger estrogen receptor binding at active enhancers after GRHL2 knockdown.
CONCLUSIONS: Our findings provide new insight into the role of GRHL2 in regulating eRNA transcription as part of estrogen receptor signaling. These results demonstrate VULCAN, available from Bioconductor, as a powerful predictive tool.

Chapman EM, Lant B, Ohashi Y, et al.
A conserved CCM complex promotes apoptosis non-autonomously by regulating zinc homeostasis.
Nat Commun. 2019; 10(1):1791 [PubMed] Free Access to Full Article Related Publications
Apoptotic death of cells damaged by genotoxic stress requires regulatory input from surrounding tissues. The C. elegans scaffold protein KRI-1, ortholog of mammalian KRIT1/CCM1, permits DNA damage-induced apoptosis of cells in the germline by an unknown cell non-autonomous mechanism. We reveal that KRI-1 exists in a complex with CCM-2 in the intestine to negatively regulate the ERK-5/MAPK pathway. This allows the KLF-3 transcription factor to facilitate expression of the SLC39 zinc transporter gene zipt-2.3, which functions to sequester zinc in the intestine. Ablation of KRI-1 results in reduced zinc sequestration in the intestine, inhibition of IR-induced MPK-1/ERK1 activation, and apoptosis in the germline. Zinc localization is also perturbed in the vasculature of krit1

Syafruddin SE, Rodrigues P, Vojtasova E, et al.
A KLF6-driven transcriptional network links lipid homeostasis and tumour growth in renal carcinoma.
Nat Commun. 2019; 10(1):1152 [PubMed] Free Access to Full Article Related Publications
Transcriptional networks are critical for the establishment of tissue-specific cellular states in health and disease, including cancer. Yet, the transcriptional circuits that control carcinogenesis remain poorly understood. Here we report that Kruppel like factor 6 (KLF6), a transcription factor of the zinc finger family, regulates lipid homeostasis in clear cell renal cell carcinoma (ccRCC). We show that KLF6 supports the expression of lipid metabolism genes and promotes the expression of PDGFB, which activates mTOR signalling and the downstream lipid metabolism regulators SREBF1 and SREBF2. KLF6 expression is driven by a robust super enhancer that integrates signals from multiple pathways, including the ccRCC-initiating VHL-HIF2A pathway. These results suggest an underlying mechanism for high mTOR activity in ccRCC cells. More generally, the link between super enhancer-driven transcriptional networks and essential metabolic pathways may provide clues to the mechanisms that maintain the stability of cell identity-defining transcriptional programmes in cancer.

Cappellesso R, Lo Mele M, Munari G, et al.
Molecular characterization of "sessile serrated" adenoma to carcinoma transition in six early colorectal cancers.
Pathol Res Pract. 2019; 215(5):957-962 [PubMed] Related Publications
Colorectal cancer (CRC) is a heterogeneous group of diseases both from the morphological and molecular point of view. The sessile serrated adenoma/polyp (SSA/P) has been proposed as the precursor lesion of CRCs characterized by CpG island methylator phenotype (CIMP), DNA mismatch repair (MMR) system deficiency, and BRAF gene mutations. However, no study so far investigated the molecular landscape of "sessile serrated" adenoma to carcinoma transition in early CRCs. Six formalin-fixed paraffin-embedded CRCs developed within SSA/P were profiled for the immunohistochemical expression of MMR proteins (MLH1, MSH2, MSH6, PMS2, and Ep-CAM), p16, and β-catenin. DNA was extracted from the two components of each sample, after microdissection, and characterized for CIMP status and by applying a custom hotspot multigene mutational profiling of 164 hotspot regions of eleven CRC-associated genes (AKT1, APC, BRAF, CTNNB1, KIT, KRAS, NRAS, PDGFRA, PIK3CA, PTEN, and TP53). Five out of the six CRCs shared the same molecular profile (i.e. CIMP positive, MSI status, and BRAF mutation) with their SSA/P components. One out of five CRCs was also APC mutated, whereas another one showed an additional TP53 mutation. The remaining case was CIMP negative and MMR proficient in both the components, harbored a BRAF mutation in the SSA/P counterpart, whereas the CRC one was APC and TP53 mutated and showed p16 and β-catenin dysregulation. This study provides the molecular evidence that SSA/P, even without cytological dysplasia, is a precursor lesion of CRC and that conventional CRC might arise from mixed polyp.

Frankell AM, Jammula S, Li X, et al.
The landscape of selection in 551 esophageal adenocarcinomas defines genomic biomarkers for the clinic.
Nat Genet. 2019; 51(3):506-516 [PubMed] Free Access to Full Article Related Publications
Esophageal adenocarcinoma (EAC) is a poor-prognosis cancer type with rapidly rising incidence. Understanding of the genetic events driving EAC development is limited, and there are few molecular biomarkers for prognostication or therapeutics. Using a cohort of 551 genomically characterized EACs with matched RNA sequencing data, we discovered 77 EAC driver genes and 21 noncoding driver elements. We identified a mean of 4.4 driver events per tumor, which were derived more commonly from mutations than copy number alterations, and compared the prevelence of these mutations to the exome-wide mutational excess calculated using non-synonymous to synonymous mutation ratios (dN/dS). We observed mutual exclusivity or co-occurrence of events within and between several dysregulated EAC pathways, a result suggestive of strong functional relationships. Indicators of poor prognosis (SMAD4 and GATA4) were verified in independent cohorts with significant predictive value. Over 50% of EACs contained sensitizing events for CDK4 and CDK6 inhibitors, which were highly correlated with clinically relevant sensitivity in a panel of EAC cell lines and organoids.

Du Q, Shi Z, Chen H, et al.
Two Novel CCM2 Heterozygous Mutations Associated with Cerebral Cavernous Malformation in a Chinese Family.
J Mol Neurosci. 2019; 67(3):467-471 [PubMed] Related Publications
Cerebral cavernous malformation (CCM) is a congenital vascular anomaly that predominantly involves the central nervous system (CNS). CCM occurs in either a sporadic or an inherited form; the latter is called familial cerebral cavernous malformation (FCCM). FCCM has an autosomal dominant transmission with incomplete penetrance and variable clinical expression that is associated with germline mutations in the CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10 genes. Herein, we disclose two novel heterozygous mutations in the CCM2 gene in a Chinese family: a deletion mutation (c.55C>T; p. R19X, 426) in exon 2 and a mutation (c.*18G>A) in the noncoding region of exon 10. Our findings provide new CCM2 gene mutation profiles and further evidence for phenotypic heterogeneity.

Xu J, Liu H, Yang Y, et al.
Genome-Wide Profiling of Cervical RNA-Binding Proteins Identifies Human Papillomavirus Regulation of RNASEH2A Expression by Viral E7 and E2F1.
MBio. 2019; 10(1) [PubMed] Free Access to Full Article Related Publications
RNA-binding proteins (RBPs) control mRNA processing, stability, transport, editing, and translation. We recently conducted transcriptome analyses comparing normal (i.e., healthy) cervical tissue samples with human papillomavirus (HPV)-positive cervical cancer tissue samples and identified 614 differentially expressed protein-coding transcripts which are enriched in cancer-related pathways and consist of 95 known RBPs. We verified the altered expression of 26 genes with a cohort of 72 cervical samples, including 24 normal cervical samples, 25 cervical intraepithelial neoplasia grade 2 (CIN2) and CIN3 samples, and 23 cervical cancer tissue samples. LY6K (lymphocyte antigen 6 complex locus K), FAM83A (family member with sequence similarity 83), CELSR3, ASF1B, IQGAP3, SEMA3F, CLDN10, MSX1, CXCL5, ASRGL1, ELAVL2, GRB7, KHSRP, NOVA1, PTBP1, and RNASEH2A were identified as novel candidate genes associated with cervical lesion progression and carcinogenesis. HPV16 or HPV18 infection was found to alter the expression of 8 RBP genes (CDKN2A, ELAVL2, GRB7, HSPB1, KHSRP, NOVA1, PTBP1, and RNASEH2A) in human vaginal and foreskin keratinocytes. Both viral E6 and E7 decreased NOVA1 expression, but only E7 increased the expression of RNASEH2A in an E2F1-dependent manner. Proliferating cell nuclear antigen (PCNA) directs RNASEH2 activity with respect to DNA replication by removing the RNA primers to promote Okazaki fragment maturation, and two factors are closely associated with neoplasia progression. Therefore, we predict that the induction of expression of RNASEH2A via viral E7 and E2F1 may promote DNA replication and cancer cell proliferation.

Balmus G, Pilger D, Coates J, et al.
ATM orchestrates the DNA-damage response to counter toxic non-homologous end-joining at broken replication forks.
Nat Commun. 2019; 10(1):87 [PubMed] Free Access to Full Article Related Publications
Mutations in the ATM tumor suppressor gene confer hypersensitivity to DNA-damaging chemotherapeutic agents. To explore genetic resistance mechanisms, we performed genome-wide CRISPR-Cas9 screens in cells treated with the DNA topoisomerase I inhibitor topotecan. Thus, we here establish that inactivating terminal components of the non-homologous end-joining (NHEJ) machinery or of the BRCA1-A complex specifically confer topotecan resistance to ATM-deficient cells. We show that hypersensitivity of ATM-mutant cells to topotecan or the poly-(ADP-ribose) polymerase (PARP) inhibitor olaparib reflects delayed engagement of homologous recombination at DNA-replication-fork associated single-ended double-strand breaks (DSBs), allowing some to be subject to toxic NHEJ. Preventing DSB ligation by NHEJ, or enhancing homologous recombination by BRCA1-A complex disruption, suppresses this toxicity, highlighting a crucial role for ATM in preventing toxic LIG4-mediated chromosome fusions. Notably, suppressor mutations in ATM-mutant backgrounds are different to those in BRCA1-mutant scenarios, suggesting new opportunities for patient stratification and additional therapeutic vulnerabilities for clinical exploitation.

Bowden AR, Tischkowitz M
Clinical implications of germline mutations in breast cancer genes: RECQL.
Breast Cancer Res Treat. 2019; 174(3):553-560 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The identification of new hereditary breast cancer genes is an area of highly active research. In 2015, two independent studies provided initial evidence for a novel breast cancer susceptibility gene, RECQL, a DNA helicase which plays an important role in the DNA damage response. Several subsequent studies in independent patient cohorts have provided further data on RECQL variant frequency in additional populations, some of which have brought in to question the increased breast cancer risk associated with RECQL mutations.
RESULTS: The initial reports present findings from whole exome sequencing of high-risk familial breast cancer cases in the French-Canadian, Polish and Han Chinese populations and estimate the carrier frequency of pathogenic RECQL mutations in high-risk breast cancer patients who have previously tested negative for BRCA1 and BRCA2 mutations to be approximately 1-2%. Proposed founder mutations were identified in French-Canadian and Polish populations. Functional studies support loss of function of the helicase activity of RECQL for some of the reported pathogenic mutations. An additional study in a cohort of Southern Chinese high-risk breast cancer patients estimated the frequency of pathogenic RECQL mutations to be 0.54%. A possible Chinese founder mutation was identified, but only a small number of controls were sequenced. Subsequent case-control studies screening for the Polish founder mutation in patients from Germany and Belarus did not find any evidence for increased breast cancer risk for this variant. An Australian case-control study also failed to identify an increased risk of breast cancer associated with RECQL loss of function variants.
CONCLUSIONS: RECQL plays an important role in DNA repair, and is a plausible candidate breast cancer susceptibility gene. Initial studies showed evidence of an association between variants in this gene and an increased breast cancer risk in three separate populations, and identified founder mutations with significantly increased odds ratios. However, several subsequent studies have failed to support the association. With the limited and conflicting evidence available, there remains debate as to whether there is an increased breast cancer risk in individuals carrying RECQL loss of function variants. Further studies are required to better quantify the risks associated with RECQL variants and the current evidence base is not sufficient to justify routine inclusion of RECQL on breast cancer gene panels in clinical use. Management of patients in whom RECQL variants have been identified should be based on clinician assessment, in the context of the family history. Further studies are required to better quantify the risks to RECQL mutation carriers and may also guide management and potential therapeutic targeting for patients.

Reuter A, Sckell A, Brandenburg LO, et al.
Overexpression of MicroRNA-1 in Prostate Cancer Cells Modulates the Blood Vessel System of an
In Vivo. 2019 Jan-Feb; 33(1):41-46 [PubMed] Free Access to Full Article Related Publications
BACKGROUND/AIM: In prostate cancer (PC), the formation of new blood vessels is stimulated by hypoxic conditions, androgens, and a number of molecular factors including microRNAs. MicroRNA-1 (miR-1) has been characterized in some tumor entities as anti-angiogenic, but this has not yet been investigated in PC.
MATERIALS AND METHODS: PC cells stably overexpressing miR-1 (LNCaP-miR-1) were incubated on an in vivo hen's egg test-chorioallantoic membrane (HET-CAM) model and compared to maternal LNCaP cells. Cell growth, blood vessel organisation, and total blood vessel area were analysed.
RESULTS: Both matrigel-embedded LNCaP and LNCaP-miR-1 cells formed compact tumor-like cell aggregates on the CAM of the HET-CAM model. Although not quantifiable, bleeding of the CAM and remodelling of the blood vessel network in the CAM indicated an influence of miR-1 on the vascular system. The statistically significant decrease in the total surface area of blood vessels in the visible CAM section to 79.4% of control cells demonstrated the antiangiogenic properties of miR-1 for the first time.
CONCLUSION: MiR-1 had a tumor-suppressive and anti-angiogenic effect in an in vivo PC model. In the clinic, miR-1-mediated anti-angiogenesis would result in reduced tumor supply and increased hypoxic stress inside the tumor. Thus, miR-1 restoration by nucleic acid-based miR-1 mimetics would represent a promising option for future PC therapy.

Tzelepis K, De Braekeleer E, Aspris D, et al.
SRPK1 maintains acute myeloid leukemia through effects on isoform usage of epigenetic regulators including BRD4.
Nat Commun. 2018; 9(1):5378 [PubMed] Free Access to Full Article Related Publications
We recently identified the splicing kinase gene SRPK1 as a genetic vulnerability of acute myeloid leukemia (AML). Here, we show that genetic or pharmacological inhibition of SRPK1 leads to cell cycle arrest, leukemic cell differentiation and prolonged survival of mice transplanted with MLL-rearranged AML. RNA-seq analysis demonstrates that SRPK1 inhibition leads to altered isoform levels of many genes including several with established roles in leukemogenesis such as MYB, BRD4 and MED24. We focus on BRD4 as its main isoforms have distinct molecular properties and find that SRPK1 inhibition produces a significant switch from the short to the long isoform at the mRNA and protein levels. This was associated with BRD4 eviction from genomic loci involved in leukemogenesis including BCL2 and MYC. We go on to show that this switch mediates at least part of the anti-leukemic effects of SRPK1 inhibition. Our findings reveal that SRPK1 represents a plausible new therapeutic target against AML.

Al-Otaibi NAS, Cassoli JS, Slater NKH, Rahmoune H
Molecular Characterization of Human Leukemia 60 (HL-60) Cells as a Model of Acute Myelogenous Leukemia Post Cryopreservation.
Methods Mol Biol. 2019; 1916:239-247 [PubMed] Related Publications
The use of human leukemic (HL)-60 cells is important for studies of acute myeloid leukemia (AML) and as a model system for investigating how specific types of blood cells are formed during the process of hematopoiesis. Here, we present a protocol for growth of HL-60 cells along with molecular and functional profiles associated with their cryostorage. We also elucidate the effects of these procedures on cell viability and functions. This method can be used to provide biomarkers as readouts for testing the efficacy and/or toxicity of novel compounds in AML research as well as in a number of other experimental manipulations.

Saltarella I, Frassanito MA, Lamanuzzi A, et al.
Homotypic and Heterotypic Activation of the Notch Pathway in Multiple Myeloma-Enhanced Angiogenesis: A Novel Therapeutic Target?
Neoplasia. 2019; 21(1):93-105 [PubMed] Free Access to Full Article Related Publications
Interactions of multiple myeloma (MM) cells with endothelial cells (ECs) enhance angiogenesis and MM progression. Here, we investigated the role of Notch signaling in the cross talk between ECs and MM cells enabling angiogenesis. MMECs showed higher expression of Jagged1/2 ligands, of activated Notch1/2 receptors, and of Hes1/Hey1 Notch target genes than ECs from monoclonal gammopathy of undetermined significance patients, suggesting that homotypic activation of Notch pathway occurs in MM. MM cells co-cultured with MMECs triggered Notch activation in these cells through a cell-to-cell contact-dependent way via Jagged1/2, resulting in Hes1/Hey1 overexpression. The angiogenic effect of Notch pathway was analyzed through Notch1/2·siRNAs and the γ-secretase inhibitor MK-0752 by in vitro (adhesion, migration, chemotaxis, angiogenesis) and in vivo (Vk12598/C57B/6 J mouse model) studies. Activated Notch1/2 pathway was associated with the overangiogenic MMEC phenotype: Notch1/2 knockdown or MK-0752 treatment reduced Hes1/Hey1 expression, impairing in vitro angiogenesis of both MMECs alone and co-cultured with MM cells. MM cells were unable to restore angiogenic abilities of treated MMECs, proving that MMEC angiogenic activities closely rely on Notch pathway. Furthermore, Notch1/2 knockdown affected VEGF/VEGFR2 axis, indicating that the Notch pathway interferes with VEGF-mediated control on angiogenesis. MK-0752 reduced secretion of proangiogenic/proinflammatory cytokines in conditioned media, thus inhibiting blood vessel formation in the CAM assay. In the Vk12598/C57B/6 J mouse, MK-0752 treatment restrained angiogenesis by reducing microvessel density. Overall, homotypic and heterotypic Jagged1/2-mediated Notch activation enhances MMECs angiogenesis. Notch axis inhibition blocked angiogenesis in vitro and in vivo, suggesting that the Notch pathway may represent a novel therapeutic target in MM.

Matsushita Y, Furutani Y, Matsuoka R, Furukawa T
Hot water extract of Agaricus blazei Murrill specifically inhibits growth and induces apoptosis in human pancreatic cancer cells.
BMC Complement Altern Med. 2018; 18(1):319 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Pancreatic cancer is one of the most aggressive human malignancies. The development of a novel drug to treat pancreatic cancer is imperative, and it is thought that complementary and alternative medicine (CAM) could yield such a candidate. Agaricus blazei Murrill is a CAM that has been tested as an anticancer drug, but its efficacy against pancreatic cancer is poorly understood. To study the potential of A. blazei in the treatment of pancreatic cancer, we examined the effects of its hot water extract on the proliferation and global gene expression profile of human pancreatic cancer cells.
METHODS: Three distinct human pancreatic cancer cell lines, MIAPaCa-2, PCI-35, and PK-8, and the immortalized human pancreatic duct-epithelial cell line, HPDE, were employed. The cells were incubated with the appropriate growth medium supplemented with the hot water extract of A. blazei at final concentrations of 0.005, 0.015%, or 0.045%, and cellular proliferation was assessed for five consecutive days using an MTT assay. Apoptosis was examined by using flow cytometry and the terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay. Caspase-dependent apoptosis was assayed using immunoblotting. Global gene expression profiles were examined using a whole human genome 44 K microarray, and the microarray results were validated by using real-time reverse transcription PCR.
RESULTS: The hot water extract of A. blazei significantly inhibited the proliferation of cultured pancreatic cancer cells through the induction of G0/G1 cell cycle arrest and caspase-dependent apoptosis; the effect was the smallest in HPDE cells. Furthermore, significant alterations in the global gene expression profiles of pancreatic cancer cells occurred following treatment with the hot water extract of A. blazei. Genes associated with kinetochore function, spindle formation, and centromere maintenance were particularly affected, as well as cyclins and cyclin-dependent kinases that are essential for cell cycle progression. In addition, proapoptotic genes were upregulated.
CONCLUSIONS: The hot water extract of A. blazei may be useful for the treatment of pancreatic cancer and is a potential candidate for the isolation of novel, active compounds specific for mitotic spindle dysfunction.

Noia G, Maltese PE, Zampino G, et al.
Cystic Hygroma: A Preliminary Genetic Study and a Short Review from the Literature.
Lymphat Res Biol. 2019; 17(1):30-39 [PubMed] Related Publications
BACKGROUND: The objective of this study is to examine the hypothesis that cystic hygroma (CH) with normal karyotype can manifest as a Mendelian inherited trait, and that a genetic similitude with hereditary lymphedema exists. To reach this goal, we investigated the prevalence of genetic variants in angiogenesis and lymphangiogenesis genes in a cohort of euploid fetuses with CH that almost resolved before delivery. A short review of cases from literature is also reported.
METHODS AND RESULTS: Five fetuses were screened using a next-generation sequencing approach by targeting 33 genes known to be associated with vascular and lymphatic malformations. The genetic evaluation revealed two novel variants in KDR and KRIT1 genes.
CONCLUSION: A review of the literature to date revealed that an association exists between CH and hereditary lymphedema and, similar to lymphedema, CH can be inherited in autosomal recessive and autosomal dominant manner, with the latter most likely associated with a better prognosis. About KDR and KRIT1 genes, no other similar associations are reported in the literature and caution is needed in their interpretation. In conclusion, we thought that a genetic test for the outcome of familial CH could be of enormous prognostic value.

Lopez-Ramirez MA, Pham A, Girard R, et al.
Cerebral cavernous malformations form an anticoagulant vascular domain in humans and mice.
Blood. 2019; 133(3):193-204 [PubMed] Article available free on PMC after 17/01/2020 Related Publications
Cerebral cavernous malformations (CCMs) are common brain vascular dysplasias that are prone to acute and chronic hemorrhage with significant clinical sequelae. The pathogenesis of recurrent bleeding in CCM is incompletely understood. Here, we show that central nervous system hemorrhage in CCMs is associated with locally elevated expression of the anticoagulant endothelial receptors thrombomodulin (TM) and endothelial protein C receptor (EPCR). TM levels are increased in human CCM lesions, as well as in the plasma of patients with CCMs. In mice, endothelial-specific genetic inactivation of

Evrenos MK, Temiz P, Çam FS, et al.
Clinicopathological characteristics and mutation profile of BRAF and NRAS mutation in cutaneous melanomas in the Western Turkish population
Turk J Med Sci. 2018; 48(5):973-979 [PubMed] Related Publications
Background/aim: Malignant melanoma is the most common cause of death due to skin cancers. The most common mutations in RAFRAS pathway from tumor oncogenes are BRAF and NRAS. In this study, we analyzed the frequency of BRAF and NRAS gene mutations and investigated their association with clinicopathological features of melanomas in the Turkish population. Materials and methods: 65 primary cutaneous melanoma were included in the study. The mutations were evaluated with real-time PCRbased PCR-array through allele-specific amplification, and the results were correlated with various clinicopathological characteristics. Results: 52.3% of the patients were female and 47.7% were male. The mean age of the patients with a mutation was lower than those without mutation. 16 patients had BRAF mutation. 12 patients had NRAS mutation. NRAS mutation was statistically more common in men (P = 0.036). The number of mitoses increased with the increase of the tumor thickness (P = 0.003). There was more mitosis in the presence of ulceration (P = 0.05). A total of 41.7% of NRAS mutations had adjuvant chemotherapy. Conclusion: We found lower mutation rate when compared to regional studies. NRAS mutation was common in men. This is the first study from our region evaluating the prognostic value of clinical stage and necessity of adjuvant treatment with the presence of BRAF and NRAS mutations.

Amelio I, Mancini M, Petrova V, et al.
p53 mutants cooperate with HIF-1 in transcriptional regulation of extracellular matrix components to promote tumor progression.
Proc Natl Acad Sci U S A. 2018; 115(46):E10869-E10878 [PubMed] Article available free on PMC after 17/01/2020 Related Publications
Mutations in the

Tinsa F, Bel Hadj I, Riant F, et al.
A novel large deletion in CCM1 gene in a Tunisian family.
Rev Neurol (Paris). 2019; 175(3):194-197 [PubMed] Related Publications
Familial CCM is a rare entity associated with the mutation of three genes: CCM1 (KRIT1), CCM2 (MGC4607), and CCM3 (PDCD10). We report here the first description of a Tunisian familial CCMs composed of six members. The father and two daughters were affected and symptomatic. The two other kindred were healthy. Surgical treatment was performed in only one affected patient. Molecular analysis of KRIT1, MGC4607 and PDCD10 genes identified a large KRIT1 deletion of the first ten exons. To the best of our knowledge, this large deletion has never been reported before.

Gara SK, Lack J, Zhang L, et al.
Metastatic adrenocortical carcinoma displays higher mutation rate and tumor heterogeneity than primary tumors.
Nat Commun. 2018; 9(1):4172 [PubMed] Article available free on PMC after 17/01/2020 Related Publications
Adrenocortical cancer (ACC) is a rare cancer with poor prognosis and high mortality due to metastatic disease. All reported genetic alterations have been in primary ACC, and it is unknown if there is molecular heterogeneity in ACC. Here, we report the genetic changes associated with metastatic ACC compared to primary ACCs and tumor heterogeneity. We performed whole-exome sequencing of 33 metastatic tumors. The overall mutation rate (per megabase) in metastatic tumors was 2.8-fold higher than primary ACC tumor samples. We found tumor heterogeneity among different metastatic sites in ACC and discovered recurrent mutations in several novel genes. We observed 37-57% overlap in genes that are mutated among different metastatic sites within the same patient. We also identified new therapeutic targets in recurrent and metastatic ACC not previously described in primary ACCs.

Pruksakorn D, Klangjorhor J, Lirdprapamongkol K, et al.
Oncogenic roles of serine-threonine kinase receptor-associated protein (STRAP) in osteosarcoma.
Cancer Chemother Pharmacol. 2018; 82(6):1039-1047 [PubMed] Related Publications
PURPOSE: To validate the presence of serine-threonine kinase receptor-associated Protein (STRAP) in osteosarcoma tissue and to investigate the oncological role of STRAP in osteosarcoma.
METHODS: Expression of STRAP protein in osteosarcoma tissue compared to soft callus (hyperactive bone healing tissue) and in multiple cell lines was examined using western blot analysis. Effects of STRAP silencing on cell proliferation, invasion, migration and re-implantability in chick chorioallantoic membrane (CAM) were observed in osteosarcoma cell lines (MNNG-HOS, 143B, and U2OS).
RESULTS: The result demonstrated that STRAP was highly up-regulated in osteosarcoma tissues compared with the normal physiological bone healing tissue (soft callus). Expression level of STRAP was markedly high in osteosarcoma cell lines with aggressive phenotype. Upon STRAP silencing, invasion and migration, but not proliferative activity, were selectively modulated in high-expression-STRAP cell lines. In addition, STRAP silencing reduced the success rate of tumor implantation and growth of MNNG-HOS cells in CAM model.
CONCLUSIONS: Serine-threonine kinase receptor-associated protein is up-regulated during osteosarcoma progression. The presence of STRAP enhances osteosarcoma cell invasion, migration and re-implantation ability, factors which play a critical role in metastasis. Serine-threonine kinase receptor-associated protein and its related pathway are worthy for further exploration as a novel target for anti-metastasis agents.

Wu GJ
METCAM/MUC18 Decreases the Malignant Propensity of Human Ovarian Carcinoma Cells.
Int J Mol Sci. 2018; 19(10) [PubMed] Article available free on PMC after 17/01/2020 Related Publications
METCAM/MUC18 is an integral membrane cell adhesion molecule (CAM) in the Ig-like gene super-family. It can carry out common functions of CAMs which is to perform intercellular interactions and interaction of cell with extracellular matrix in tumor microenvironment, to interact with various signaling pathways and to regulate general behaviors of cells. We and other two groups previously suggested that METCAM/MUC18 probably be utilized as a biomarker for predicting the malignant tendency of clinical ovarian carcinomas, since METAM/MUC18 expression appears to associate with the carcinoma at advanced stages. It has been further postulated to promote the malignant tendency of the carcinoma. However, our recent research results appear to support the conclusion that the above positive correlation is fortuitous; actually METCAM/MUC18 acts as a tumor and metastasis suppressor for the ovarian carcinoma cells. We also suggest possible mechanisms in the METCAM/MUC18-mediated early tumor development and metastasis of ovarian carcinoma. Moreover, we propose to employ recombinant METCAM/MUC18 proteins and other derived products as therapeutic agents to treat the ovarian cancer patients by decreasing the malignant potential of ovarian carcinoma.

Casey RT, Giger O, Seetho I, et al.
Rapid disease progression in a patient with mismatch repair-deficient and cortisol secreting adrenocortical carcinoma treated with pembrolizumab.
Semin Oncol. 2018; 45(3):151-155 [PubMed] Article available free on PMC after 17/01/2020 Related Publications
CONTEXT: Metastatic adrenocortical carcinoma (ACC) is an aggressive malignancy with a poor prognosis and limited therapeutic options. A subset of ACC is due to Lynch syndrome, an inherited tumor syndrome resulting from germline mutations in mismatch repair (MMR) genes. It has been demonstrated that several cancers characterized by MMR deficiency are sensitive to immune checkpoint inhibitors that target PD-1. Here, we provide the first report of PD-1 blockade with pembrolizumab in a patient with Lynch syndrome and progressive cortisol-secreting metastatic ACC.
CASE REPORT: A 58-year-old female with known Lynch syndrome presented with severe Cushing's syndrome and was diagnosed with a cortisol-secreting ACC. Three months following surgical resection and adjuvant mitotane therapy the patient developed metastatic disease and persistent hypercortisolemia. She commenced pembrolizumab, but her second cycle was delayed due to a transient transaminitis. Computed tomography performed after 12 weeks and 2 cycles of pembrolizumab administration revealed significant disease progression and treatment was discontinued. After 7 weeks, the patient became jaundiced and soon died due to fulminant liver failure.
CONCLUSION: Treatment of MMR-deficient cortisol-secreting ACC with pembrolizumab may be ineffective due to supraphysiological levels of circulating corticosteroids, which may in turn mask severe drug-induced organ damage.

Wang Y, Li Y, Zou J, et al.
The cerebral cavernous malformation disease causing gene KRIT1 participates in intestinal epithelial barrier maintenance and regulation.
FASEB J. 2019; 33(2):2132-2143 [PubMed] Article available free on PMC after 17/01/2020 Related Publications
Epithelial barrier maintenance and regulation requires an intact perijunctional actomyosin ring underneath the cell-cell junctions. By searching for known factors affecting the actin cytoskeleton, we identified Krev interaction trapped protein 1 (KRIT1) as a major regulator for epithelial barrier function through multiple mechanisms. KRIT1 is expressed in both small intestinal and colonic epithelium, and KRIT1 knockdown in differentiated Caco-2 intestinal epithelium decreases epithelial barrier function and increases cation selectivity. KRIT1 knockdown abolished Rho-associated protein kinase-induced and myosin II motor inhibitor-induced barrier loss by limiting both small and large molecule permeability but did not affect myosin light chain kinase-induced increases in epithelial barrier function. These data suggest that KRIT1 participates in Rho-associated protein kinase- and myosin II motor-dependent (but not myosin light chain kinase-dependent) epithelial barrier regulation. KRIT1 knockdown exacerbated low-dose TNF-induced barrier loss, along with increased cleaved caspase-3 production. Both events are blocked by pan-caspase inhibition, indicating that KRIT1 regulates TNF-induced barrier loss through limiting epithelial apoptosis. These data indicate that KRIT1 controls epithelial barrier maintenance and regulation through multiple pathways, suggesting that KRIT1 mutation in cerebral cavernous malformation disease may alter epithelial function and affect human health.-Wang, Y., Li, Y., Zou, J., Polster, S. P., Lightle, R., Moore, T., Dimaano, M., He, T.-C., Weber, C. R., Awad, I. A., Shen, L. The cerebral cavernous malformation disease causing gene KRIT1 participates in intestinal epithelial barrier maintenance and regulation.

Mangolini M, Götte F, Moore A, et al.
Notch2 controls non-autonomous Wnt-signalling in chronic lymphocytic leukaemia.
Nat Commun. 2018; 9(1):3839 [PubMed] Article available free on PMC after 17/01/2020 Related Publications
The Wnt signalling pathway, one of the core de-regulated pathways in chronic lymphocytic leukaemia (CLL), is activated in only a subset of patients through somatic mutations. Here we describe alternative, microenvironment-dependent mechanisms of Wnt activation in malignant B cells. We show that tumour cells specifically induce Notch2 activity in mesenchymal stromal cells (MSCs) required for the transcription of the complement factor C1q. MSC-derived C1q in turn inhibits Gsk3-β mediated degradation of β-catenin in CLL cells. Additionally, stromal Notch2 activity regulates N-cadherin expression in CLL cells, which interacts with and further stabilises β-catenin. Together, these stroma Notch2-dependent mechanisms induce strong activation of canonical Wnt signalling in CLL cells. Pharmacological inhibition of the Wnt pathway impairs microenvironment-mediated survival of tumour cells. Similarly, inhibition of Notch signalling diminishes survival of stroma-protected CLL cells in vitro and disease engraftment in vivo. Notch2 activation in the microenvironment is a pre-requisite for the activation of canonical Wnt signalling in tumour cells.

Palin K, Pitkänen E, Turunen M, et al.
Contribution of allelic imbalance to colorectal cancer.
Nat Commun. 2018; 9(1):3664 [PubMed] Article available free on PMC after 17/01/2020 Related Publications
Point mutations in cancer have been extensively studied but chromosomal gains and losses have been more challenging to interpret due to their unspecific nature. Here we examine high-resolution allelic imbalance (AI) landscape in 1699 colorectal cancers, 256 of which have been whole-genome sequenced (WGSed). The imbalances pinpoint 38 genes as plausible AI targets based on previous knowledge. Unbiased CRISPR-Cas9 knockout and activation screens identified in total 79 genes within AI peaks regulating cell growth. Genetic and functional data implicate loss of TP53 as a sufficient driver of AI. The WGS highlights an influence of copy number aberrations on the rate of detected somatic point mutations. Importantly, the data reveal several associations between AI target genes, suggesting a role for a network of lineage-determining transcription factors in colorectal tumorigenesis. Overall, the results unravel the contribution of AI in colorectal cancer and provide a plausible explanation why so few genes are commonly affected by point mutations in cancers.

Gammage PA, Minczuk M
Enhanced Manipulation of Human Mitochondrial DNA Heteroplasmy In Vitro Using Tunable mtZFN Technology.
Methods Mol Biol. 2018; 1867:43-56 [PubMed] Related Publications
As a platform capable of mtDNA heteroplasmy manipulation, mitochondrially targeted zinc-finger nuclease (mtZFN) technology holds significant potential for the future of mitochondrial genome engineering, in both laboratory and clinic. Recent work highlights the importance of finely controlled mtZFN levels in mitochondria, permitting far greater mtDNA heteroplasmy modification efficiencies than observed in early applications. An initial approach, differential fluorescence-activated cell sorting (dFACS), allowing selection of transfected cells expressing various levels of mtZFN, demonstrated improved heteroplasmy modification. A further, key optimization has been the use of an engineered hammerhead ribozyme as a means for dynamic regulation of mtZFN expression, which has allowed the development of a unique isogenic cellular model of mitochondrial dysfunction arising from mutations in mtDNA, known as mTUNE. Protocols detailing these transformative optimizations are described in this chapter.

Kelemen LE, Earp M, Fridley BL, et al.
rs495139 in the TYMS-ENOSF1 Region and Risk of Ovarian Carcinoma of Mucinous Histology.
Int J Mol Sci. 2018; 19(9) [PubMed] Article available free on PMC after 17/01/2020 Related Publications
Thymidylate synthase (TYMS) is a crucial enzyme for DNA synthesis. TYMS expression is regulated by its antisense mRNA, ENOSF1. Disrupted regulation may promote uncontrolled DNA synthesis and tumor growth. We sought to replicate our previously reported association between rs495139 in the

Lazarus KA, Hadi F, Zambon E, et al.
BCL11A interacts with SOX2 to control the expression of epigenetic regulators in lung squamous carcinoma.
Nat Commun. 2018; 9(1):3327 [PubMed] Article available free on PMC after 17/01/2020 Related Publications
Patients diagnosed with lung squamous cell carcinoma (LUSC) have limited targeted therapies. We report here the identification and characterisation of BCL11A, as a LUSC oncogene. Analysis of cancer genomics datasets revealed BCL11A to be upregulated in LUSC but not in lung adenocarcinoma (LUAD). Experimentally we demonstrate that non-physiological levels of BCL11A in vitro and in vivo promote squamous-like phenotypes, while its knockdown abolishes xenograft tumour formation. At the molecular level we found that BCL11A is transcriptionally regulated by SOX2 and is required for its oncogenic functions. Furthermore, we show that BCL11A and SOX2 regulate the expression of several transcription factors, including SETD8. We demonstrate that shRNA-mediated or pharmacological inhibition of SETD8 selectively inhibits LUSC growth. Collectively, our study indicates that BCL11A is integral to LUSC pathology and highlights the disruption of the BCL11A-SOX2 transcriptional programme as a novel candidate for drug development.

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