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KRT8; keratin 8 (12q13)

Gene Summary

Gene:KRT8; keratin 8
Aliases: K8, KO, CK8, CK-8, CYK8, K2C8, CARD2
Location:12q13
Summary:This gene is a member of the type II keratin family clustered on the long arm of chromosome 12. Type I and type II keratins heteropolymerize to form intermediate-sized filaments in the cytoplasm of epithelial cells. The product of this gene typically dimerizes with keratin 18 to form an intermediate filament in simple single-layered epithelial cells. This protein plays a role in maintaining cellular structural integrity and also functions in signal transduction and cellular differentiation. Mutations in this gene cause cryptogenic cirrhosis. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2012]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:keratin, type II cytoskeletal 8
HPRD
Source:NCBI
Updated:12 December, 2014

Gene
Ontology:

What does this gene/protein do?
Show (10)

Pathways:

What pathways are this gene/protein implicaed in?
- Cell Communication KEGG
Data from KEGG and BioCarta [BIOCARTA terms] via CGAP

Cancer Overview

Research Indicators

Publications Per Year (1989-2014)
Graph generated 12 December 2014 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.

  • Keratin-18
  • Phosphoserine
  • Tumor Markers
  • Hepacivirus
  • Breast Cancer
  • Proteomics
  • Tunisia
  • Prostate Cancer
  • Case-Control Studies
  • Apoptosis
  • Papillomaviridae
  • Down-Regulation
  • Keratin-8
  • Squamous Cell Carcinoma
  • Immunohistochemistry
  • Chromosome 12
  • Cell Proliferation
  • Cancer Gene Expression Regulation
  • Transfection
  • Western Blotting
  • Epithelium
  • Androgen Receptors
  • Oligonucleotide Array Sequence Analysis
  • Up-Regulation
  • Neoplasm Invasiveness
  • Nucleic Acid Hybridization
  • Vimentin
  • Brain Tumours
  • siRNA
  • Gene Expression Profiling
  • Ovarian Cancer
  • Tandem Mass Spectrometry
  • Genome-Wide Association Study
  • Liver Cancer
  • Neoplasm Proteins
  • RTPCR
  • Tumor Suppressor Proteins
  • Wilms Tumour
  • Cell Movement
  • Neoplastic Cell Transformation
Tag cloud generated 12 December, 2014 using data from PubMed, MeSH and CancerIndex

Notable (6)

Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Breast CancerKRT8 and Breast Cancer View Publications6
Ovarian CancerKRT8 and Ovarian Cancer View Publications2
Prostate CancerKRT8 and Prostate Cancer View Publications2
Wilms TumourKRT8 and Wilms Tumour View Publications1
Brain Tumours, ChildhoodKRT8 and Brain Tumours View Publications2
Liver CancerKRT8 and Liver Cancer View Publications2

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Related Links

Latest Publications: KRT8 (cancer-related)

Perry JR, Day F, Elks CE, et al.
Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.
Nature. 2014; 514(7520):92-7 [PubMed] Article available free on PMC after 02/04/2015 Related Publications
Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.

Related: Breast Cancer


Cornu M, Oppliger W, Albert V, et al.
Hepatic mTORC1 controls locomotor activity, body temperature, and lipid metabolism through FGF21.
Proc Natl Acad Sci U S A. 2014; 111(32):11592-9 [PubMed] Article available free on PMC after 12/02/2015 Related Publications
The liver is a key metabolic organ that controls whole-body physiology in response to nutrient availability. Mammalian target of rapamycin (mTOR) is a nutrient-activated kinase and central controller of growth and metabolism that is negatively regulated by the tumor suppressor tuberous sclerosis complex 1 (TSC1). To investigate the role of hepatic mTOR complex 1 (mTORC1) in whole-body physiology, we generated liver-specific Tsc1 (L-Tsc1 KO) knockout mice. L-Tsc1 KO mice displayed reduced locomotor activity, body temperature, and hepatic triglyceride content in a rapamycin-sensitive manner. Ectopic activation of mTORC1 also caused depletion of hepatic and plasma glutamine, leading to peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α)-dependent fibroblast growth factor 21 (FGF21) expression in the liver. Injection of glutamine or knockdown of PGC-1α or FGF21 in the liver suppressed the behavioral and metabolic defects due to mTORC1 activation. Thus, mTORC1 in the liver controls whole-body physiology through PGC-1α and FGF21. Finally, mTORC1 signaling correlated with FGF21 expression in human liver tumors, suggesting that treatment of glutamine-addicted cancers with mTOR inhibitors might have beneficial effects at both the tumor and whole-body level.

Related: Liver Cancer Signal Transduction


Aldaz CM, Ferguson BW, Abba MC
WWOX at the crossroads of cancer, metabolic syndrome related traits and CNS pathologies.
Biochim Biophys Acta. 2014; 1846(1):188-200 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
WWOX was cloned as a putative tumor suppressor gene mapping to chromosomal fragile site FRA16D. Deletions affecting WWOX accompanied by loss of expression are frequent in various epithelial cancers. Translocations and deletions affecting WWOX are also common in multiple myeloma and are associated with worse prognosis. Metanalysis of gene expression datasets demonstrates that low WWOX expression is significantly associated with shorter relapse-free survival in ovarian and breast cancer patients. Although somatic mutations affecting WWOX are not frequent, analysis of TCGA tumor datasets led to identifying 44 novel mutations in various tumor types. The highest frequencies of mutations were found in head and neck cancers and uterine and gastric adenocarcinomas. Mouse models of gene ablation led us to conclude that Wwox does not behave as a highly penetrant, classical tumor suppressor gene since its deletion is not tumorigenic in most models and its role is more likely to be of relevance in tumor progression rather than in initiation. Analysis of signaling pathways associated with WWOX expression confirmed previous in vivo and in vitro observations linking WWOX function with the TGFβ/SMAD and WNT signaling pathways and with specific metabolic processes. Supporting these conclusions recently we demonstrated that indeed WWOX behaves as a modulator of TGFβ/SMAD signaling by binding and sequestering SMAD3 in the cytoplasmic compartment. As a consequence progressive loss of WWOX expression in advanced breast cancer would contribute to the pro-metastatic effects resulting from TGFβ/SMAD3 hyperactive signaling in breast cancer. Recently, GWAS and resequencing studies have linked the WWOX locus with familial dyslipidemias and metabolic syndrome related traits. Indeed, gene expression studies in liver conditional KO mice confirmed an association between WWOX expression and lipid metabolism. Finally, very recently the first human pedigrees with probands carrying homozygous germline loss of function WWOX mutations have been identified. These patients are characterized by severe CNS related pathology that includes epilepsy, ataxia and mental retardation. In summary, WWOX is a highly conserved and tightly regulated gene throughout evolution and when defective or deregulated the consequences are important and deleterious as demonstrated by its association not only with poor prognosis in cancer but also with other important human pathologies such as metabolic syndrome and CNS related pathologic conditions.

Related: Cancer Prevention and Risk Reduction


Chao CH, Chang CC, Wu MJ, et al.
MicroRNA-205 signaling regulates mammary stem cell fate and tumorigenesis.
J Clin Invest. 2014; 124(7):3093-106 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
Dysregulation of epigenetic controls is associated with tumorigenesis in response to microenvironmental stimuli; however, the regulatory pathways involved in epigenetic dysfunction are largely unclear. We have determined that a critical epigenetic regulator, microRNA-205 (miR-205), is repressed by the ligand jagged1, which is secreted from the tumor stroma to promote a cancer-associated stem cell phenotype. Knockdown of miR-205 in mammary epithelial cells promoted epithelial-mesenchymal transition (EMT), disrupted epithelial cell polarity, and enhanced symmetric division to expand the stem cell population. Furthermore, miR-205-deficient mice spontaneously developed mammary lesions, while activation of miR-205 markedly diminished breast cancer stemness. These data provide evidence that links tumor microenvironment and microRNA-dependent regulation to disruption of epithelial polarity and aberrant mammary stem cell division, which in turn leads to an expansion of stem cell population and tumorigenesis. This study elucidates an important role for miR-205 in the regulation of mammary stem cell fate, suggesting a potential therapeutic target for limiting breast cancer genesis.

Related: Breast Cancer NOTCH2 gene Signal Transduction


Piao Y, Hung SS, Lim SY, et al.
Efficient generation of integration-free human induced pluripotent stem cells from keratinocytes by simple transfection of episomal vectors.
Stem Cells Transl Med. 2014; 3(7):787-91 [PubMed] Article available free on PMC after 01/01/2015 Related Publications
Keratinocytes represent an easily accessible cell source for derivation of human induced pluripotent stem (hiPS) cells, reportedly achieving higher reprogramming efficiency than fibroblasts. However, most studies utilized a retroviral or lentiviral method for reprogramming of keratinocytes, which introduces undesirable transgene integrations into the host genome. Moreover, current protocols of generating integration-free hiPS cells from keratinocytes are mostly inefficient. In this paper, we describe a more efficient, simple-to-use, and cost-effective method for generating integration-free hiPS cells from keratinocytes. Our improved method using lipid-mediated transfection achieved a reprogramming efficiency of ∼0.14% on average. Keratinocyte-derived hiPS cells showed no integration of episomal vectors, expressed stem cell-specific markers and possessed potentials to differentiate into all three germ layers by in vitro embryoid body formation as well as in vivo teratoma formation. To our knowledge, this represents the most efficient method to generate integration-free hiPS cells from keratinocytes.


Chuang CH, Wang WJ, Li CF, et al.
The combination of the prodrugs perforin-CEBPD and perforin-granzyme B efficiently enhances the activation of caspase signaling and kills prostate cancer.
Cell Death Dis. 2014; 5:e1220 [PubMed] Article available free on PMC after 01/01/2015 Related Publications
The survival of prostate cancer (PrCa) patients is associated with the transition to hormone-independent tumor growth and metastasis. Clinically, the dysregulation of androgen action has been associated with the formation of PrCa and the outcome of androgen deprivation therapy in PrCa. CCAAT/enhancer binding protein delta (CEBPD) is a transcription factor that has been reported to act as an oncogene or tumor suppressor, depending on the extra- and intracellular environments following tumorigenesis. We found that androgen can activate CEBPD transcription by direct binding of the androgen receptor (AR) to the CEBPD promoter region. Increases of suppressor of zeste 12 (SUZ12) and enhancer of zeste homolog 2 (EZH2) attenuated the androgen-induced transcription of CEBPD. Importantly, the increases in E2F1, SUZ12 and EZH2 as well as the inactivation of CEBPD were associated with the clinicopathological variables and survival of PrCa patients. We revealed that caspase 8 (CASP8), an apoptotic initiator, is responsive to CEBPD induction. Reporter and in vivo DNA-binding assays revealed that CEBPD directly binds to and activates CASP8 reporter activity. A prodrug system was developed for therapeutic application in AR-independent or androgen-insensitive PrCa to avoid the epigenetic effects on the suppression of CEBPD expression. Our results showed that the combination of a perforin (PF)-CEBPD prodrug (which increases the level of procaspase-8) and a PF-granzyme B prodrug (which activates CASP8 and caspase 3 (CASP3)) showed an additive effect in triggering the apoptotic pathway and enhancing apoptosis in PrCa cells.

Related: Apoptosis CASP3 E2F1 Transcription Factor Prostate Cancer Signal Transduction AR: androgen receptor


Do SI, Ko E, Kang SY, et al.
Aberrant DNA methylation of integrin α4 in human breast cancer.
Tumour Biol. 2014; 35(7):7079-84 [PubMed] Related Publications
Integrins are cell surface receptors that mediate cell-cell/extracellular interactions and have shown an association with metastasis or transformation in several cancers. However, the correlation between the clinicopathological status of breast cancer and the altered integrin α4 status is not clear. In this study, we investigated DNA methylation of integrin α4 in breast cancer. We retrieved 351 cases of surgically resected breast cancer (290 invasive carcinoma and 61 intraductal carcinoma). Methylation-specific polymerase chain reaction was performed to determine integrin α4 methylation status. Integrin α4 methylation was frequently observed in breast cancer specimens (145/351 cases, 41.3 %). In addition, DNA methylation of integrin α4 showed statistical correlation with HER2 positivity and higher histologic grade (p = 0.001, 0.008 in ductal carcinoma in situ and 0.003 in invasive ductal carcinoma). However, other clinicopathological data such as estrogen receptor, progesterone receptor, metastasis, and TNM status showed no statistical correlation. Moreover, we found that the downregulated expression of integrin α4 in a heavily methylated breast cancer cell line (ZR-75) was restored by treatment with 5-aza-2'deoxycytidine, a DNA methyltransferase inhibitor, implying transcriptional silencing by DNA methylation. We observed that integrin α4 methylation is associated with the histologic grade of tumors and lymph node metastasis. Also, this data supports a previous study that suggested integrin α4 and HER2 are involved in the same signaling pathway. DNA methylation of integrin α4 may be a poor prognostic factor which affects undifferentiated histologic change of breast cancer.

Related: Breast Cancer Signal Transduction


Ko E, Jung G
Positive association of long telomeres with the invasive capacity of hepatocellular carcinoma cells.
Biochem Biophys Res Commun. 2014; 447(2):358-63 [PubMed] Related Publications
Invasion, the representative feature of malignant tumors, leads to an increase in mortality. The malignant liver tumor - hepatocellular carcinoma (HCC) - has an enhanced invasive capacity that results in increased patient mortality. Moreover, this enhanced invasive capacity is due to the up-regulation of invasion promoters such as zinc finger protein SNAI1 (Snail) and matrix metalloproteinases (MMPs), and the down-regulation of invasion suppressor molecules such as E-cadherin. Telomerase reverse transcriptase (TERT), which encodes the catalytic subunit of telomerase, is highly expressed in a variety of invasive cancers, including HCC. Telomerase activation induces telomere elongation, thereby leading to cell immortalization during malignant tumor progression. However, the relationship between telomere length and invasion is yet to be experimentally corroborated. In this paper, we revealed that invasive HCC cells passing through the Matrigel display significantly longer telomeres than non-invasive HCC cells. Moreover, we established a method that can distinguish and sort cells containing long telomeres and short telomeres. Using this system, we observed that the HCC cells containing long telomeres had a high-level expression of invasion-promoting genes and a low-level expression of invasion-suppressing E-cadherin. Furthermore, HCC cells containing long telomeres exhibited a higher invasive capacity than HCC cells containing short telomeres. Taken together, our findings suggest that long telomeres are positively associated with the invasive capacity of HCC cells and may be a potent target for malignant liver cancer treatment.

Related: Liver Cancer


Ko YC, Fang WH, Lin TC, et al.
MicroRNA let-7a-3 gene methylation is associated with karyotyping, CEBPA promoter methylation, and survival in acute myeloid leukemia.
Leuk Res. 2014; 38(5):625-31 [PubMed] Related Publications
Let-7a-3 transcribes the miRNA let-7a, of which the expression is dysregulated in cancer. We evaluated the significance of let-7a-3 gene methylation in patients with de novo acute myeloid leukemia (AML). Let-7a-3 was methylated in 81.1% (73/90), partially methylated in 12.2% (11/90), or unmethylated in 6.7% (6/90) of patients. Let-7a-3 methylation correlated with AML karyotyping and CCAAT/enhancer binding protein α (CEBPA) methylation. Kaplan-Meier survival analysis predicted that let-7a-3 hypermethylation correlated with better survival in AML with hypomethylated CEBPA or with hypomethylated CEBPA without the favorable karyotype. We conclude that let-7a-3 methylation is a positive prognosticator for AML patients with hypomethylated CEBPA.

Related: Acute Myeloid Leukemia (AML)


Sherman-Baust CA, Kuhn E, Valle BL, et al.
A genetically engineered ovarian cancer mouse model based on fallopian tube transformation mimics human high-grade serous carcinoma development.
J Pathol. 2014; 233(3):228-37 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Recent evidence suggests that ovarian high-grade serous carcinoma (HGSC) originates from the epithelium of the fallopian tube. However, most mouse models are based on the previous prevailing view that ovarian cancer develops from the transformation of the ovarian surface epithelium. Here, we report the extensive histological and molecular characterization of the mogp-TAg transgenic mouse, which expresses the SV40 large T-antigen (TAg) under the control of the mouse müllerian-specific Ovgp-1 promoter. Histological analysis of the fallopian tubes of mogp-TAg mice identified a variety of neoplastic lesions analogous to those described as precursors to ovarian HGSC. We identified areas of normal-appearing p53-positive epithelium that are similar to 'p53 signatures' in the human fallopian tube. More advanced proliferative lesions with nuclear atypia and epithelial stratification were also identified that were morphologically and immunohistochemically reminiscent of human serous tubal intraepithelial carcinoma (STIC), a potential precursor of ovarian HGSC. Beside these non-invasive precursor lesions, we also identified invasive adenocarcinoma in the ovaries of 56% of the mice. Microarray analysis revealed several genes differentially expressed between the fallopian tube of mogp-TAg and wild-type (WT) C57BL/6. One of these genes, Top2a, which encodes topoisomerase IIα, was shown by immunohistochemistry to be concurrently expressed with elevated p53 and was specifically elevated in mouse STICs but not in the surrounding tissues. TOP2A protein was also found elevated in human STICs, low-grade and high-grade serous carcinoma. The mouse model reported here displays a progression from normal tubal epithelium to invasive HGSC in the ovary, and therefore closely simulates the current emerging model of human ovarian HGSC pathogenesis. This mouse therefore has the potential to be a very useful new model for elucidating the mechanisms of serous ovarian tumourigenesis, as well as for developing novel approaches for the prevention, diagnosis and therapy of this disease.

Related: Ovarian Cancer TP53


Kim T, Cui R, Jeon YJ, et al.
Long-range interaction and correlation between MYC enhancer and oncogenic long noncoding RNA CARLo-5.
Proc Natl Acad Sci U S A. 2014; 111(11):4173-8 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
The mechanism by which the 8q24 MYC enhancer region, including cancer-associated variant rs6983267, increases cancer risk is unknown due to the lack of protein-coding genes at 8q24.21. Here we report the identification of long noncoding RNAs named cancer-associated region long noncoding RNAs (CARLos) in the 8q24 region. The expression of one of the long noncoding RNAs, CARLo-5, is significantly correlated with the rs6983267 allele associated with increased cancer susceptibility. We also found the MYC enhancer region physically interacts with the active regulatory region of the CARLo-5 promoter, suggesting long-range interaction of MYC enhancer with the CARLo-5 promoter regulates CARLo-5 expression. Finally, we demonstrate that CARLo-5 has a function in cell-cycle regulation and tumor development. Overall, our data provide a key of the mystery of the 8q24 gene desert.

Related: Chromosome 8 Cancer Prevention and Risk Reduction


Yoo HY, Sung MK, Lee SH, et al.
A recurrent inactivating mutation in RHOA GTPase in angioimmunoblastic T cell lymphoma.
Nat Genet. 2014; 46(4):371-5 [PubMed] Related Publications
The molecular mechanisms underlying angioimmunoblastic T cell lymphoma (AITL), a common type of mature T cell lymphoma of poor prognosis, are largely unknown. Here we report a frequent somatic mutation in RHOA (encoding p.Gly17Val) using exome and transcriptome sequencing of samples from individuals with AITL. Further examination of the RHOA mutation encoding p.Gly17Val in 239 lymphoma samples showed that the mutation was specific to T cell lymphoma and was absent from B cell lymphoma. We demonstrate that the RHOA mutation encoding p.Gly17Val, which was found in 53.3% (24 of 45) of the AITL cases examined, is oncogenic in nature using multiple molecular assays. Molecular modeling and docking simulations provided a structural basis for the loss of GTPase activity in the RHOA Gly17Val mutant. Our experimental data and modeling results suggest that the RHOA mutation encoding p.Gly17Val is a driver mutation in AITL. On the basis of these data and through integrated pathway analysis, we build a comprehensive signaling network for AITL oncogenesis.

Related: CGH Signal Transduction RHOA


Abbas M, Kramer MW, Spieker T, et al.
Primary mucinous adenocarcinoma of the renal pelvis with carcinoma in situ in the ureter.
J Egypt Natl Canc Inst. 2014; 26(1):51-4 [PubMed] Related Publications
Primary epithelial tumor of the renal pelvis is rare and only 100 cases are reported in the literature [1]. Histological examination of the tumor showed glands, cysts, and papillae lined by pseudostratified columnar epithelium with hyperchromatic nuclei. Scattered signet ring-type cells were also seen floating in large pools of extracellular mucin. Sections from the ureter showed a component of adenocarcinoma in situ. No invasive tumor was identified in ureteric tissue. One case was reported with carcinoma in situ of the ureter (2). Immunohistochemically: The tumor showed positivity for CK7, CK20, CK8/18, GATA-3, MSH-2, MSH-6, MLH-1, Ber-EP4, and S-100-P with focal positivity for CDX-2, weak positivity for PMS-2 and negativity in TTF-1 and Her-2. Molecular pathological analysis revealed microsatellite stability and without mutation in K-ras-gene. Thus, a diagnosis of mucinous adenocarcinoma of the renal pelvis with in situ adenocarcinoma of the ureter was made.

Related: Kidney Cancer


Wray CJ, Ko TC, Tan FK
Secondary use of existing public microarray data to predict outcome for hepatocellular carcinoma.
J Surg Res. 2014; 188(1):137-42 [PubMed] Related Publications
BACKGROUND: Since 1990, numerous public repositories of microarray data have been created to store vast genomic data sets. Our hypothesis is that a secondary analysis of an available hepatocellular carcinoma (HCC) public data set could generate new findings and additional hypotheses.
METHODS: The Gene Expression Omnibus at the National Center for Biotechnology Information was queried for available data sets specific for 'HCC' and 'clinical data.' Genes that passed filtering and normalization criteria were analyzed using the class comparison and prediction functions in BRB-ArrayTools. Ingenuity pathway analysis software was used to identify potential gene networks up- or down-regulated.
RESULTS: The file GDS274, which measured gene expression in primary HCC lesions with or without hepatic metastases from a cohort of Chinese patients, was identified as an appropriate data set and was imported into BRB-ArrayTools. 9984 genes passed filtering criteria. Clinical data demonstrated alpha fetoprotein (AFP) >100 ng/mL predictive of worse survival (HR 5.87, 95% confidence interval: 1.11-31.0). A class comparison between patients with an AFP >100 and those with AFP <100 demonstrated 92 genes to be differentially expressed. Ingenuity pathway analyses demonstrated the top networks associated with the observed gene expression.
CONCLUSIONS: Using available HCC microarray data, we identified genes differentially expressed based on AFP >100. Canonical pathway analysis demonstrated functional gene pathways and associated upstream regulators. This study maximizes the use of publicly available data by generating new findings. Secondary analyses of these data sets should be considered by investigators before embarking on new genomic experiments.

Related: Liver Cancer


Haery L, Lugo-Picó JG, Henry RA, et al.
Histone acetyltransferase-deficient p300 mutants in diffuse large B cell lymphoma have altered transcriptional regulatory activities and are required for optimal cell growth.
Mol Cancer. 2014; 13:29 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
BACKGROUND: Recent genome-wide studies have shown that approximately 30% of diffuse large B-cell lymphoma (DLBCL) cases harbor mutations in the histone acetyltransferase (HAT) coactivators p300 or CBP. The majority of these mutations reduce or eliminate the catalytic HAT activity. We previously demonstrated that the human DLBCL cell line RC-K8 expresses a C-terminally truncated, HAT-defective p300 protein (p300ΔC-1087), whose expression is essential for cell proliferation.
METHODS: Using results from large-scale DLBCL studies, we have identified and characterized a second C-terminally truncated, HAT-defective p300 mutant, p300ΔC-820, expressed in the SUDHL2 DLBCL cell line. Properties of p300ΔC-820 were characterized in the SUDHL2 DLBCL cell line by Western blotting, co-immunoprecipitation, and shRNA gene knockdown, as well by using cDNA expression vectors for p300ΔC-820 in pull-down assays, transcriptional reporter assays, and immunofluorescence experiments. A mass spectrometry-based method was used to compare the histone acetylation profile of DLBCL cell lines expressing various levels of wild-type p300.
RESULTS: We show that the SUDHL2 cell line expresses a C-terminally truncated, HAT-defective form of p300 (p300ΔC-820), but no wild-type p300. The p300ΔC-820 protein has a wild-type ability to localize to subnuclear "speckles," but has a reduced ability to enhance transactivation by transcription factor REL. Knockdown of p300ΔC-820 in SUDHL2 cells reduced their proliferation and soft agar colony-forming ability. In RC-K8 cells, knockdown of p300ΔC-1087 resulted in increased expression of mRNA and protein for REL target genes A20 and IκBα, two genes that have been shown to limit the growth of RC-K8 cells when overexpressed. Among a panel of B-lymphoma cell lines, low-level expression of full-length p300 protein, which is characteristic of the SUDHL2 and RC-K8 cells, was associated with decreased acetylation of histone H3 at lysines 14 and 18.
CONCLUSIONS: The high prevalence of p300 mutations in DLBCL suggests that HAT-deficient p300 activity defines a subtype of DLBCL, which we have investigated using human DLBCL cell lines RC-K8 and SUDHL2. Our results suggest that truncated p300 proteins contribute to DLBCL cell growth by affecting the expression of specific genes, perhaps through a mechanism that involves alterations in global histone acetylation.


Yoon H, Choi YL, Song JY, et al.
Targeted inhibition of FAK, PYK2 and BCL-XL synergistically enhances apoptosis in ovarian clear cell carcinoma cell lines.
PLoS One. 2014; 9(2):e88587 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Ovarian clear cell carcinoma (OCCC) displays a higher resistance to first line chemotherapy, requiring the development of new therapeutics. We previously identified a frequent chromosomal gain at 8q24 that harbors the focal-adhesion kinase (FAK) gene; the potential of this gene as a therapeutic target remains to be evaluated in OCCCs. We first examined the dependence of OCCCs on FAK and the PI3K/AKT signaling pathway. FAK was overexpressed in 20% of 67 OCCC samples, and this overexpression was correlated with its copy number gain. FAK copy number gains and mutations in PIK3CA accounted for about 40% of OCCC samples, suggesting that the FAK/PI3K/AKT axis is an attractive candidate for targeted therapeutics. We, therefore, treated ovarian cancer cell lines, including OCCC subtypes, with the FAK inhibitors PF-562,271 (PF271), and PF-573,228 (PF228). Ovarian cancer cells were more sensitive to PF271 than PF228. We then searched for single agents that exhibited a synergistic effect on cell death in combination with PF271. We found that co-treatment of PF271 with ABT-737, a BCL-2/BCL-XL antagonist, was profoundly effective at inducing apoptosis. RMGI and OVISE cells were more sensitive to ABT-737 than OVMANA and SKOV3 cells, which have PIK3CA mutations. Mechanistically, PF271 treatment resulted in the transient down-regulation of the anti-apoptotic protein MCL1 via the PI3K/AKT pathway. Therefore, PF271/ABT-737 treatment led to the inhibition of the anti-apoptotic proteins MCL1 and BCL-XL/BCL-2. We suggest that pharmacological inhibition of BCL-XL and FAK/PYK2 can be a potential therapeutic strategy for the treatment of OCCC.

Related: Apoptosis Ovarian Cancer MCL1


Ko HK, Akakura S, Peresie J, et al.
A transgenic mouse model for early prostate metastasis to lymph nodes.
Cancer Res. 2014; 74(3):945-53 [PubMed] Article available free on PMC after 01/02/2015 Related Publications
The emergence of recurrent, metastatic prostate cancer following the failure of androgen-deprivation therapy represents the lethal phenotype of this disease. However, little is known regarding the genes and pathways that regulate this metastatic process, and moreover, it is unclear whether metastasis is an early or late event. The individual genetic loss of the metastasis suppressor, SSeCKS/Gravin/AKAP12 or Rb, genes that are downregulated or deleted in human prostate cancer, results in prostatic hyperplasia. Here, we show that the combined loss of Akap12 and Rb results in prostatic intraepithelial neoplasia (PIN) that fails to progress to malignancy after 18 months. Strikingly, 83% of mice with PIN lesions exhibited metastases to draining lymph nodes, marked by relatively differentiated tumor cells expressing markers of basal (p63, cytokeratin 14) and luminal (cytokeratin 8 and androgen receptor) epithelial cells, although none expressed the basal marker, cytokeratin 5. The finding that PIN lesions contain increased numbers of p63/AR-positive, cytokeratin 5-negative basal cells compared with WT or Akap12-/- prostate lobes suggests that these transitional cells may be the source of the lymph node metastases. Taken together, these data suggest that in the context of Rb loss, Akap12 suppresses the oncogenic proliferation and early metastatic spread of basal-luminal prostate tumor cells.

Related: Prostate Cancer RB1


Salhia B, Kiefer J, Ross JT, et al.
Integrated genomic and epigenomic analysis of breast cancer brain metastasis.
PLoS One. 2014; 9(1):e85448 [PubMed] Article available free on PMC after 01/02/2015 Related Publications
The brain is a common site of metastatic disease in patients with breast cancer, which has few therapeutic options and dismal outcomes. The purpose of our study was to identify common and rare events that underlie breast cancer brain metastasis. We performed deep genomic profiling, which integrated gene copy number, gene expression and DNA methylation datasets on a collection of breast brain metastases. We identified frequent large chromosomal gains in 1q, 5p, 8q, 11q, and 20q and frequent broad-level deletions involving 8p, 17p, 21p and Xq. Frequently amplified and overexpressed genes included ATAD2, BRAF, DERL1, DNMTRB and NEK2A. The ATM, CRYAB and HSPB2 genes were commonly deleted and underexpressed. Knowledge mining revealed enrichment in cell cycle and G2/M transition pathways, which contained AURKA, AURKB and FOXM1. Using the PAM50 breast cancer intrinsic classifier, Luminal B, Her2+/ER negative, and basal-like tumors were identified as the most commonly represented breast cancer subtypes in our brain metastasis cohort. While overall methylation levels were increased in breast cancer brain metastasis, basal-like brain metastases were associated with significantly lower levels of methylation. Integrating DNA methylation data with gene expression revealed defects in cell migration and adhesion due to hypermethylation and downregulation of PENK, EDN3, and ITGAM. Hypomethylation and upregulation of KRT8 likely affects adhesion and permeability. Genomic and epigenomic profiling of breast brain metastasis has provided insight into the somatic events underlying this disease, which have potential in forming the basis of future therapeutic strategies.

Related: Breast Cancer


Ko JH, Gu W, Lim I, et al.
Ion channel gene expression in lung adenocarcinoma: potential role in prognosis and diagnosis.
PLoS One. 2014; 9(1):e86569 [PubMed] Article available free on PMC after 01/02/2015 Related Publications
Ion channels are known to regulate cancer processes at all stages. The roles of ion channels in cancer pathology are extremely diverse. We systematically analyzed the expression patterns of ion channel genes in lung adenocarcinoma. First, we compared the expression of ion channel genes between normal and tumor tissues in patients with lung adenocarcinoma. Thirty-seven ion channel genes were identified as being differentially expressed between the two groups. Next, we investigated the prognostic power of ion channel genes in lung adenocarcinoma. We assigned a risk score to each lung adenocarcinoma patient based on the expression of the differentially expressed ion channel genes. We demonstrated that the risk score effectively predicted overall survival and recurrence-free survival in lung adenocarcinoma. We also found that the risk scores for ever-smokers were higher than those for never-smokers. Multivariate analysis indicated that the risk score was a significant prognostic factor for survival, which is independent of patient age, gender, stage, smoking history, Myc level, and EGFR/KRAS/ALK gene mutation status. Finally, we investigated the difference in ion channel gene expression between the two major subtypes of non-small cell lung cancer: adenocarcinoma and squamous-cell carcinoma. Thirty ion channel genes were identified as being differentially expressed between the two groups. We suggest that ion channel gene expression can be used to improve the subtype classification in non-small cell lung cancer at the molecular level. The findings in this study have been validated in several independent lung cancer cohorts.

Related: Lung Cancer


Lee KH, Kim HS, Han BK, et al.
Incidence and predictive factors of inadequate fine-needle aspirates for BRAF(V600E) mutation analysis in thyroid nodules.
AJR Am J Roentgenol. 2014; 202(2):391-6 [PubMed] Related Publications
OBJECTIVE: BRAF(V600E) mutation (valine-to-glutamate substitution at residue 600 of the B-type Raf kinase gene) analysis from thyroid aspirates is increasingly used as a prognostic or diagnostic marker. However, it is limited under some conditions. The purpose of this study was to assess the incidence and predictive factors of thyroid nodules with specimens inadequate for BRAF(V600E) mutation analysis.
MATERIALS AND METHODS: We performed a retrospective cohort study of consecutive patients who underwent ultrasound-guided fine-needle aspiration (FNA) and molecular testing of aspiration specimens. Patients who had inadequate specimens in both allele-specific polymerase chain reaction and direct DNA-sequencing methods were selected. Univariate and multivariate logistic regression analyses were performed to identify predictive factors of specimens inadequate for molecular tests.
RESULTS: Specimens inadequate for BRAF(V600E) mutation analysis were seen in 168 of 7001 (2.4%) patients. Factors, including patient age and sex, nodule size, ultrasound diagnosis, the presence of calcification, and cystic changes within thyroid nodules, were not significant predictors of inadequate mutation analysis. Oval-to-round or irregular shapes (e.g., not taller-than-wide) and final benign results were significant factors in univariate analysis (p = 0.0002 and p = 0.0013, respectively). However, nodules aspirated by operators with less than 1 year of experience (odds ratio [OR], 3.005; p = 0.0070), and those that had spiculated margins (OR, 6.139; p = 0.0142), isoechogenicity (OR, 10.374; p = 0.0442), or nondiagnostic cytologic findings (OR, 73.637; p = 0.0055) remained significant risk factors after adjustment in multivariable analysis.
CONCLUSION: Thyroid nodule specimens inadequate for BRAF(V600E) mutation analysis were frequently associated with FNA aspiration performed by inexperienced operators, nondiagnostic cytologic findings, benign nodules on final diagnosis, and probably benign ultrasound findings, such as isoechogenicity and not-taller-than-wide shape.

Related: BRAF gene Thyroid Cancer


Ko JC, Chiu HC, Syu JJ, et al.
Tamoxifen enhances erlotinib-induced cytotoxicity through down-regulating AKT-mediated thymidine phosphorylase expression in human non-small-cell lung cancer cells.
Biochem Pharmacol. 2014; 88(1):119-27 [PubMed] Related Publications
Tamoxifen is a triphenylethylene nonsteroidal estrogen receptor (ER) antagonist used worldwide as an adjuvant hormone therapeutic agent in the treatment of breast cancer. However, the molecular mechanism of tamoxifen-induced cytotoxicity in non-small cell lung cancer (NSCLC) cells has not been identified. Thymidine phosphorylase (TP) is an enzyme of the pyrimidine salvage pathway which is upregulated in cancers. In this study, tamoxifen treatment inhibited cell survival in two NSCLC cells, H520 and H1975. Treatment with tamoxifen decreased TP mRNA and protein levels through AKT inactivation. Furthermore, expression of constitutively active AKT (AKT-CA) vectors significantly rescued the decreased TP protein and mRNA levels in tamoxifen-treated NSCLC cells. In contrast, combination treatment with PI3K inhibitors (LY294002 or wortmannin) and tamoxifen further decreased the TP expression and cell viability of NSCLC cells. Knocking down TP expression by transfection with small interfering RNA of TP enhanced the cytotoxicity and cell growth inhibition of tamoxifen. Erlotinib (Tarceva, OSI-774), an orally available small molecular inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, is approved for clinical treatment of NSCLC. Compared to a single agent alone, tamoxifen combined with erlotinib resulted in cytotoxicity and cell growth inhibition synergistically in NSCLC cells, accompanied with reduced activation of phospho-AKT and phospho-ERK1/2, and reduced TP protein levels. These findings may have implications for the rational design of future drug regimens incorporating tamoxifen and erlotinib for the treatment of NSCLC.

Related: Non-Small Cell Lung Cancer Lung Cancer AKT1 Erlotinib (Tarceva)


Wang L, Zhao Z, Meyer MB, et al.
CARM1 methylates chromatin remodeling factor BAF155 to enhance tumor progression and metastasis.
Cancer Cell. 2014; 25(1):21-36 [PubMed] Article available free on PMC after 01/02/2015 Related Publications
Coactivator-associated arginine methyltransferase 1 (CARM1), a coactivator for various cancer-relevant transcription factors, is overexpressed in breast cancer. To elucidate the functions of CARM1 in tumorigenesis, we knocked out CARM1 from several breast cancer cell lines using Zinc-Finger Nuclease technology, which resulted in drastic phenotypic and biochemical changes. The CARM1 KO cell lines enabled identification of CARM1 substrates, notably the SWI/SNF core subunit BAF155. Methylation of BAF155 at R1064 was found to be an independent prognostic biomarker for cancer recurrence and to regulate breast cancer cell migration and metastasis. Furthermore, CARM1-mediated BAF155 methylation affects gene expression by directing methylated BAF155 to unique chromatin regions (e.g., c-Myc pathway genes). Collectively, our studies uncover a mechanism by which BAF155 acquires tumorigenic functions via arginine methylation.

Related: Breast Cancer


Zhang B, Chen J, Cheng AS, Ko BC
Depletion of sirtuin 1 (SIRT1) leads to epigenetic modifications of telomerase (TERT) gene in hepatocellular carcinoma cells.
PLoS One. 2014; 9(1):e84931 [PubMed] Article available free on PMC after 01/02/2015 Related Publications
Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase that is implicated in plethora of biological processes, including metabolism, aging, stress response, and tumorigenesis. Telomerase (TERT) is essential for telomere maintenance. Activation of TERT is considered a crucial step in tumorigenesis, and therefore it is a potential therapeutic target against cancer. We have recently found that SIRT1 expression is highly elevated in hepatocellular carcinoma, and the depletion of SIRT1 leads to substantial reduction in TERT mRNA and protein expression. However, the underlying molecular mechanism of SIRT1-dependent TERT expression remains uncharacterized. Here, we elucidated if SIRT1 regulates TERT expression via transcriptional, epigenetic and post-transcriptional mechanisms. We report that depletion of SIRT1 does not lead to significant change in transcriptional activity and CpG methylation patterns of the TERT promoter, nor does it affect mRNA stability or 3'-UTR regulation of TERT. Intriguingly, depletion of SIRT1 is associated with substantial induction of acetylated histone H3-K9 and reduction of trimethyl H3-K9 at the TERT gene, which are known to be associated with gene activation. Our data revealed that SIRT1 regulates histone acetylation and methylation at the TERT promoter. We postulated that SIRT1 may regulate TERT expression via long-range interaction, or via yet unidentified histone modifications.

Related: Liver Cancer


Choi EJ, Yun JA, Jeon EK, et al.
Prognostic significance of RSPO1, WNT1, P16, WT1, and SDC1 expressions in invasive ductal carcinoma of the breast.
World J Surg Oncol. 2013; 11:314 [PubMed] Article available free on PMC after 01/02/2015 Related Publications
BACKGROUND: To better understand the mechanisms of the SDC1 expression in invasive ductal carcinoma, we studied the correlations between SDC1 expression and related gene expressions (RSPO1, WNT1, WT1, and P16).
METHODS: Using 100 cases of invasive ductal carcinoma tissue, we screened expressions of RSPO1, WNT1, WT1, P16, and SDC1 using immunohistochemistry. We analyzed the association between the immunoreactivities and clinicopathological parameters.
RESULTS: WT1 expression was associated with tumor grade. RSPO1 expression was associated with progesterone receptor expression. Expressions of RSPO1, WT1, and P16 were significantly associated with disease-free survival. RSPO1 and P16 showed statistically significant hazard ratios. SDC1 ectodomain expression was significantly associated only with P16 expression. Immunoreactivity of SDC1 cytoplasmic domain was associated with WT1 and WNT1. However, WNT1 expression failed to show a significant association with disease-free survival.
CONCLUSIONS: RSPO1 and P16 immunoreactivity was found to be an independent prognostic indicator in invasive ductal cancer. Cytoplasmic expression of SDC1 is positively correlated with tumor-prone proteins (WT1 and WNT1) and membranous expression of SDC1 is positively correlated with the tumor suppressor (P16).

Related: Breast Cancer WT1 SDC1


Yu H, Pak H, Hammond-Martel I, et al.
Tumor suppressor and deubiquitinase BAP1 promotes DNA double-strand break repair.
Proc Natl Acad Sci U S A. 2014; 111(1):285-90 [PubMed] Article available free on PMC after 01/02/2015 Related Publications
The cellular response to highly genotoxic DNA double-strand breaks (DSBs) involves the exquisite coordination of multiple signaling and repair factors. Here, we conducted a functional RNAi screen and identified BAP1 as a deubiquitinase required for efficient assembly of the homologous recombination (HR) factors BRCA1 and RAD51 at ionizing radiation (IR) -induced foci. BAP1 is a chromatin-associated protein frequently inactivated in cancers of various tissues. To further investigate the role of BAP1 in DSB repair, we used a gene targeting approach to knockout (KO) this deubiquitinase in chicken DT40 cells. We show that BAP1-deficient cells are (i) sensitive to IR and other agents that induce DSBs, (ii) defective in HR-mediated immunoglobulin gene conversion, and (iii) exhibit an increased frequency of chromosomal breaks after IR treatment. We also show that BAP1 is recruited to chromatin in the proximity of a single site-specific I-SceI-induced DSB. Finally, we identified six IR-induced phosphorylation sites in BAP1 and showed that mutation of these residues inhibits BAP1 recruitment to DSB sites. We also found that both BAP1 catalytic activity and its phosphorylation are critical for promoting DNA repair and cellular recovery from DNA damage. Our data reveal an important role for BAP1 in DSB repair by HR, thereby providing a possible molecular basis for its tumor suppressor function.

Related: Cancer Prevention and Risk Reduction BAP1 gene


Choi YK, Woo SM, Cho SG, et al.
Brain-metastatic triple-negative breast cancer cells regain growth ability by altering gene expression patterns.
Cancer Genomics Proteomics. 2013 Nov-Dec; 10(6):265-75 [PubMed] Related Publications
UNLABELLED: BACKGROUD/AIM: Triple-negative breast cancer (TNBC) frequently metastasizes to the brain (BrM). However, genes responsible for BrM of TNBC are yet to be identified.
MATERIALS AND METHODS: Gene expression profiling of TNBC and BrM was conducted, and studies with cultured cells in vitro were performed to verify functions of genes identified in these analyses.
RESULTS: According to gene expression analyses of TNBC and BrM, periplakin (PPL) and mitogen-activated protein kinase 13 (MAPK13) were chosen for further investigations. PPL and MAPK13 were highly expressed in TNBC compared to BrM. While silencing of either PPL or MAPK13 in TNBC cells increased cell growth and reduced cell motility, overexpression of either PPL or MAPK13 in BrM cells, retarded growth rates and facilitated cell motility.
CONCLUSION: Gene expression patterns in TNBC and BrM reflect cancer cell growth in regions of metastasis.

Related: Apoptosis


Huang WC, Chan SH, Jang TH, et al.
miRNA-491-5p and GIT1 serve as modulators and biomarkers for oral squamous cell carcinoma invasion and metastasis.
Cancer Res. 2014; 74(3):751-64 [PubMed] Related Publications
MicroRNAs offer tools to identify and treat invasive cancers. Using highly invasive isogenic oral squamous cell carcinoma (OSCC) cells, established using in vitro and in vivo selection protocols from poorly invasive parental cell populations, we used microarray expression analysis to identify a relative and specific decrease in miR-491-5p in invasive cells. Lower expression of miR-491-5p correlated with poor overall survival of patients with OSCCs. miR-491-5p overexpression in invasive OSCC cells suppressed their migratory behavior in vitro and lung metastatic behavior in vivo. We defined the G-protein-coupled receptor kinase-interacting protein 1 (GIT1)-as a direct target gene for miR-491-5p control. GIT1 overexpression was sufficient to rescue miR-491-5p-mediated inhibition of migration/invasion and lung metastasis. Conversely, GIT1 silencing phenocopied the ability of miR-491-5p to inhibit migration/invasion and metastasis of OSCC cells. Mechanistic investigations indicated that miR-491-5p overexpression or GIT1 attenuation reduced focal adhesions, with a concurrent decrease in steady-state levels of paxillin, phospho-paxillin, phospho-FAK, EGF/EGFR-mediated extracellular signal-regulated kinase (ERK1/2) activation, and MMP2/9 levels and activities. In clinical specimens of OSCCs, GIT1 levels were elevated relative to paired normal tissues and were correlated with lymph node metastasis, with expression levels of miR-491-5p and GIT1 correlated inversely in OSCCs, where they informed tumor grade. Together, our findings identify a functional axis for OSCC invasion that suggests miR-491-5p and GIT1 as biomarkers for prognosis in this cancer.

Related: MMP2 MMP9: matrix metallopeptidase 9 Oral Cancer Signal Transduction


Cho YB, Hong HK, Choi YL, et al.
Colorectal cancer patient-derived xenografted tumors maintain characteristic features of the original tumors.
J Surg Res. 2014; 187(2):502-9 [PubMed] Related Publications
BACKGROUND: Despite significant improvements in colon cancer outcomes over the past few decades, preclinical development of more effective therapeutic strategies is still limited by the availability of clinically relevant animal models. To meet those clinical unmet needs, we generated a well-characterized in vivo preclinical platform for colorectal cancer using fresh surgical samples.
METHODS: Primary and metastatic colorectal tumor tissues (1-2 mm(3)) that originate from surgery were implanted into the subcutaneous space of nude mice and serially passaged in vivo. Mutation status, hematoxylin and eosin staining, short tandem repeat profiling, and array comparative genomic hybridization were used to validate the similarity of molecular characteristics between the patient tumors and tumors obtained from xenografts.
RESULTS: From surgical specimens of 143 patients, 97 xenograft models were obtained in immunodeficient mice (establish rate = 67%). Thirty-nine xenograft models were serially expanded further in mice with a mean time to reach a size of 1000-1500 mm(3) of 90 ± 20 d. Histologic and immunohistochemical analyses revealed a high degree of pathologic similarity including histologic architecture and expression of CEA, CK7, and CD20 between the patient and xenograft tumors. Molecular analysis showed that genetic mutations, genomic alterations, and gene expression patterns of each patient tumor were also well conserved in the corresponding xenograft tumor.
CONCLUSIONS: Xenograft animal models derived from fresh surgical sample maintained the key characteristic features of the original tumors, suggesting that this in vivo platform can be useful for preclinical development of novel therapeutic approaches to colorectal cancers.

Related: Colorectal (Bowel) Cancer


Ko SY, Ladanyi A, Lengyel E, Naora H
Expression of the homeobox gene HOXA9 in ovarian cancer induces peritoneal macrophages to acquire an M2 tumor-promoting phenotype.
Am J Pathol. 2014; 184(1):271-81 [PubMed] Article available free on PMC after 01/01/2015 Related Publications
Tumor-associated macrophages (TAMs) exhibit an M2 macrophage phenotype that suppresses anti-tumor immune responses and often correlates with poor outcomes in patients with cancer. Patients with ovarian cancer frequently present with peritoneal carcinomatosis, but the mechanisms that induce naïve peritoneal macrophages into TAMs are poorly understood. In this study, we found an increased abundance of TAMs in mouse i.p. xenograft models of ovarian cancer that expressed HOXA9, a homeobox gene that is associated with poor prognosis in patients with ovarian cancer. HOXA9 expression in ovarian cancer cells stimulated chemotaxis of peritoneal macrophages and induced macrophages to acquire TAM-like features. These features included induction of the M2 markers, CD163 and CD206, and the immunosuppressive cytokines, IL-10 and chemokine ligand 17, and down-regulation of the immunostimulatory cytokine, IL-12. HOXA9-mediated induction of TAMs was primarily due to the combinatorial effects of HOXA9-induced, tumor-derived transforming growth factor-β2 and chemokine ligand 2 levels. High HOXA9 expression in clinical specimens of ovarian cancer was strongly associated with increased abundance of TAMs and intratumoral T-regulatory cells and decreased abundance of CD8(+) tumor-infiltrating lymphocytes. Levels of immunosuppressive cytokines were also elevated in ascites fluid of patients with tumors that highly expressed HOXA9. HOXA9 may, therefore, stimulate ovarian cancer progression by promoting an immunosuppressive microenvironment via paracrine effects on peritoneal macrophages.

Related: Ovarian Cancer HOXA9 gene


Ko JS, Billings SD, Lanigan CP, et al.
Fully automated dual-color dual-hapten silver in situ hybridization staining for MYC amplification: a diagnostic tool for discriminating secondary angiosarcoma.
J Cutan Pathol. 2014; 41(3):286-92 [PubMed] Related Publications
BACKGROUND: MYC amplification occurs in post-radiation and chronic lymphedema-associated secondary angiosarcoma and some primary angiosarcomas. In this study, we tested the ability of automated dual-color dual-hapten in situ hybridization (DISH) staining to discriminate secondary angiosarcoma from radiation-associated atypical vascular lesions (AVL), and to correlate with fluorescence in situ hybridization (FISH) for MYC amplification.
METHODS: Cases of secondary angiosarcoma, including 11 biopsies and 3 excisions from 11 patients, and 5 AVL biopsies from 5 patients, were examined by FISH and DISH. DISH staining was performed using the Dual Color Open Probe software on a Ventana Benchmark XT automated slide stainer. Metallic black silver (MYC) and reference CHR8 red signals were qualitatively and semi-quantitatively enumerated for tumor nuclei. Small and large clusters of silver signals were recorded as 6 or 12 signals, respectively. MYC amplification was defined as MYC/CHR8 ratio >2.0.
RESULTS: Where tissue was available for both DISH and FISH, all secondary angiosarcoma cases showed MYC amplification (11/11 = 100%) by both DISH and FISH. All AVL were negative for MYC amplification by both techniques (0/5 = 0%).
CONCLUSION: In the current cohort, use of DISH identified all MYC amplified cases, and distinguished secondary angiosarcoma from AVL. DISH staining may be useful in distinguishing secondary angiosarcoma from AVL in challenging cases.

Related: Skin Cancer


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Cite this page: Cotterill SJ. KRT8, Cancer Genetics Web: http://www.cancerindex.org/geneweb/KRT8.htm Accessed: date

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