CHIA

Gene Summary

Gene:CHIA; chitinase, acidic
Aliases: CHIT2, AMCASE, TSA1902
Location:1p13.2
Summary:The protein encoded by this gene degrades chitin, which is found in the cell wall of most fungi as well as in arthropods and some nematodes. The encoded protein can also stimulate interleukin 13 expression, and variations in this gene can lead to asthma susceptibility. Several transcript variants encoding a few different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:acidic mammalian chitinase
HPRD
Source:NCBIAccessed: 17 August, 2015

Ontology:

What does this gene/protein do?
Show (22)
Pathways:What pathways are this gene/protein implicaed in?
Show (1)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 17 August 2015 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.

  • Chromosome 1
  • Gene Expression Profiling
  • Messenger RNA
  • Lung Cancer
  • Case-Control Studies
  • Cohort Studies
  • Breast Cancer
  • Apoptosis
  • DNA-Binding Proteins
  • Adenocarcinoma
  • Prostate Cancer
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins
  • Risk Factors
  • Nasopharyngeal Cancer
  • Promoter Regions
  • DNA Methylation
  • Cell Proliferation
  • SOXB1 Transcription Factors
  • Colorectal Cancer
  • Cancer Gene Expression Regulation
  • Single Nucleotide Polymorphism
  • p21-Activated Kinases
  • Asian Continental Ancestry Group
  • Tumor Markers
  • Radiotherapy, Adjuvant
  • Neoplasm Proteins
  • Mice, Inbred BALB C
  • Staging
  • Oligonucleotide Array Sequence Analysis
  • Mutation
  • Estrogen Receptors
  • beta-Galactosidase
  • Genetic Predisposition
  • Antineoplastic Agents
  • Immunohistochemistry
  • Genotype
  • Adjuvant Chemotherapy
  • Transcription
  • Logistic Models
Tag cloud generated 17 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

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: CHIA (cancer-related)

Michailidou K, Beesley J, Lindstrom S, et al.
Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer.
Nat Genet. 2015; 47(4):373-80 [PubMed] Related Publications
Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1.

Bertrand D, Chng KR, Sherbaf FG, et al.
Patient-specific driver gene prediction and risk assessment through integrated network analysis of cancer omics profiles.
Nucleic Acids Res. 2015; 43(7):e44 [PubMed] Free Access to Full Article Related Publications
Extensive and multi-dimensional data sets generated from recent cancer omics profiling projects have presented new challenges and opportunities for unraveling the complexity of cancer genome landscapes. In particular, distinguishing the unique complement of genes that drive tumorigenesis in each patient from a sea of passenger mutations is necessary for translating the full benefit of cancer genome sequencing into the clinic. We address this need by presenting a data integration framework (OncoIMPACT) to nominate patient-specific driver genes based on their phenotypic impact. Extensive in silico and in vitro validation helped establish OncoIMPACT's robustness, improved precision over competing approaches and verifiable patient and cell line specific predictions (2/2 and 6/7 true positives and negatives, respectively). In particular, we computationally predicted and experimentally validated the gene TRIM24 as a putative novel amplified driver in a melanoma patient. Applying OncoIMPACT to more than 1000 tumor samples, we generated patient-specific driver gene lists in five different cancer types to identify modes of synergistic action. We also provide the first demonstration that computationally derived driver mutation signatures can be overall superior to single gene and gene expression based signatures in enabling patient stratification and prognostication. Source code and executables for OncoIMPACT are freely available from http://sourceforge.net/projects/oncoimpact.

Sun QY, Ding LW, Xiao JF, et al.
SETDB1 accelerates tumourigenesis by regulating the WNT signalling pathway.
J Pathol. 2015; 235(4):559-70 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
We investigated the oncogenic role of SETDB1, focusing on non-small cell lung cancer (NSCLC), which has high expression of this protein. A total of 387 lung cancer cases were examined by immunohistochemistry; 72% of NSCLC samples were positive for SETDB1 staining, compared to 46% samples of normal bronchial epithelium (106 cases) (p <0.0001). The percentage of positive cells and the intensity of staining increased significantly with increased grade of disease. Forced expression of SETDB1 in NSCLC cell lines enhanced their clonogenic growth in vitro and markedly increased tumour size in a murine xenograft model, while silencing (shRNA) SETDB1 in NSCLC cells slowed their proliferation. SETDB1 positively stimulated activity of the WNT-β-catenin pathway and diminished P53 expression, resulting in enhanced NSCLC growth in vitro and in vivo. Our finding suggests that therapeutic targeting of SETDB1 may benefit patients whose tumours express high levels of SETDB1.

Shan YS, Chen YL, Lai MD, Hsu HP
Nestin predicts a favorable prognosis in early ampullary adenocarcinoma and functions as a promoter of metastasis in advanced cancer.
Oncol Rep. 2015; 33(1):40-8 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
Nestin exhibits stemness characteristics and is overexpressed in several types of cancers. Downstream signaling of nestin [cyclin-dependent kinase 5 (CDK5) and Ras-related C3 botulinum toxin substrate 1 (Rac1)] functions in cancer to modulate cellular behaviors. We studied the function of nestin in ampullary adenocarcinoma. Immunohistochemistry (IHC), reverse transcription-polymerase chain reaction, and cDNA microarray of nestin in ampullary adenocarcinoma was compared with normal duodenum. CDK5 and Rac1 were assessed by western blotting. We hypothesized that nestin/CDK5/Rac1 signaling behaves different in early and advanced cancer. We found that the presence of nestin mRNA was increased in the early stages of cancer (T2N0 or T3N0) and advanced cancer with lymph node metastasis (T4N1). A total of 102 patients were enrolled in the IHC staining. Weak nestin expression was correlated with favorable characteristics of cancer, decreased incidence of local recurrence and lower risk of recurrence within 12 months after surgery. Patients with weak nestin expression had the most favorable recurrence‑free survival rates. Patients with mild to strong nestin expression exhibited an advanced behavior of cancer and increased possibility of cancer recurrence. The reciprocal expression of nestin and RAC1 were explored using a cDNA microarray analysis in the early stages of ampullary adenocarcinoma. Increased level of CDK5 with simultaneously decreased expression of Rac1 was detected by western blotting of ampullary adenocarcinoma in patients without cancer recurrence. The activation of multiple oncogenic pathways, combined with the stemness characteristics of nestin, formed a complex network in advanced ampullary adenocarcinoma. Our study demonstrated that nestin performs a dual role in ampullary adenocarcinoma. Appropriate amount of nestin enhances CDK5 function to suppress Rac1 and excessive nestin/CDK5 participates in multiple oncogenic pathways to promote cancer invasiveness. Inhibiting nestin in patients who exhibit nestin‑overexpressed ampullary adenocarcinoma may be a method of preventing cancer recurrence.

Shan YS, Hsu HP, Lai MD, et al.
Increased expression of argininosuccinate synthetase protein predicts poor prognosis in human gastric cancer.
Oncol Rep. 2015; 33(1):49-57 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
Aberrant expression of argininosuccinate synthetase (ASS1, also known as ASS) has been found in cancer cells and is involved in the carcinogenesis of gastric cancer. The aim of the present study was to investigate the level of ASS expression in human gastric cancer and to determine the possible correlations between ASS expression and clinicopathological findings. Immunohistochemistry was performed on paraffin‑embedded tissues to determine whether ASS was expressed in 11 of 11 specimens from patients with gastric cancer. The protein was localized primarily to the cytoplasm of cancer cells and normal epithelium. In the Oncomine cancer microarray database, expression of the ASS gene was significantly increased in gastric cancer tissues. To investigate the clinicopathological and prognostic roles of ASS expression, we performed western blot analysis of 35 matched specimens of gastric adenocarcinomas and normal tissue obtained from patients treated at the National Cheng Kung University Hospital. The ratio of relative ASS expression (expressed as the ASS/β-actin ratio) in tumor tissues to that in normal tissues was correlated with large tumor size (P=0.007) and with the tumor, node, metastasis (TNM) stage of the American Joint Committee on Cancer staging system (P=0.031). Patients whose cancer had increased the relative expression of ASS were positive for perineural invasion and had poor recurrence-free survival. In summary, ASS expression in gastric cancer was associated with a poor prognosis. Further study of mechanisms to silence the ASS gene or decrease the enzymatic activity of ASS protein has the potential to provide new treatments for patients with gastric cancer.

Wei F, Lin CC, Joon A, et al.
Noninvasive saliva-based EGFR gene mutation detection in patients with lung cancer.
Am J Respir Crit Care Med. 2014; 190(10):1117-26 [PubMed] Related Publications
RATIONALE: Constitutive activation of the epidermal growth factor receptor (EGFR) is prevalent in epithelial cancers, particularly in non-small cell lung carcinoma (NSCLC). Mutations identified in EGFR predict the sensitivity to EGFR-targeted therapy. Detection of these mutations is mainly based on tissue biopsy, which is invasive, expensive, and time consuming.
OBJECTIVES: Noninvasive, real-time, inexpensive detection and monitoring of EGFR mutations in patients with NSCLC is highly desirable.
METHODS: We developed a novel core technology, electric field-induced release and measurement (EFIRM), which relies on a multiplexible electrochemical sensor that can detect EGFR mutations directly in bodily fluids.
MEASUREMENTS AND MAIN RESULTS: We established EFIRM for the detection of the EGFR mutations in vitro and correlated the results with tumor size from xenografted mice. In clinical application, we demonstrated that EFIRM could detect EGFR mutations in the saliva and plasma of 22 patients with NSCLC. Finally, a blinded test was performed on saliva samples from 40 patients with NSCLC. The receiver operating characteristic analysis indicated that EFIRM detected the exon 19 deletion with an area under the curve of 0.94 and the L858R mutation with an area under the curve of 0.96.
CONCLUSIONS: Our data indicate that EFIRM is effective, accurate, rapid, user-friendly, and cost effective for the detection of EGFR mutations in the saliva of patients with NSCLC. We termed this saliva-based EGFR mutation detection (SABER).

Keld R, Thian M, Hau C, et al.
Polymorphisms of MTHFR and susceptibility to oesophageal adenocarcinoma in a Caucasian United Kingdom population.
World J Gastroenterol. 2014; 20(34):12212-6 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
AIM: To identify if methylene tetra-hydrofolatereductase (MTHFR) C677T polymorphisms are associated with oesophageal adenocarcinomas in a Caucasian population and to test whether folic acid and homocysteine levels are linked with cancer risk.
METHODS: A case control study comprising of 58 non cancer and 48 cancer patients, MTHFR C667T genotyping was made and serum folate, homocysteine and vitamin B12 levels were made. Tumour stage, differentiation and survival was recorded. A P value of less than 0.05 was taken to be significant. The χ(2) used to compare discrete variables and the Mantel-Cox was used to compare survival. A P value less than 0.05 was deemed to be significant.
RESULTS: MTHFR polymorphisms is associated with an increased risk of several cancers. A link between MTHFR C677T polymorphisms and oesophageal squamous cell carcinoma and gastric cardia adenocarcinoma has been demonstrated in at risk Chinese populations. In a Western European population the role of the MTHFR gene has not previously been investigated in the setting of oesophageal adenocarcinoma. No association between folic acid levels and cancer patients was found. The unstable MTHFR 667 TT genotype occurred in 11% cancers and 7% controls, but statistical significance was not reached, homocysteine levels and folic acid levels were not affected, cancer patients with TT genotype displayed a trend for a shorter survival 7 mo vs 20 mo. Serum vitamin B12 levels were higher in the cancer group. The MTHFR 667 TT genotype is much lower than previous population studies.
CONCLUSION: We conclude that serum folic acid and MTHFR polymorphisms are not associated with an increased risk of oesophageal adenocarcinoma, although cancers with unstable TT genotype may indicate a more aggressive disease course.

Lin CY, Hung SY, Chen HT, et al.
Brain-derived neurotrophic factor increases vascular endothelial growth factor expression and enhances angiogenesis in human chondrosarcoma cells.
Biochem Pharmacol. 2014; 91(4):522-33 [PubMed] Related Publications
Chondrosarcomas are a type of primary malignant bone cancer, with a potent capacity for local invasion and distant metastasis. Brain-derived neurotrophic factor (BDNF) is commonly upregulated during neurogenesis. The aim of the present study was to examine the mechanism involved in BDNF-mediated vascular endothelial growth factor (VEGF) expression and angiogenesis in human chondrosarcoma cells. Here, we knocked down BDNF expression in chondrosarcoma cells and assessed their capacity to control VEGF expression and angiogenesis in vitro and in vivo. We found knockdown of BDNF decreased VEGF expression and abolished chondrosarcoma conditional medium-mediated angiogenesis in vitro as well as angiogenesis effects in vivo in the chick chorioallantoic membrane and Matrigel plug nude mouse models. In addition, in the xenograft tumor angiogenesis model, the knockdown of BDNF significantly reduced tumor growth and tumor-associated angiogenesis. BDNF increased VEGF expression and angiogenesis through the TrkB receptor, PLCγ, PKCα, and the HIF-1α signaling pathway. Finally, we analyzed samples from chondrosarcoma patients by immunohistochemical staining. The expression of BDNF and VEGF protein in 56 chondrosarcoma patients was significantly higher than in normal cartilage. In addition, the high level of BDNF expression correlated strongly with VEGF expression and tumor stage. Taken together, our results indicate that BDNF increases VEGF expression and enhances angiogenesis through a signal transduction pathway that involves the TrkB receptor, PLCγ, PKCα, and the HIF-1α. Therefore, BDNF may represent a novel target for anti-angiogenic therapy for human chondrosarcoma.

Yang YC, Tang YA, Shieh JM, et al.
DNMT3B overexpression by deregulation of FOXO3a-mediated transcription repression and MDM2 overexpression in lung cancer.
J Thorac Oncol. 2014; 9(9):1305-15 [PubMed] Related Publications
INTRODUCTION: DNA methyltransferase 3B (DNMT3B) contributes to de novo DNA methylation and its overexpression promotes tumorigenesis. However, whether DNMT3B is upregulated by transcriptional deregulation remains unclear.
METHODS: We studied the transcriptional repression of DNMT3B by forkhead O transcription factor 3a (FOXO3a) in lung cancer cell, animal, and clinical models.
RESULTS: The results of luciferase reporter assay showed that FOXO3a negatively regulated DNMT3B promoter activity by preferentially interacting with the binding element FOXO3a-E (+166 to +173) of DNMT3B promoter. Ectopically overexpressed FOXO3a or combined treatment with doxorubicin to induce FOXO3a nuclear accumulation further bound at the distal site, FOXO3a-P (-249 to -242) by chromatin-immunoprecipitation assay. Knockdown of FOXO3a resulted in an open chromatin structure and high DNMT3B mRNA and protein expression. Abundant FOXO3a repressed DNMT3B promoter by establishing a repressed chromatin structure. Note that FOXO3a is a degradation substrate of MDM2 E3-ligase. Cotreatment with doxorubicin and MDM2 inhibitor, Nutlin-3, further enforced abundant nuclear accumulation of FOXO3a resulting in decrease expression of DNMT3B leading to synergistic inhibition of tumor growth and decrease of methylation status on tumor suppressor genes in xenograft specimens. Clinically, lung cancer patients with DNMT3B high, FOXO3a low, and MDM2 high expression profile correlated with poor prognosis examined by immunohistochemistry and Kaplan-Meier survival analysis.
CONCLUSIONS: We reveal a new mechanism that FOXO3a transcriptionally represses DNMT3B expression and this regulation can be attenuated by MDM2 overexpression in human lung cancer model. Cotreatment with doxorubicin and Nutlin-3 is a novel therapeutic strategy through epigenetic modulation.

Shen KH, Liao AC, Hung JH, et al.
α-Solanine inhibits invasion of human prostate cancer cell by suppressing epithelial-mesenchymal transition and MMPs expression.
Molecules. 2014; 19(8):11896-914 [PubMed] Related Publications
α-Solanine, a naturally occurring steroidal glycoalkaloid found in nightshade (Solanum nigrum Linn.), was found to inhibit proliferation and induce apoptosis of tumor cells. However, the mechanism involved in suppression of cancer cell metastasis by α-solanine remains unclear. This study investigates the suppression mechanism of α-solanine on motility of the human prostate cancer cell PC-3. Results show that α-solanine reduces the viability of PC-3 cells. When treated with non-toxic doses of α-solanine, cell invasion is markedly suppressed by α-solanine. α-Solanine also significantly elevates epithelial marker E-cadherin expression, while it concomitantly decreases mesenchymal marker vimentin expression, suggesting it suppresses epithelial-mesenchymal transition (EMT). α-Solanine reduces the mRNA level of matrix metalloproteinase-2 (MMP-2), MMP-9 and extracellular inducer of matrix metalloproteinase (EMMPRIN), but increases the expression of reversion-inducing cysteine-rich protein with kazal motifs (RECK), and tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2. Immunoblotting assays indicate α-solanine is effective in suppressing the phosphorylation of phosphatidylinositide-3 kinase (PI3K), Akt and ERK. Moreover, α-solanine downregulates oncogenic microRNA-21 (miR-21) and upregulates tumor suppressor miR-138 expression. Taken together, the results suggest that inhibition of PC-3 cell invasion by α-solanine may be, at least in part, through blocking EMT and MMPs expression. α-Solanine also reduces ERK and PI3K/Akt signaling pathways and regulates expression of miR-21 and miR-138. These findings suggest an attractive therapeutic potential of α-solanine for suppressing invasion of prostate cancer cell.

Weng TY, Yen MC, Huang CT, et al.
DNA vaccine elicits an efficient antitumor response by targeting the mutant Kras in a transgenic mouse lung cancer model.
Gene Ther. 2014; 21(10):888-96 [PubMed] Related Publications
Mutant Kras (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) is observed in more than 20% of non-small-cell lung cancers; however, no effective Kras target therapy is available at present. The Kras DNA vaccine may represent as a novel immunotherapeutic agent in lung cancer. In this study, we investigated the antitumor efficacy of the Kras DNA vaccine in a genetically engineered inducible mouse lung tumor model driven by Kras(G12D). Lung tumors were induced by doxycycline, and the therapeutic effects of Kras DNA vaccine were evaluated with delivery of Kras(G12D) plasmids. Mutant Kras(G12D) DNA vaccine significantly decreased the tumor nodules. A dominant-negative mutant Kras(G12D)N17, devoid of oncogenic activity, achieved similar therapeutic effects. The T-helper 1 immune response was enhanced in mice treated with Kras DNA vaccine. Splenocytes from mice receiving Kras DNA vaccine presented an antigen-specific response by treatment with peptides of Kras but not Hras or OVA. The number of tumor-infiltrating CD8(+) T cells increased after Kras vaccination. In contrast, Kras DNA vaccine was not effective in the lung tumor in transgenic mice, which was induced by mutant L858R epidermal growth factor receptor. Overall, these results indicate that Kras DNA vaccine produces an effective antitumor response in transgenic mice, and may be useful in treating lung cancer-carrying Ras mutation.

Chia NY, Deng N, Das K, et al.
Regulatory crosstalk between lineage-survival oncogenes KLF5, GATA4 and GATA6 cooperatively promotes gastric cancer development.
Gut. 2015; 64(5):707-19 [PubMed] Related Publications
OBJECTIVE: Gastric cancer (GC) is a deadly malignancy for which new therapeutic strategies are needed. Three transcription factors, KLF5, GATA4 and GATA6, have been previously reported to exhibit genomic amplification in GC. We sought to validate these findings, investigate how these factors function to promote GC, and identify potential treatment strategies for GCs harbouring these amplifications.
DESIGN: KLF5, GATA4 and GATA6 copy number and gene expression was examined in multiple GC cohorts. Chromatin immunoprecipitation with DNA sequencing was used to identify KLF5/GATA4/GATA6 genomic binding sites in GC cell lines, and integrated with transcriptomics to highlight direct target genes. Phenotypical assays were conducted to assess the function of these factors in GC cell lines and xenografts in nude mice.
RESULTS: KLF5, GATA4 and GATA6 amplifications were confirmed in independent GC cohorts. Although factor amplifications occurred in distinct sets of GCs, they exhibited significant mRNA coexpression in primary GCs, consistent with KLF5/GATA4/GATA6 cross-regulation. Chromatin immunoprecipitation with DNA sequencing revealed a large number of genomic sites co-occupied by KLF5 and GATA4/GATA6, primarily located at gene promoters and exhibiting higher binding strengths. KLF5 physically interacted with GATA factors, supporting KLF5/GATA4/GATA6 cooperative regulation on co-occupied genes. Depletion and overexpression of these factors, singly or in combination, reduced and promoted cancer proliferation, respectively, in vitro and in vivo. Among the KLF5/GATA4/GATA6 direct target genes relevant for cancer development, one target gene, HNF4α, was also required for GC proliferation and could be targeted by the antidiabetic drug metformin, revealing a therapeutic opportunity for KLF5/GATA4/GATA6 amplified GCs.
CONCLUSIONS: KLF5/GATA4/GATA6 may promote GC development by engaging in mutual crosstalk, collaborating to maintain a pro-oncogenic transcriptional regulatory network in GC cells.

Lin CH, Chao LK, Hung PH, Chen YJ
EGCG inhibits the growth and tumorigenicity of nasopharyngeal tumor-initiating cells through attenuation of STAT3 activation.
Int J Clin Exp Pathol. 2014; 7(5):2372-81 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
A subset of cancer cells, termed cancer stem cells (CSCs) or tumor-initiating cells (TICs) could initiate tumors and are responsible for tumor recurrence and chemotherapeutic resistance. In this study, we enriched TICs in nasopharyngeal carcinoma (NPC) by the spheres formation and characterized the stem-like signatures such as self-renewal, proliferation, chemoresistance and tumorigenicity. By this method, we investigated that epigallocathechin gallate (EGCG), the major polyphenol in green tea could target TICs and potently inhibit sphere formation, eliminate the stem-like properties and enhance chemosensitivity in NPC through attenuation of STAT3 activation, which could be important in regulating the stemness expression in NPC. Our results demonstrated that STAT3 pathway plays an important role in mediating tumor-initiating capacities in NPC and suggest that inactivation of STAT3 with EGCG may represent a potential preventive and therapeutic approach for NPC.

Kuo IY, Chang JM, Jiang SS, et al.
Prognostic CpG methylation biomarkers identified by methylation array in esophageal squamous cell carcinoma patients.
Int J Med Sci. 2014; 11(8):779-87 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is an aggressive cancer with poor prognosis. We aimed to identify a panel of CpG methylation biomarkers for prognosis prediction of ESCC patients.
METHODS: Illumina's GoldenGate methylation array, supervised principal components, Kaplan-Meier survival analyses and Cox regression model were conducted on dissected tumor tissues from a training cohort of 40 ESCC patients to identify potential CpG methylation biomarkers. Pyrosequencing quantitative methylation assay were performed to validate prognostic CpG methylation biomarkers in 61 ESCC patients. The correlation between DNA methylation and RNA expression of a validated marker, SOX17, was examined in a validation cohort of 61 ESCC patients.
RESULTS: We identified a panel of nine CpG methylation probes located at promoter or exon1 region of eight genes including DDIT3, FES, FLT3, NTRK3, SEPT5, SEPT9, SOX1, and SOX17, for prognosis prediction in ESCC patients. Risk score calculated using the eight-gene panel statistically predicted poor outcome for patients with high risk score. These eight-gene also showed a significantly higher methylation level in tumor tissues than their corresponding normal samples in all patients analyzed. In addition, we also detected an inverse correlation between CpG hypermethylation and the mRNA expression level of SOX17 gene in ESCC patients, indicating that DNA hypermethylation was responsible for decreased expression of SOX17.
CONCLUSIONS: This study established a proof-of-concept CpG methylation biomarker panel for ESCC prognosis that can be further validated by multiple cohort studies. Functional characterization of the eight prognostic methylation genes in our biomarker panel could help to dissect the mechanism of ESCC tumorigenesis.

Shieh JM, Shen CJ, Chang WC, et al.
An increase in reactive oxygen species by deregulation of ARNT enhances chemotherapeutic drug-induced cancer cell death.
PLoS One. 2014; 9(6):e99242 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
BACKGROUND: Unique characteristics of tumor microenvironments can be used as targets of cancer therapy. The aryl hydrocarbon receptor nuclear translocator (ARNT) is an important mediator of tumor progression. However, the functional role of ARNT in chemotherapeutic drug-treated cancer remains unclear.
METHODOLOGY/PRINCIPAL FINDINGS: Here, we found that knockdown of ARNT in cancer cells reduced the proliferation rate and the transformation ability of those cells. Moreover, cisplatin-induced cell apoptosis was enhanced in ARNT-deficient cells. Expression of ARNT also decreased in the presence of cisplatin through proteasomal degradation pathway. However, ARNT level was maintained in cisplatin-treated drug-resistant cells, which prevented cell from apoptosis. Interestingly, reactive oxygen species (ROS) dramatically increased when ARNT was knocked down in cancer cells, enhancing cisplatin-induced apoptosis. ROS promoted cell death was inhibited in cells treated with the ROS scavenger, N-acetyl-cysteine (NAC).
CONCLUSIONS/SIGNIFICANCE: These results suggested that the anticancer activity of cisplatin is attributable to its induction of the production of ROS by ARNT degradation. Targeting ARNT could be a potential strategy to eliminate drug resistance in cancer cells.

Hsu YC, Huang TY, Chen MJ
Therapeutic ROS targeting of GADD45γ in the induction of G2/M arrest in primary human colorectal cancer cell lines by cucurbitacin E.
Cell Death Dis. 2014; 5:e1198 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
Cucurbitacin E (CuE) or α-elaterin is a natural compound previously shown to be an antifeedant as well as a potent chemopreventive agent against several types of cancer. The present study investigated the anticancer effects of CuE on colorectal cancer (CRC) using primary cell lines isolated from five CRC patients in Taiwan, Specifically, we explored the anti-proliferation and cell cycle G2/M arrest induced by CuE in CRC cells. MPM-2 flow cytometry tests show that CuE-treated cells accumulated in metaphase (CuE 2.5-7.5 μM). Results further indicate that CuE produced G2/M arrest as well as the downregulation of CDC2 and cyclin B1 expression and dissociation. Both effects increased proportionally with the dose of CuE; however, the inhibition of proliferation, arrest of mitosis, production of reactive oxygen species (ROS), and loss of mitochondrial membrane potential (ΔΨm) were found to be dependent on the quantity of CuE used to treat the cancer cells. In addition, cell cycle arrest in treated cells coincided with the activation of the gene GADD45(α, β, γ). Incubation with CuE resulted in the binding of GADD45γ to CDC2, which suggests that the delay in CuE-induced mitosis is regulated by the overexpression of GADD45γ. Our findings suggest that, in addition to the known effects on cancer prevention, CuE may have antitumor activities in established CRC.

Tung CL, Chiu HC, Jian YJ, et al.
Down-regulation of MSH2 expression by an Hsp90 inhibitor enhances pemetrexed-induced cytotoxicity in human non-small-cell lung cancer cells.
Exp Cell Res. 2014; 322(2):345-54 [PubMed] Related Publications
Elevated heat shock protein 90 (Hsp90) expression has been linked to poor prognosis in patients with non-small cell lung cancer (NSCLC). The multitargeted antifolate pemetrexed has demonstrated certain clinical activities against NSCLC. However, the efficacy of the combination of pemtrexed and Hsp90 inhibitor to prolong the survival of patients with NSCLC still remains unclear. Human MutS homolog 2 (MSH2), a crucial element of the highly conserved DNA mismatch repair system, and defects or polymorphisms of MSH2 have been found in lung cancer. In this study, we evaluated the effects of pemetrexed on NSCLC cell lines (H520 and H1703) and found that treatment with this drug at 20-50 µM increased the MSH2 mRNA and protein levels in a MKK3/6-p38 MAPK signal activation-dependent manner. Furthermore, the knockdown of MSH2 expression by transfection with small interfering RNA of MSH2 or the blockage of p38 MAPK activation by SB202190 enhanced the cytotoxicity of pemetrexed. Combining the drug treatment with an Hsp90 inhibitor resulted in an enhanced pemetrexed-induced cytotoxic effect, accompanied with the reduction of MSH2 protein and mRNA levels. The expression of constitutively active MKK6 (MKK6E) or HA-p38 MAPK vectors significantly rescued the decreased p38 MAPK activity, and restored the MSH2 protein levels and cell survival in NSCLC cells co-treated with pemetrexed and Hsp90 inhibitor. In this study, we have demonstrated that down-regulation of the MKK3/6-p38 MAPK signal with the subsequent reduction of MSH2 enhanced the cytotoxic effect of pemetrexed in H520 and H1703 cells. The results suggest a potential future benefit of combining pemetrexed and the Hsp90 inhibitor to treat lung cancer.

Huang ZM, Chen HA, Chiang YT, et al.
Association of polymorphisms in iNOS and NQO1 with bladder cancer risk in cigarette smokers.
J Chin Med Assoc. 2014; 77(2):83-8 [PubMed] Related Publications

Chia WK, Teo M, Wang WW, et al.
Adoptive T-cell transfer and chemotherapy in the first-line treatment of metastatic and/or locally recurrent nasopharyngeal carcinoma.
Mol Ther. 2014; 22(1):132-9 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
The outcomes for patients with metastatic or locally recurrent Epstein-Barr virus (EBV)-positive nasopharyngeal carcinoma (NPC) remain poor. Adoptive immunotherapy with EBV-specific cytotoxic T lymphocytes (EBV-CTLs) has proven clinical efficacy, but it has never been evaluated in the first-line treatment setting in combination with chemotherapy. To evaluate the safety and efficacy of a chemotherapy in combination with adoptive EBV-CTL transfer, we conducted a phase 2 clinical trial consisting of four cycles of gemcitabine and carboplatin (GC) followed by up to six doses of EBV-CTL. Thirty-eight patients were enrolled, and 35 received GC and EBV-CTL. GC-CTL therapy resulted in a response rate of 71.4% with 3 complete responses and 22 partial responses. With a median follow up of 29.9 months, the 2-year and 3-year overall survival (OS) rate was 62.9 and 37.1%, respectively. Five patients did not require further chemotherapy for more than 34 months since initiation of CTL. Infusion of CTL products containing T cells specific for LMP2 positively correlated with OS (hazard ratio: 0.35; 95% confidence interval: 0.14-0.84; P = 0.014). Our study achieved one of the best survival outcomes in patients with advanced NPC, setting the stage for a future randomized study of chemotherapy with and without EBV-CTL.

Wilson S, Chia S
New agents in locally advanced breast cancer.
Curr Opin Support Palliat Care. 2014; 8(1):64-9 [PubMed] Related Publications
PURPOSE OF REVIEW: Sequential anthracycline/taxane regimens are routinely used as neoadjuvant therapy (NAT) for locally advanced breast cancer. Unfortunately, the majority of patients do not achieve a pathological complete response (pCR). Efforts to improve pCR rates include the addition of novel targeted agents. The purpose of this article is to review recent developments in this area and to demonstrate the clinical and research advantages of a neoadjuvant platform for the evaluation of novel targeted therapy.
RECENT FINDINGS: Dual human epidermal growth factor 2 (HER2)-targeting concurrent with chemotherapy has demonstrated superiority over chemotherapy with trastuzumab alone. Bevacizumab appears to have a modest effect on pCR rates and its role in neoadjuvant treatment remains uncertain. Despite promising preclinical signals, mTOR inhibition in combination with chemotherapy has yet to yield a benefit in the neoadjuvant setting and trials are ongoing. In contrast, mTOR inhibition in combination with endocrine therapy has demonstrated potential as NAT.
SUMMARY: Dual HER2-targeting considerably improves pCR rates. Thus, far incorporation of non-HER2 targeted agents has been less successful. NAT provides an opportunity to evaluate novel agents, and thereby assist the development of a rationale adjuvant strategy, and facilitates the collection of samples for correlative research into breast cancer biology and predictive biomarkers/pathways.

Liu MH, Cheung E
Estrogen receptor-mediated long-range chromatin interactions and transcription in breast cancer.
Mol Cell Endocrinol. 2014; 382(1):624-32 [PubMed] Related Publications
Estrogen induces the binding of ERα to thousands of locations in the breast cancer genome, preferring intergenic and distal regions rather than near the promoters of estrogen-regulated genes. With recent technological innovations in mapping and characterization of global chromatin organization, evidence now indicates ERα mediates long-range chromatin interactions to control gene transcription. The principles that govern how ERα communicates with their putative target genes via chromosomal interactions are also beginning to unravel. Herein, we summarize our current knowledge on the functional significance of chromatin looping in estrogen-mediated transcription. ERα collaborative factors and other players that contribute to define the genomic interactions in breast cancer cells will also be discussed. Defects in chromatin organization are emerging key players in diseases such as cancer, thus understanding how ERα-mediated chromatin looping affects genome organization will clarify the receptor's role in estrogen responsive pathways sensitive to defects in chromatin organization.

Gill DJ, Tham KM, Chia J, et al.
Initiation of GalNAc-type O-glycosylation in the endoplasmic reticulum promotes cancer cell invasiveness.
Proc Natl Acad Sci U S A. 2013; 110(34):E3152-61 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
Invasiveness underlies cancer aggressiveness and is a hallmark of malignancy. Most malignant tumors have elevated levels of Tn, an O-GalNAc glycan. Mechanisms underlying Tn up-regulation and its effects remain unclear. Here we show that Golgi-to-endoplasmic reticulum relocation of polypeptide N-acetylgalactosamine-transferases (GalNAc-Ts) drives high Tn levels in cancer cell lines and in 70% of malignant breast tumors. This process stimulates cell adhesion to the extracellular matrix, as well as migration and invasiveness. The GalNAc-Ts lectin domain, mediating high-density glycosylation, is critical for these effects. Interfering with the lectin domain function inhibited carcinoma cell migration in vitro and metastatic potential in mice. We also show that stimulation of cell migration is dependent on Tn-bearing proteins present in lamellipodia of migrating cells. Our findings suggest that relocation of GalNAc-Ts to the endoplasmic reticulum frequently occurs upon cancerous transformation to enhance tumor cell migration and invasiveness through modification of cell surface proteins.

Lau C, Kim Y, Chia D, et al.
Role of pancreatic cancer-derived exosomes in salivary biomarker development.
J Biol Chem. 2013; 288(37):26888-97 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
Recent studies have demonstrated that discriminatory salivary biomarkers can be readily detected upon the development of systemic diseases such as pancreatic cancer, breast cancer, lung cancer, and ovarian cancer. However, the utility of salivary biomarkers for the detection of systemic diseases has been undermined due to the absence of the biological and mechanistic rationale as to why distal diseases from the oral cavity would lead to the development of discriminatory biomarkers in saliva. Here, we examine the hypothesis that pancreatic tumor-derived exosomes are mechanistically involved in the development of pancreatic cancer-discriminatory salivary transcriptomic biomarkers. We first developed a pancreatic cancer mouse model that yielded discriminatory salivary biomarkers by implanting the mouse pancreatic cancer cell line Panc02 into the pancreas of the syngeneic host C57BL/6. The role of pancreatic cancer-derived exosomes in the development of discriminatory salivary biomarkers was then tested by engineering a Panc02 cell line that is suppressed for exosome biogenesis, implanting into the C56BL/6 mouse, and examining whether the discriminatory salivary biomarker profile was ablated or disrupted. Suppression of exosome biogenesis results in the ablation of discriminatory salivary biomarker development. This study supports that tumor-derived exosomes provide a mechanism in the development of discriminatory biomarkers in saliva and distal systemic diseases.

Brooks K, Chia KM, Spoerri L, et al.
Defective decatenation checkpoint function is a common feature of melanoma.
J Invest Dermatol. 2014; 134(1):150-8 [PubMed] Related Publications
A hallmark of cancer is genomic instability that is considered to provide the adaptive capacity of cancers to thrive under conditions in which the normal precursors would not survive. Recent genomic analysis has revealed a very high degree of genomic instability in melanomas, although the mechanism by which this instability arises is not known. Here we report that a high proportion (68%) of melanoma cell lines are either partially (40%) or severely (28%) compromised for the G2 phase decatenation checkpoint that normally functions to ensure that the sister chromatids are able to separate correctly during mitosis. The consequence of this loss of checkpoint function is a severely reduced ability to partition the replicated genome in mitosis and thereby increase genomic instability. We also demonstrate that decatenation is dependent on both TopoIIα and β isoforms. The high incidence of decatenation checkpoint defect is likely to be a major contributor to the high level of genomic instability found in melanomas.

Pataky R, Armstrong L, Chia S, et al.
Cost-effectiveness of MRI for breast cancer screening in BRCA1/2 mutation carriers.
BMC Cancer. 2013; 13:339 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
BACKGROUND: Women with mutations in BRCA1 or BRCA2 are at high risk of developing breast cancer and, in British Columbia, Canada, are offered screening with both magnetic resonance imaging (MRI) and mammography to facilitate early detection. MRI is more sensitive than mammography but is more costly and produces more false positive results. The purpose of this study was to calculate the cost-effectiveness of MRI screening for breast cancer in BRCA1/2 mutation carriers in a Canadian setting.
METHODS: We constructed a Markov model of annual MRI and mammography screening for BRCA1/2 carriers, using local data and published values. We calculated cost-effectiveness as cost per quality-adjusted life-year gained (QALY), and conducted one-way and probabilistic sensitivity analysis.
RESULTS: The incremental cost-effectiveness ratio (ICER) of annual mammography plus MRI screening, compared to annual mammography alone, was $50,900/QALY. After incorporating parameter uncertainty, MRI screening is expected to be a cost-effective option 86% of the time at a willingness-to-pay of $100,000/QALY, and 53% of the time at a willingness-to-pay of $50,000/QALY. The model is highly sensitive to the cost of MRI; as the cost is increased from $200 to $700 per scan, the ICER ranges from $37,100/QALY to $133,000/QALY.
CONCLUSIONS: The cost-effectiveness of using MRI and mammography in combination to screen for breast cancer in BRCA1/2 mutation carriers is finely balanced. The sensitivity of the results to the cost of the MRI screen itself warrants consideration: in jurisdictions with higher MRI costs, screening may not be a cost-effective use of resources, but improving the efficiency of MRI screening will also improve cost-effectiveness.

Chang CM, Chia VM, Gunter MJ, et al.
Innate immunity gene polymorphisms and the risk of colorectal neoplasia.
Carcinogenesis. 2013; 34(11):2512-20 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
Inherited variation in genes that regulate innate immunity and inflammation may contribute to colorectal neoplasia risk. To evaluate this association, we conducted a nested case-control study of 451 colorectal cancer cases, 694 colorectal advanced adenoma cases and 696 controls of European descent within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. A total of 935 tag single-nucleotide polymorphisms (SNPs) in 98 genes were evaluated. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association with colorectal neoplasia. Sixteen SNPs were associated with colorectal neoplasia risk at P < 0.01, but after adjustment for multiple testing, only rs2838732 (ITGB2) remained suggestively associated with colorectal neoplasia (OR(per T allele) = 0.68, 95% CI: 0.57-0.83, P = 7.7 × 10(-5), adjusted P = 0.07). ITGB2 codes for the CD18 protein in the integrin beta chain family. The ITGB2 association was stronger for colorectal cancer (OR(per T allele) = 0.41, 95% CI: 0.30-0.55, P = 2.4 × 10(-) (9)) than for adenoma (OR(per T allele) = 0.84, 95%CI: 0.69-1.03, P = 0.08), but it did not replicate in the validation study. The ITGB2 rs2838732 association was significantly modified by smoking status (P value for interaction = 0.003). Among never and former smokers, it was inversely associated with colorectal neoplasia (OR(per T allele) = 0.5, 95% CI: 0.37-0.69 and OR(per T allele) = 0.72, 95% CI: 0.54-0.95, respectively), but no association was seen among current smokers. Other notable findings were observed for SNPs in BPI/LBP and MYD88. Although the results need to be replicated, our findings suggest that genetic variation in inflammation-related genes may be related to the risk of colorectal neoplasia.

Chay WY, Chew SH, Ong WS, et al.
HER2 amplification and clinicopathological characteristics in a large Asian cohort of rare mucinous ovarian cancer.
PLoS One. 2013; 8(4):e61565 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
Mucinous epithelial ovarian cancer has a poor prognosis in the advanced stages and responds poorly to conventional chemotherapy. We aim to elucidate the clinicopathological factors and incidence of HER2 expression of this cancer in a large Asian retrospective cohort from Singapore. Of a total of 133 cases, the median age at diagnosis was 48.3 years (range, 15.8-89.0 years), comparatively younger than western cohorts. Most were Chinese (71%), followed by Malays (16%), others (9.0%), and Indians (5%). 24% were noted to have a significant family history of malignancy of which breast and gastrointestinal cancers the most prominent. Majority of the patients (80%) had stage I disease at diagnosis. Information on HER2 status was available in 113 cases (85%). Of these, 31 cases (27.4%) were HER2+, higher than 18.8% reported in western population. HER2 positivity appeared to be lower among Chinese and higher among Malays patients (p = 0.052). With the current standard of care, there was no discernible impact of HER2 status on overall survival. (HR = 1.79; 95% CI, 0.66-4.85; p = 0.249). On the other hand, positive family history of cancer, presence of lymphovascular invasion, and ovarian surface involvements were significantly associated with inferior overall survival on univariate and continued to be statistically significant after adjustment for stage. While these clinical factors identify high risk patients, it is promising that the finding of a high incidence of HER2 in our Asian population may allow development of a HER2 targeted therapy to improve the management of mucinous ovarian cancers.

Davidson JA, Cromwell I, Ellard SL, et al.
A prospective clinical utility and pharmacoeconomic study of the impact of the 21-gene Recurrence Score® assay in oestrogen receptor positive node negative breast cancer.
Eur J Cancer. 2013; 49(11):2469-75 [PubMed] Related Publications
PURPOSE: The primary purpose of this study was to measure the impact of the 21-gene Recurrence Score® result on systemic treatment recommendations and to perform a prospective health economic analysis in stage I-II, node-negative, oestrogen receptor positive (ER+) breast cancer.
METHODS: Consenting patients with ER+ node negative invasive breast cancer and their treating medial oncologists were asked to complete questionnaires about treatment preferences, level of confidence in those preferences and a decisional conflict scale (patients only) after a discussion of their diagnosis and risk without knowledge of the Recurrence Score. At a subsequent visit, the assay result and final treatment recommendations were discussed prior to both parties completing a second set of questionnaires. A Markov health state transition model was constructed, simulating the costs and outcomes experienced by a hypothetical 'assay naïve' population and an 'assay informed' population.
RESULTS: One hundred and fifty-six patients across two cancer centres were enrolled. Of the 150 for whom successful assay results were obtained, physicians changed their chemotherapy recommendations in 45 cases (30%; 95% confidence interval (CI) 22.8-38.0%); either to add (10%; 95% CI 5.7-16.0%) or omit (20%; 95% CI 13.9-27.3%) adjuvant chemotherapy. There was an overall significant improvement in physician confidence post-assay (p<0.001). Patient decisional conflict also significantly decreased following the assay (p<0.001). The simulation model found an incremental cost-effectiveness ratio of Canadian Dollars (CAD) $6630/quality-adjusted life years (QALY).
CONCLUSION: Within the context of a publicly funded health care system, the Recurrence Score assay significantly affects adjuvant treatment recommendations and is cost effective in ER+ node negative breast cancer.

Garcia-Closas M, Couch FJ, Lindstrom S, et al.
Genome-wide association studies identify four ER negative-specific breast cancer risk loci.
Nat Genet. 2013; 45(4):392-8, 398e1-2 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
Estrogen receptor (ER)-negative tumors represent 20-30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry. The etiology and clinical behavior of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition. To identify susceptibility loci specific to ER-negative disease, we combined in a meta-analysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P = 2.1 × 10(-12) and LGR6, P = 1.4 × 10(-8)), 2p24.1 (P = 4.6 × 10(-8)) and 16q12.2 (FTO, P = 4.0 × 10(-8)), were associated with ER-negative but not ER-positive breast cancer (P > 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers.

Sharifah NA, Zakaria Z, Chia WK
FISH analysis using PPAR γ-specific probes for detection of PAX8-PPAR γ translocation in follicular thyroid neoplasms.
Methods Mol Biol. 2013; 952:187-96 [PubMed] Related Publications
Fluorescence in situ hybridization (FISH) is increasingly gaining importance in clinical diagnostics settings. Due to the ability of the technique to detect chromosomal abnormalities in samples with low cellularity or containing a mixed population of cells even at a single-cell level, it has become more popular in cancer research and diagnosis. Here, we describe the FISH technique for detection of PAX8-PPARγ translocation in follicular thyroid neoplasms, and the optimal protocol for the detection of this fusion gene using in archival formalin-fixed paraffin-embedded (FFPE) thyroid tissue sections.

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