GOPC

Gene Summary

Gene:GOPC; golgi associated PDZ and coiled-coil motif containing
Aliases: CAL, FIG, PIST, GOPC1, dJ94G16.2
Location:6q22.1
Summary:This gene encodes a Golgi protein with a PDZ domain. The PDZ domain is globular and proteins which contain them bind other proteins through short motifs near the C-termini. Mice which are deficient in the orthologous protein have globozoospermia and are infertile. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:Golgi-associated PDZ and coiled-coil motif-containing protein
Source:NCBIAccessed: 16 March, 2017

Ontology:

What does this gene/protein do?
Show (23)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 16 March 2017 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.

  • Catalytic Domain
  • Gene Rearrangement
  • Adenocarcinoma
  • Non-Small Cell Lung Cancer
  • FIG-ROS1 fusion
  • Cancer Gene Expression Regulation
  • Genetic Testing
  • Receptor Protein-Tyrosine Kinases
  • Reading Frames
  • ALK
  • Proto-Oncogene Proteins
  • Adolescents
  • Chromosome Deletion
  • Disease Progression
  • Single Nucleotide Polymorphism
  • ROS1
  • Chromosome 3
  • Lung Cancer
  • Protein-Tyrosine Kinases
  • Chromosome 6
  • DNA Sequence Analysis
  • GOPC
  • Gene Expression
  • Genomics
  • COS Cells
  • Base Sequence
  • Young Adult
  • Neoplasm Metastasis
  • Molecular Sequence Data
  • Chromosome Mapping
  • Molecular Weight
  • Amino Acid Sequence
  • Ovarian Cancer
  • Golgi membrane glycoproteins
  • Genotype
  • Genome-Wide Association Study
  • Mutation
  • Carrier Proteins
  • Membrane Proteins
  • Oncogene Fusion Proteins
Tag cloud generated 16 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

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

Latest Publications: GOPC (cancer-related)

Allen JC, Nault JC, Zhu G, et al.
The transcriptomic G1-G6 signature of hepatocellular carcinoma in an Asian population: Association of G3 with microvascular invasion.
Medicine (Baltimore). 2016; 95(47):e5263 [PubMed] Free Access to Full Article Related Publications
In this study, a transcriptomic group classification based on a European population is tested on a Singapore cohort. The results highlight the genotype/phenotype correlation in a Southeast Asian population. The G1-G6 transcriptomic classification derived from hepatocellular carcinoma (HCC) resected from European patients, robustly reflected group-specific clinical/pathological features. We investigated the application of this molecular classification in Southeast Asian HCC patients.Gene expression analysis was carried out on HCC surgically resected in Singapore patients who were grouped into G1-G6 transcriptomic categories according to expression of 16 predictor genes (illustrated in Supplementary Table 1, http://links.lww.com/MD/B413 and Supplementary Fig. 1, http://links.lww.com/MD/B413) using quantitative reverse transcription polymerase chain reaction (RT-PCR). Univariate and multivariate polytomous logistic regression was used to investigate association between clinical variables and pooled transcriptomic classes G12, G3, and G456.HCC from Singapore (n = 82) were distributed (%) into G1 (13.4), G2 (24.4), G3 (15.9), G4 (24.4), G5 (14.6), and G6 (7.3) subgroups. Compared to the European data, the Singapore samples were relatively enriched in G1-G3 versus G4-G6 tumors (53.7% vs 46.3%) reflecting the higher proportion of hepatitis B virus (HBV) patients in Singapore versus Europe samples (43% vs 30%). Pooled classes were defined as G12, G3, and G456. G12 was associated with higher alpha-fetoprotein (AFP) concentrations (OR = 1.69, 95% CI: 1.30-2.20; P < 0.0001) and G3 with microvascular invasion (OR = 4.91, 95% CI: 1.06-24.8; P = 0.047).The European and Singapore cohorts were generally similar relative to associations between transcriptomic groups and clinical features. This lends credence to the G1-G6 transcriptomic classifications being applicable regardless of the ethnic origin of HCC patients. The G3 group was associated with microvascular invasion and holds potential for investigation into the underlying mechanisms and selection for therapeutic clinical trials.

Zhang K, Yu M, Hao F, et al.
Knockdown of S100A4 blocks growth and metastasis of anaplastic thyroid cancer cells in vitro and in vivo.
Cancer Biomark. 2016; 17(3):281-291 [PubMed] Related Publications
Anaplastic thyroid cancer (ATC) is a locally aggressive type of thyroid tumor with high rate of distant metastases. It is often incurable because it does not respond to radioiodine, radiotherapy, or chemotherapy. With conventional treatment, the median survival is about 6 months; therefore, new treatment options are needed. S100A4 is a calcium-binding protein related to the metastatic potential of carcinoma. Previous study has found S100A4 was overexpressed in human papillary thyroid carcinomas (PTC) tissues, and overexpression of S100A4 is associated with thyroid tumour invasion and metastasis. In the present study, we first examined S100A4 protein expression in 14 ATC tissues, 20 PTC tissues and 14 normal thyroid tissue by immunohistochemistry analysis. We then knocked down of S100A4 expression by RNA interference (S100A4 siRNA) and investigated its effects on growth and metastasis in two human ATC cell lines 8505C (BRAFV600E) and Cal-62 (BRAFwt) in vitro and in vivo. S100A4 and BRAFV600E protein expression was evaluated by western blot assay and immunohistochemistry analysis. Using immunohistochemistry, we found that high levels of S100A4 were detected in ATC specimens and PTC specimens. No S100A4 staining was observed in normal thyroid tissues. S100A4 siRNA significantly decreased proliferation and increased apoptosis, and inhibited the invasive potential of the two cells in vitro. In addition, S100A4 siRNA could effectively inhibit BRAFV600E expression in the 8505C cells, and treatment with 100 ng/ml human recombinant BRAF V600E in S100A4 siRNA/8505C cells could partly restore its proliferative and invasive ability. Results of implantation in vivo showed S100A4 shRNA could significantly inhibit abdominal cavity metastasis and tumor growth in vivo. Furthermore, knockdown of S100A4 has significant role on invasion, metastasis and growth inhibition in the 8505C cells than that of in the Cal-62 cells. These results support the hypothesis that S100A4 contributes significantly to growth and metastasis, and that down-regulation of S100A4 expression decreases the metastatic potential of ATC cells. Furthermore, down-regulation of S100A4 expression is more marked in BRAFV600E cells than that of in the BRAFwt cells.

Michna A, Schötz U, Selmansberger M, et al.
Transcriptomic analyses of the radiation response in head and neck squamous cell carcinoma subclones with different radiation sensitivity: time-course gene expression profiles and gene association networks.
Radiat Oncol. 2016; 11:94 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Acquired and inherent radioresistance of tumor cells is related to tumor relapse and poor prognosis - not only in head and neck squamous cell carcinoma (HNSCC). The underlying molecular mechanisms are largely unknown. Therefore, systemic in-depth analyses are needed to identify key regulators of radioresistance. In the present study, subclones of the CAL-33 HNSCC cell line with different radiosensitivity were analyzed to identify signaling pathways related to the different phenotypes.
METHODS: Subclones with altered radiosensitivity were generated by fractionated irradiation of the parental CAL-33 cells. Differences in radiosensitivity were confirmed in colony formation assays. Selected subclones were characterized at the genomic and transcriptomic level by SKY, array CGH, and mRNA-microarray analyses. Time-course gene expression analyses upon irradiation using a natural cubic spline regression model identified temporally differentially expressed genes. Moreover, early and late responding genes were identified. Gene association networks were reconstructed using partial correlation. The Reactome pathway database was employed to conduct pathway enrichment analyses.
RESULTS: The characterization of two subclones with enhanced radiation resistance (RP) and enhanced radiosensitivity (SP) revealed distinct genomic and transcriptomic changes compared to the parental cells. Differentially expressed genes after irradiation shared by both subclones pointed to important pathways of the early and late radiation response, including senescence, apoptosis, DNA repair, Wnt, PI3K/AKT, and Rho GTPase signaling. The analysis of the most important nodes of the gene association networks revealed pathways specific to the radiation response in different phenotypes of radiosensitivity. Exemplarily, for the RP subclone the senescence-associated secretory phenotype (SASP) together with GPCR ligand binding were considered as crucial. Also, the expression of endogenous retrovirus ERV3-1in response to irradiation has been observed, and the related gene association networks have been identified.
CONCLUSIONS: Our study presents comprehensive gene expression data of CAL-33 subclones with different radiation sensitivity. The resulting networks and pathways associated with the resistant phenotype are of special interest and include the SASP. The radiation-associated expression of ERV3-1 also appears highly attractive for further studies of the molecular mechanisms underlying acquired radioresistance. The identified pathways may represent key players of radioresistance, which could serve as potential targets for molecularly designed, therapeutical intervention.

Buurman R, Sandbothe M, Schlegelberger B, Skawran B
HDAC inhibition activates the apoptosome via Apaf1 upregulation in hepatocellular carcinoma.
Eur J Med Res. 2016; 21(1):26 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Histone deacetylation, a common hallmark in malignant tumors, strongly alters the transcription of genes involved in the control of proliferation, cell survival, differentiation and genetic stability. We have previously shown that HDAC1, HDAC2, and HDAC3 (HDAC1-3) genes encoding histone deacetylases 1-3 are upregulated in primary human hepatocellular carcinoma (HCC). The aim of this study was to characterize the functional effects of HDAC1-3 downregulation and to identify functionally important target genes of histone deacetylation in HCC.
METHODS: Therefore, HCC cell lines were treated with the histone deacetylase inhibitor (HDACi) trichostatin A and by siRNA-knockdown of HDAC1-3. Differentially expressed mRNAs were identified after siRNA-knockdown of HDAC1-3 using mRNA expression profiling. Findings were validated after siRNA-mediated silencing of HDAC1-3 using qRTPCR and Western blotting assays.
RESULTS: mRNA profiling identified apoptotic protease-activating factor 1 (Apaf1) to be significantly upregulated after HDAC inhibition (HLE siRNA#1/siRNA#2 p < 0.05, HLF siRNA#1/siRNA#2 p < 0.05). As a component of the apoptosome, a caspase-activating complex, Apaf1 plays a central role in the mitochondrial caspase activation pathway of apoptosis. Using annexin V, a significant increase in apoptosis could also be shown in HLE (siRNA #1 p = 0.0034) and HLF after siRNA against HDAC1-3 (Fig. 3a, b). In parallel, caspase-9 activity was increased after siRNA-knockdown of HDAC1-3 leading to enhanced apoptosis after HDAC inhibition (Fig. 3c, d).
CONCLUSIONS: The present data show that siRNA-knockdown of HDAC1-3 plays a major role in mediating apoptotic response to HDAC inhibitors through regulation of Apaf1.

Evans DG, Bowers N, Burkitt-Wright E, et al.
Comprehensive RNA Analysis of the NF1 Gene in Classically Affected NF1 Affected Individuals Meeting NIH Criteria has High Sensitivity and Mutation Negative Testing is Reassuring in Isolated Cases With Pigmentary Features Only.
EBioMedicine. 2016; 7:212-20 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The detection rate for identifying the underlying mutation in neurocutaneous syndromes is affected by the sensitivity of the mutation test and the heterogeneity of the disease based on the diagnostic criteria. Neurofibromatosis type (NF1) has been defined for 29years by the National Institutes for Health (NIH) criteria which include ≥6 Café au Lait macules (CAL) as a defining criterion. The discovery of SPRED1 as a cause of Legius syndrome which is manifested by CAL, freckling and learning difficulties has introduced substantial heterogeneity to the NIH criteria.
METHODS: We have defined the sensitivity of comprehensive RNA analysis on blood of presumed NF1 patients meeting NIH criteria with at least one nonpigmentary criterion and determined the proportion of children with ≥6 CAL and no family history that has an NF1 or SPRED1 genetic variant. RNA analysis was carried out from 04/2009-12/2015 on 361 NF1 patients.
FINDINGS: A presumed causative NF1 mutation was found in 166/171 (97.08%-95% CI 94.56-99.6%) of familial cases and 182/190 (95.8%-95% CI 92.93-98.65%) sporadic de novo cases. Two of thirteen (15%) mutation negative individuals had dysembryoplastic neuroepithelial tumour (DNET) compared to 2/348 (0.6%) with an NF1 variant (p=0.007). No SPRED1 variants were found in the thirteen individuals with no NF1 variant. Of seventy-one individuals with ≥6 CAL and no non-pigmentary criterion aged 0-20years, 47 (66.2%) had an NF1 variant six (8.5%) a SPRED1 variant and 18 (25.3%) no disease causing variant. Using the 95.8% detection rate the likelihood of a child with ≥6 CAL having constitutional NF1 drops from 2/3 to 1/9 after negative RNA analysis.
INTERPRETATION: RNA analysis in individuals with presumed NF1 has high sensitivity and includes a small subset with DNET without an NF1 variant. Furthermore negative analysis for NF1/SPRED1 provides strong reassurance to children with ≥6 CAL that they are unlikely to have NF1.

Sarsik B, Doganavsargil B, Simsir A, et al.
P21 and p27 Immunoexpression in Upper Urinary Tract Urothelial Carcinomas.
Pathol Oncol Res. 2016; 22(4):839-45 [PubMed] Related Publications
p21 and p27 are members of cyclin-dependent kinase family, which function as tumor suppressors and they are involved in development and progression of several malignancies. We investigated their expression in upper urinary tract urothelial carcinoma (UUTUC). Radical nephroureterectomy materials of 34 patients were assessed by immunohistochemistry to evaluate expression of p21 and p27 in UUTUC. Results were correlated with various clinicopathological variables as age, gender, tumor grade and stage, tumor architecture, multifocality, subsequent bladder carcinoma development and clinical outcome.p21 and p27 expression was observed in 52.9 % (n = 18) and 88.2 % (n = 30), respectively. A total of 21 tumors (61.7 %) showed either total loss of p21 expression (n = 16, 47 %) or lower expression (n = 5, 14.7 %). No correlation was found between p21 expression and clinicopathologic variables. Cases showing total loss or lower p27 expression (11.7 % and <25.6 %, respectively) (n = 19, 55.8 %) constituted 67.6 % (n = 23) of the cases totally. This loss or lower p27 expression correlated with a shorter overall survival in both univariate and multivariate analysis (p = 0.039 and p = 0.037, respectively). None of the noninvasive tumors (papillary and nodular tumors) showed loss of p27 (p = 0.016) while 33.3 % of invasive ones showed p27 loss. Noninvasive tumor architecture also correlated with subsequent bladder carcinoma development (p = 0.032) while invasive tumor architecture correlated with advanced stage (T3 and T4) (p = 0.003). p27 is widely expressed in UUTUC, while p21 expression is observed in half of the cases. Loss of p27 expression correlated with tumor architecture and overall survival in UUTUC. However, further research is needed to assess their role in UUTUC.

Dastjerdi MN, Valiani A, Mardani M, Ra MZ
Adenosine A1 receptor modifies P53 expression and apoptosis in breast cancer cell line Mcf-7.
Bratisl Lek Listy. 2016; 117(4):242-6 [PubMed] Related Publications
BACKGROUND: Breast cancer cells over-express the adenosine receptor A1 and in most of these cells, P53 gene is a wild type. Because of this finding and relationship between A1 receptor and cell apoptosis and proliferation, this study aimed to determine the effect of agonist and antagonist of A1 receptor on cell apoptosis and proliferation and recognize the relationship between this receptor and P53 expression.
METHODS: We used a Real-Time PCR test for measuring expression of p53 gene also flow cytometry assay for apoptotic and survival cell rate after treatment of MCF-7 cells with A1 receptor agonist CPA (N6-Cyclopentyladenosine) and A1 receptor antagonist DPCPX (1,3-dipropyl-8-cyclopentylxanthine) in 24,48 and 72 hours.
RESULTS: Our flow cytometry findings indicate that DPCPX significantly induces apoptosis in MCF-7. Also the expression of P53 becomes upregulated with time of DPCPX treatment. CPA treatment increased the survival cell rate and down-regulated this apoptosis-relevant gene P53 (p > 0.05).
CONCLUSION: DPCPX can induce P53 expression which consequently promotes the cell apoptosis in MCF-7. Therefore, DPCPX could be used as an anti-cancer agent (Tab. 1, Fig. 3, Ref. 5).

Ahirwar R, Vellarikkal SK, Sett A, et al.
Aptamer-Assisted Detection of the Altered Expression of Estrogen Receptor Alpha in Human Breast Cancer.
PLoS One. 2016; 11(4):e0153001 [PubMed] Free Access to Full Article Related Publications
An increase in the expression of estrogen receptors (ER) and the expanded population of ER-positive cells are two common phenotypes of breast cancer. Detection of the aberrantly expressed ERα in breast cancer is carried out using ERα-antibodies and radiolabelled ligands to make decisions about cancer treatment and targeted therapy. Capitalizing on the beneficial advantages of aptamer over the conventional antibody or radiolabelled ligand, we have identified a DNA aptamer that selectively binds and facilitates the detection of ERα in human breast cancer tissue sections. The aptamer is identified using the high throughput sequencing assisted SELEX screening. Biophysical characterization confirms the binding and formation of a thermodynamically stable complex between the identified DNA aptamer (ERaptD4) and ERα (Ka = 1.55±0.298×108 M(-1); ΔH = 4.32×104±801.1 cal/mol; ΔS = -108 cal/mol/deg). Interestingly, the specificity measurements suggest that the ERaptD4 internalizes into ERα-positive breast cancer cells in a target-selective manner and localizes specifically in the nuclear region. To harness these characteristics of ERaptD4 for detection of ERα expression in breast cancer samples, we performed the aptamer-assisted histochemical analysis of ERα in tissue samples from breast cancer patients. The results were validated by performing the immunohistochemistry on same samples with an ERα-antibody. We found that the two methods agree strongly in assay output (kappa value = 0.930, p-value <0.05 for strong ERα positive and the ERα negative samples; kappa value = 0.823, p-value <0.05 for the weak/moderate ER+ve samples, n = 20). Further, the aptamer stain the ERα-positive cells in breast tissues without cross-reacting to ERα-deficient fibroblasts, adipocytes, or the inflammatory cells. Our results demonstrate a significant consistency in the aptamer-assisted detection of ERα in strong ERα positive, moderate ERα positive and ERα negative breast cancer tissues. We anticipate that the ERaptD4 aptamer targeting ERα may potentially be used for an efficient grading of ERα expression in cancer tissues.

Namvar A, Bolhassani A, Hashemi M
HPV16 L2 improves HPV16 L1 gene delivery as an important approach for vaccine design against cervical cancer.
Bratisl Lek Listy. 2016; 117(3):179-84 [PubMed] Related Publications
BACKGROUND: High-risk human papillomavirus (HPV) infections have been associated with the development of cervical cancer. HPV16 is the most dominant high-risk types of HPV worldwide. L1 and L2 are the major and minor capsid proteins of HPV, respectively. Both proteins are able to self-assemble as a virus-like particle (VLP).
METHODS: In the current study, the human embryonic kidney cells were transfected with the plasmid DNA encoding HPV 16 L1 or L1-L2 genes and their expression was compared using different transfection reagents.
RESULTS: Our data showed that the recombinant L1-L2 DNAs were expressed in a high efficiency compared to L1 DNAs as detected by western blotting, fluorescent microscopy, and flow cytometry. In addition, Lipofectamine and Turbofect as the transfection reagents conferred more potent delivery than PEI 25 kDa indicating high toxicity of this system on HEK-293 cells. These results suggest the use of the full length of L2 as an efficient agent for overcoming the cell barriers and poor uptake of DNA in vitro and in vivo.
CONCLUSION: The high expression of HPV16 L1-L2 in HEK-293 cells using different delivery systems opens the way for new studies concerning to the use of L2 for DNA delivery via covalent linkage with the gene of interest (Fig. 5, Ref. 20).

Mohamedi Y, Fontanil T, Solares L, et al.
Fibulin-5 downregulates Ki-67 and inhibits proliferation and invasion of breast cancer cells.
Int J Oncol. 2016; 48(4):1447-56 [PubMed] Related Publications
Fibulins not only function as molecular bridges within the cellular microenvironment but also influence cell behavior. Thus, fibulins may contribute to create a permissive microenvironment for tumor growth but can also stimulate different mechanisms that may impede tumor progression. This is the case with Fibulin-5, which has been shown to display both tumor-promoting and tumor-protective functions by mechanisms that are not totally defined. We show new evidence on the tumor-protective functions displayed by Fibulin-5 in MCF-7, T47D and MDA-MB-231 breast cancer cells including the inhibition of invasion and proliferation capacity and hampering the ability to form mammospheres. Reduction in the level of phosphorylation of Ser residues involved in the nuclear translocation of β-catenin may underlie these antitumor effects. We also found that Fibulin-5 reduces the level of expression of Ki-67, a nuclear protein associated with cell proliferation. Moreover, reduction in Fibulin-5 expression corresponds to an increase of Ki-67 detection in breast tissue samples. Overall, our data provide new insights into the influence of Fibulin-5 to modify breast cancer cell behavior and contribute to better understand the connections between fibulins and cancer.

Ng HY, Ko JM, Yu VZ, et al.
DESC1, a novel tumor suppressor, sensitizes cells to apoptosis by downregulating the EGFR/AKT pathway in esophageal squamous cell carcinoma.
Int J Cancer. 2016; 138(12):2940-51 [PubMed] Related Publications
Esophageal cancer is ranked as the eighth most common cancer and the sixth leading cause of cancer deaths worldwide. To identify candidate tumor suppressor genes related to esophageal squamous cell carcinoma (ESCC) development, a cDNA microarray analysis was performed using paired tumor and nontumor tissue samples from ESCC patients. Differentially expressed in squamous cell carcinoma 1 (DESC1), which belongs to the Type II transmembrane serine protease family, was frequently downregulated in ESCC. This study aims to elucidate the molecular mechanism for the tumor suppressive function of DESC1 in ESCC. We show that DESC1 reduced cell viability and sensitized cells to apoptosis, when cells were under apoptotic stimuli. The proapoptotic effect of DESC1 was mediated through downregulating AKT1 activation and the restoration of AKT activation by the introduction of the constitutively active AKT, myr-AKT, abolished the apoptosis-sensitizing effect of DESC1. DESC1 also reduced EGFR protein level, which was abrogated when the proteolytic function of DESC1 was lost, suggesting that DESC1 cleaved EGFR and downregulated the EGFR/AKT pathway to favor apoptosis. The transmembrane localization and the structural domains provide an opportunity for DESC1 to interact with the extracellular environment. The importance of such interaction was highlighted by the finding that DESC1 reduced cell colony formation ability in three-dimensional culture. In line with this, DESC1 reduced tumor growth kinetics in the in vivo orthotopic tumorigenesis assay. Taken together, our novel findings suggest how DESC1 may suppress ESCC development by sensitizing cells to apoptosis under an apoptotic stimulus through downregulating the EGFR/AKT signaling pathway.

Menschikowski M, Hagelgans A, Nacke B, et al.
Epigenetic control of group V phospholipase A2 expression in human malignant cells.
Tumour Biol. 2016; 37(6):8097-105 [PubMed] Related Publications
Secreted phospholipases A2 (sPLA2) are suggested to play an important role in inflammation and tumorigenesis. Different mechanisms of epigenetic regulation are involved in the control of group IIA, III and X sPLA2s expression in cancer cells, but group V sPLA2 (GV-PLA2) in this respect has not been studied. Here, we demonstrate the role of epigenetic mechanisms in regulation of GV-PLA2 expression in different cell lines originating from leukaemia and solid cancers. In blood leukocytes from leukaemic patients, levels of GV-PLA2 transcripts were significantly lower in comparison to those from healthy individuals. Similarly, in DU-145 and PC-3 prostate and CAL-51 and MCF-7 mammary cancer cell lines, levels of GV-PLA2 transcripts were significantly lower in relation to those found in normal epithelial cells of prostate or mammary. By sequencing and methylation-specific high-resolution melting (MS-HRM) analyses of bisulphite-modified DNA, distinct CpG sites in the GV-PLA2 promoter region were identified that were differentially methylated in cancer cells in comparison to normal epithelial and endothelial cells. Spearman rank order analysis revealed a significant negative correlation between the methylation degree and the cellular expression of GV-PLA2 (r = -0.697; p = 0.01). The effects of demethylating agent (5-aza-2'-deoxycytidine) and histone deacetylase inhibitor (trichostatin A) on GV-PLA2 transcription in the analysed cells confirmed the importance of DNA methylation and histone modification in the regulation of the GV-PLA2 gene expression in leukaemic, prostate and mammary cancer cell lines. The exposure of tumour cells to human recombinant GV-PLA2 resulted in a reduced colony forming activity of MCF-7, HepG2 and PC-3 cells, but not of DU-145 cells suggesting a cell-type-dependent effect of GV-PLA2 on cell growth. In conclusion, our results suggest that epigenetic mechanisms such as DNA methylation and histone modification play an important role in downregulation of GV-PLA2 expression in cancer cells.

O'Dwyer KM, Advani AS
When to Treat Adults Like Children: Optimizing Therapy for Lymphoblastic Lymphoma in Young Adults.
J Clin Oncol. 2016; 34(6):533-8 [PubMed] Related Publications
A 23-year-old man was urgently referred for evaluation of rapidly enlarging cervical lymphadenopathy, progressive dyspnea, fatigue, night sweats, and an unintentional weight loss of 25 pounds. A computed tomography scan of the neck performed 30 days before referral revealed bilateral cervical and supraclavicular lymphadenopathy (6 × 5 cm). A fine-needle aspirate of nasopharyngeal tissue demonstrated fibroadipose tissue. Tissue collected by core needle biopsy of a left internal jugular lymph node demonstrated a reactive lymph node but no malignancy. The patient was admitted to an academic medical center hospital. His physical examination was remarkable for bulky cervical and supraclavicular lymphadenopathy. A testicular examination was normal. The patient's lactate dehydrogenase concentration was 327 U/L (normal range, 118-225 U/L). A positron emission tomography scan revealed bilateral cervical and supraclavicular lymphadenopathy (6 × 5 cm with a standardized uptake value [SUV] of 14), a 1.3-cm subcutaneous nodule in the left thigh (SUV 16), and two 2.7-cm liver lesions (SUV 14). He underwent an excisional lymph node biopsy. The lymph node revealed effacement of the architecture by an interfollicular infiltrate of lymphoid cells (Fig 1). Mitotic figures were abundant (Ki-67 stain 80% to 90% positive) and there were multiple foci of tissue necrosis. The lymphoblasts were examined by flow cytometry and immunohistochemistry and expressed the T-cell markers CD2, CD3, CD4, and terminal deoxynucleotidyl transferase. A subpopulation of T cells was positive for both CD4 and CD8. Polymerase chain reaction studies revealed a clonal rearrangement of the T-cell receptor γ gene. A marrow aspirate and biopsy revealed normal trilineage hematopoiesis with no evidence of lymphoma and a normal male karyotype (46, XY). A lumbar puncture sample did not contain lymphoma cells. The patient's diagnosis was T-lymphoblastic lymphoma.

Benjamin RS, Casali PG
Adjuvant Imatinib for GI Stromal Tumors: When and For How Long?
J Clin Oncol. 2016; 34(3):215-8 [PubMed] Related Publications
A 45-year-old woman presented with syncope. She was severely anemic, with a hemoglobin level of 6 g/dL, and was found to have lower GI bleeding. A diagnostic colonoscopy was negative. A subsequent computed tomography scan of the abdomen and pelvis was performed, revealing a 3.2 × 3 × 2.9-cm contrast-enhancing right lower-quadrant mass arising from the wall of the ileum. There was no evidence of metastatic disease. The patient underwent laparotomy, and a 3.5-cm mass was resected with negative margins. Pathology revealed a GI stromal tumor with mixed spindle and epithelioid features involving the mucosa and submucosa (Fig 1A). The tumor cells were positive for CD117 (c-kit) (Fig 1B) and DOG-1(Fig 1C). There were eight to 10 mitoses per 50 high-power fields (Fig 1D). Molecular studies showed a 42-base pair deletion in exon 11 of the KIT gene that would delete all or part of codons 558 to 572 (V559_D572del) and would change the 558-encoding amino acid from Lys to Asn (K558N).

Lohberger B, Leithner A, Stuendl N, et al.
Diacerein retards cell growth of chondrosarcoma cells at the G2/M cell cycle checkpoint via cyclin B1/CDK1 and CDK2 downregulation.
BMC Cancer. 2015; 15:891 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Chondrosarcoma is characterized for its lack of response to conventional cytotoxic chemotherapy, propensity for developing lung metastases, and low rates of survival. Research within the field of development and expansion of new treatment options for unresectable or metastatic diseases is of particular priority. Diacerein, a symptomatic slow acting drug in osteoarthritis (SYSADOA), implicates a therapeutic benefit for the treatment of chondrosarcoma by an antitumor activity.
METHODS: After treatment with diacerein the growth behaviour of the cells was analyzed with the xCELLigence system and MTS assay. Cell cycle was examined using flow cytometric analysis, RT-PCR, and western blot analysis of specific checkpoint regulators. The status for phosophorylation of mitogen-activated protein kinases (MAPKs) was analyzed with a proteome profiler assay. In addition, the possible impact of diacerein on apoptosis was investigated using cleaved caspase 3 and Annexin V/PI flow cytometric analysis.
RESULTS: Diacerein decreased the cell viability and the cell proliferation in two different chondrosarcoma cell lines in a dose dependent manner. Flow cytometric analysis showed a classical G2/M arrest. mRNA and protein analysis revealed that diacerein induced a down-regulation of the cyclin B1-CDK1 complex and a reduction in CDK2 expression. Furthermore, diacerein treatment increased the phosphorylation of p38α and p38β MAPKs, and Akt1, Akt2, and Akt 3 in SW-1353, whereas in Cal-78 the opposite effect has been demonstrated. These observations accordingly to our cell cycle flow cytometric analysis and protein expression data may explain the G2/M phase arrest. In addition, no apoptotic induction after diacerein treatment, neither in the Cal-78 nor in the SW-1353 cell line was observed.
CONCLUSIONS: Our results demonstrate for the first time that the SYSADOA diacerein decreased the viability of human chondrosarcoma cells and induces G2/M cell cycle arrest by CDK1/cyclin B1 down-regulation.

Li DF, Yang MF, Shi SL, et al.
TM4SF5-CTD-2354A18.1-miR-4697-3P may play a key role in the pathogenesis of gastric cancer.
Bratisl Lek Listy. 2015; 116(10):608-15 [PubMed] Related Publications
AIMS: Our aim is to identify important lncRNAs and mRNAs which may play a key role in contributing to pathogenesis of gastric cancer.
METHODS: Different LncRNAs and mRNAs are identified by microarray in gastric cancer tissue and corresponding normal tissues. The function and relationship of different LncRNAs and mRNAs is performed by GO analysis and Pathway analysis and made code-non-code network (CNC) by Pearson correlation coefficients (PCC). Then mRNA-miRNA relationship is predicted through mRNA-miRNA relationship software (http://www.targetscan.org). Lastly, mRNA-miRNA-LncRNA network is established for further research.
RESULTS: The expression profiles of 3732 lncRNAs showed different expression (fold change (FC)≥2.0, p<0.05) in gastric cancer tissue and normal tissue and expression profiles of 3994 mRNAs also showed different expression (FC≥2.0, p<0.05) in gastric cancer and corresponding normal tissue.
CONCLUSION: The expression of TM4SF5, CTD-2354A18.1 and miR-4697-3P is in balance at physiological conditions, however, the balance is disrupted by some situations, which may contribute to gastric cancer. GO analysis and Pathway analysis also showed TM4SF5 played an important role in proliferation, differentiation and apoptosis. Therefore, TM4SF5-miR-4697-3P- CTD-2354A18.1 may play a key role in the pathogenesis of gastric cancer (Tab. 2, Fig. 4, Ref. 30).

Jeon MJ, Kim WG, Lim S, et al.
Alpha lipoic acid inhibits proliferation and epithelial mesenchymal transition of thyroid cancer cells.
Mol Cell Endocrinol. 2016; 419:113-23 [PubMed] Related Publications
The naturally occurring short-chain fatty acid, α-lipoic acid (ALA) is a powerful antioxidant which is clinically used for treatment of diabetic neuropathy. Recent studies suggested the possibility of ALA as a potential anti-cancer agent, because it could activate adenosine monophosphate activated protein kinase (AMPK) and inhibit transforming growth factor-β (TGFβ) pathway. In this study, we evaluate the effects of ALA on thyroid cancer cell proliferation, migration and invasion. We performed in vitro cell proliferation analysis using BCPAP, HTH-83, CAL-62 and FTC-133 cells. ALA suppressed thyroid cancer cell proliferation through activation of AMPK and subsequent down-regulation of mammalian target of rapamycin (mTOR)-S6 signaling pathway. Low-dose ALA, which had minimal effects on cell proliferation, also decreased cell migration and invasion of BCPAP, CAL-62 and HTH-83 cells. ALA inhibited epithelial mesenchymal transition (EMT) evidently by increase of E-cadherin and decreases of activated β-catenin, vimentin, snail, and twist in these cells. ALA suppressed TGFβ production and inhibited induction of p-Smad2 and twist by TGFβ1 or TGFβ2. These findings indicate that ALA reduces cancer cell migration and invasion through suppression of TGFβ production and inhibition of TGFβ signaling pathways in thyroid cancer cells. ALA also significantly suppressed tumor growth in mouse xenograft model using BCPAP and FTC-133 cells. This is the first study to show anti-cancer effect of ALA on thyroid cancer cells. ALA could be a potential therapeutic agent for treatment of advanced thyroid cancer, possibly as an adjuvant therapy with other systemic therapeutic agents.

Amayiri N, Tabori U, Campbell B, et al.
High frequency of mismatch repair deficiency among pediatric high grade gliomas in Jordan.
Int J Cancer. 2016; 138(2):380-5 [PubMed] Related Publications
Biallelic mismatch repair deficiency (bMMRD) is a cancer predisposition syndrome affecting primarily individuals from consanguinous families resulting in multiple childhood cancers including high grade gliomas (HGG). This is the first study to assess the prevalence of bMMRD among patients with HGG in countries where consanguinity is high. We collected molecular and clinical information on all children diagnosed with HGG and supratentorial primitive neuroectodermal tumors (sPNET) between 2003 and 2013 at King Hussein Cancer Center, Jordan. Comparison was made to a similar cohort from Toronto. Clinical data regarding presence of café au lait macules(CAL), family history of cancer, consanguinity, pathology and treatment were collected. Tumors were centrally reviewed and tested for MMRD by immunohistochemistry of the corresponding proteins. Forty-two patients fulfilled the inclusion criteria, including 36 with HGG. MMRD was observed in 39% of HGG of whom 79% also lost MMR staining in the corresponding normal cells suggestive of bMMRD. P53 dysfunction was highly enriched in MMR deficient tumors (p = 0.0003).The frequency of MMRD was significantly lower in Toronto cohort (23%, p = 0.03). Both evidence of CAL and consanguinity correlated with bMMRD (p = 0.005 and 0.05,respectively) but family history of cancer didn't. HGG with all three bMMRD risk factors had evidence of MMRD and all children affected by multiple bMMRD related cancers had identical gene loss by immunohistochemical staining. In Jordan, the frequency of clinical and immunohistochemical alterations suggestive of bMMRD in pediatric HGG is high. Genetic testing will enable appropriate counseling and cancer screening to improve survival of these patients.

Chen LL, Han WF, Geng Y, Su JS
A genome-wide study of DNA methylation modified by epigallocatechin-3-gallate in the CAL-27 cell line.
Mol Med Rep. 2015; 12(4):5886-90 [PubMed] Related Publications
In order to gain greater understanding of the mechanisms underlying the effect of epigallocatechin-3-gallate (EGCG) on DNA methylation and its chemopreventative action in oral squamous cell carcinoma (OSCC), a genome‑wide methylation and mRNA expression screen was performed in the CAL‑27 cell line with and without EGCG (100 µM) treatment. A total of 761 differentially methylated gene loci were identified following treatment with EGCG. Comparison of gene expression profiling in OSCC samples revealed 184 transcripts with a significant difference (P<0.05) and a fold change difference >2 compared with controls. Gene ontology analysis of differentially methylated loci and functional annotation of the differentially expressed genes indicated that the main pathways involved were metabolic, mitogen‑activated protein kinase (MAPK), wnt, and cell cycle pathways. In conclusion, the present study indicates that EGCG can affect the methylation status and gene expression in the CAL‑27 cell line. Additionally, the changes in several important signaling pathways may reveal the antitumor mechanism of EGCG.

Li D, Xu D, Lu Z, et al.
Overexpression of transforming growth factor type III receptor restores TGF-β1 sensitivity in human tongue squamous cell carcinoma cells.
Biosci Rep. 2015; 35(4) [PubMed] Free Access to Full Article Related Publications
The transforming growth factor type III receptor (TβRIII), also known as β-glycan, is a multi-functional sensor that regulates growth, migration and apoptosis in most cancer cells. We hereby investigated the expression of TβRIII in clinical specimens of tongue squamous cell carcinoma (TSCC) and the underlying mechanism that TβRIII inhibits the growth of CAL-27 human oral squamous cells. The TSCC tissues showed a significant decrease in TβRIII protein expression as detected by immunohistochemistry (IHC) and western blot analysis. Transfection of TβRIII-containing plasmid DNA dramatically promoted TGF-β1 (10 ng/ml)-induced decrease in cell viability, apoptosis and cell arrest at the G0-/G1-phase. Moreover, transient overexpression of TβRIII enhanced the TGF-β1-induced cyclin-dependent kinase inhibitor 2b (CDKN2b) and p38 protein activity, but did not affect the activities of extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase 1/2 (JNK1/2) in CAL-27 cells. These results suggest overexpression of TβRIII receptor restored TGF-β1 sensitivity in CAL-27 cells, which may provide some new insights on exploiting this molecule therapeutically.

Stamatkin C, Ratermann KL, Overley CW, Black EP
Inhibition of class IA PI3K enzymes in non-small cell lung cancer cells uncovers functional compensation among isoforms.
Cancer Biol Ther. 2015; 16(9):1341-52 [PubMed] Free Access to Full Article Related Publications
Deregulation of the phosphatidylinositol 3-kinase (PI3K) pathway is central to many human malignancies while normal cell proliferation requires pathway functionality. Although inhibitors of the PI3K pathway are in clinical trials or approved for therapy, an understanding of the functional activities of pathway members in specific malignancies is needed. In lung cancers, the PI3K pathway is often aberrantly activated by mutation of genes encoding EGFR, KRAS, and PIK3CA proteins. We sought to understand whether class IA PI3K enzymes represent rational therapeutic targets in cells of non-squamous lung cancers by exploring pharmacological and genetic inhibitors of PI3K enzymes in a non-small cell lung cancer (NSCLC) cell line system. We found that class IA PI3K enzymes were expressed in all cell lines tested, but treatment of NSCLC lines with isoform-selective inhibitors (A66, TGX-221, CAL-101 and IC488743) had little effect on cell proliferation or prolonged inhibition of AKT activity. Inhibitory pharmacokinetic and pharmacodynamic responses were observed using these agents at non-isoform selective concentrations and with the pan-class I (ZSTK474) agent. Response to pharmacological inhibition suggested that PI3K isoforms may functionally compensate for one another thus limiting efficacy of single agent treatment. However, combination of ZSTK474 and an EGFR inhibitor (erlotinib) in NSCLC resistant to each single agent reduced cellular proliferation. These studies uncovered unanticipated cellular responses to PI3K isoform inhibition in NSCLC that does not correlate with PI3K mutations, suggesting that patients bearing tumors with wildtype EGFR and KRAS are unlikely to benefit from inhibitors of single isoforms but may respond to pan-isoform inhibition.

Wu J, Xie H
Expression of long noncoding RNA-HOX transcript antisense intergenic RNA in oral squamous cell carcinoma and effect on cell growth.
Tumour Biol. 2015; 36(11):8573-8 [PubMed] Related Publications
The aim of this study was to analyze the correlation between long noncoding RNA-HOX transcript antisense intergenic RNA (HOTAIR) and the clinical pathological characteristics and prognosis of oral squamous cell carcinoma (OSCC) and to evaluate the effect on cell growth. HOTAIR expressions in 50 surgically resected samples (including tumor and paracancerous tissues) collected from OSCC patients treated in our hospital from January 2009 to December 2010 were detected by real-time quantitative reverse transcription-PCR, and the relationship with clinical pathological characteristics and prognosis was analyzed. The effect of small interfering RNA treatment on cell growth (Tca8113, UM-1, and CAL-27 cells) was evaluated by MTT assay, and those on apoptosis and cell cycle were assessed by flow cytometry. HOTAIR was positively expressed in 45 samples (90 %). The expression level in tumor tissues was significantly higher than that in paracancerous tissues (t = 5.459, P < 0.01). Relative expression level of HOTAIR was correlated with tumor size and clinical stage (P < 0.05). More HOTAIR was expressed in OSCC cell lines than in normal oral epithelial cells. Interfering with HOTAIR expression in Tca8113 cells significantly decelerated cell growth, arrested cell cycle, and promoted apoptosis (P < 0.01). HOTAIR was highly expressed in OSCC tissues and facilitated the growth of OSCC cells, thus probably being an eligible molecular marker for OSCC diagnosis and prognosis determination.

Magbanua MJ, Wolf DM, Yau C, et al.
Serial expression analysis of breast tumors during neoadjuvant chemotherapy reveals changes in cell cycle and immune pathways associated with recurrence and response.
Breast Cancer Res. 2015; 17:73 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: The molecular biology involving neoadjuvant chemotherapy (NAC) response is poorly understood. To elucidate the impact of NAC on the breast cancer transcriptome and its association with clinical outcome, we analyzed gene expression data derived from serial tumor samples of patients with breast cancer who received NAC in the I-SPY 1 TRIAL.
METHODS: Expression data were collected before treatment (T1), 24-96 hours after initiation of chemotherapy (T2) and at surgery (TS). Expression levels between T1 and T2 (T1 vs. T2; n = 36) and between T1 and TS (T1 vs. TS; n = 39) were compared. Subtype was assigned using the PAM50 gene signature. Differences in early gene expression changes (T2 - T1) between responders and nonresponders, as defined by residual cancer burden, were evaluated. Cox proportional hazards modeling was used to identify genes in residual tumors associated with recurrence-free survival (RFS). Pathway analysis was performed with Ingenuity software.
RESULTS: When we compared expression profiles at T1 vs. T2 and at T1 vs. TS, we detected significantly altered expression of 150 and 59 transcripts, respectively. We observed notable downregulation of proliferation and immune-related genes at T2. Lower concordance in subtype assignment was observed between T1 and TS (62 %) than between T1 and T2 (75 %). Analysis of early gene expression changes (T2 - T1) revealed that decreased expression of cell cycle inhibitors was associated with poor response. Increased interferon signaling (TS - T1) and high expression of cell proliferation genes in residual tumors (TS) were associated with reduced RFS.
CONCLUSIONS: Serial gene expression analysis revealed candidate immune and proliferation pathways associated with response and recurrence. Larger studies incorporating the approach described here are warranted to identify predictive and prognostic biomarkers in the NAC setting for specific targeted therapies.
CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00033397 . Registered 9 Apr 2002.

Park GB, Hur DY, Kim D
Combining CAL-101 with Celecoxib Enhances Apoptosis of EBV-transformed B-Cells Through MAPK-induced ER Stress.
Anticancer Res. 2015; 35(5):2699-708 [PubMed] Related Publications
BACKGROUND: Phosphoinositide-3 kinase (PI3K) inhibition attenuates proliferation and survival in B-cell malignancies. Celecoxib induces endoplasmic reticulum (ER) stress-induced apoptosis via a cyclo-oxgenase-2 (COX2)-independent manner in certain types of cancer cells. In the present study, we assessed the effects of combinations of drugs with a p110δ-specific inhibitor, CAL-101, and celecoxib to induce apoptosis in Epstein-Barr virus (EBV)-transformed B-cells and non-Hodgkin's lymphoma (NHL) cells.
MATERIALS AND METHODS: The apoptotic effect of combination treatment with CAL-101 and celecoxib on B-cell malignancies was determined by flow cytometry and immunoblotting.
RESULTS: Exposure to CAL-101 and celecoxib significantly increased apoptosis, which was accompanied by the inactivation of AKT, Ras homolog gene family, member A (RHOA), Rho-associated coiled-coil containing protein kinase 1 (ROCK1), and ROCK2 as well as up-regulation of Phosphatase and tensin homolog (PTEN). Co-treatment with CAL-101 and celecoxib triggered the ER stress response and the down-regulation of BCL2 and BCL-XL. SB203580, SP600125, and salubrinal effectively inhibited apoptosis and attenuated expression of phosphorylated protein kinase RNA-like endoplasmic reticulum kinase (PERK) and CCAAT-enhancer-binding protein homologous protein (CHOP). Levels of apoptosis signal-regulating kinase 1 (ASK1) were also increased after treatment with CAL-101 and celecoxib.
CONCLUSION: The apoptosis of EBV-transformed B-cells and NHL cells caused by CAL-101 and celecoxib might be related to inhibiting the RHOA/ROCK pathway and might also be associated with mitogen-activated protein kinase (MAPK)-mediated ER stress.

Govindan SV, Kulsum S, Pandian RS, et al.
Establishment and characterization of triple drug resistant head and neck squamous cell carcinoma cell lines.
Mol Med Rep. 2015; 12(2):3025-32 [PubMed] Related Publications
Resistance to chemotherapy leading to poor outcome and survival remains a challenge for developing strategies for therapeutic interventions in all types of cancer, including head and neck cancer. In vitro chemoresistant cell line models are an indispensable resource towards delineating the mechanisms involved in drug resistance/response and for the development of novel drugs. Current treatment for head and neck cancer includes chemotherapy with cisplatin, docetaxel and 5-fluorouracil (5-FU) and the response rates to these drugs in patients is 60-80%. The present study aimed to generate head and neck cancer triple drug-resistant cell lines in an effort towards elucidating the mechanisms underlying chemoresistance and providing a resourceful tool for drug design. Using two head and neck squamous cell carcinoma cell lines, Hep-2 (larynx) and CAL-27 (oral cavity), the present study sequentially exposed these cells to increasing concentrations of the combination of docetaxel, cisplatin and 5-FU (TPF) to generate triple drug-resistant cells, termed Hep-2 TPF resistant (TPFR) and CAL-27 TPFR. The effect of the drug treatments on the cell viability, apoptosis, cell cycle and the expression of genes associated with multidrug resistance were analyzed in the parental cells and drug-resistant counterparts.

Xu P, Li Y, Yang S, et al.
Micro-ribonucleic acid 143 (MiR-143) inhibits oral squamous cell carcinoma (OSCC) cell migration and invasion by downregulation of phospho-c-Met through targeting CD44 v3.
Oral Surg Oral Med Oral Pathol Oral Radiol. 2015; 120(1):43-51 [PubMed] Related Publications
OBJECTIVE: The aim of this study was to investigate the roles and mechanisms of Micro-ribonucleic acid 143 (miR-143) in oral squamous cell carcinoma cells.
STUDY DESIGN: Following the detection of miR-143 expression, cell proliferation, migration, and invasion assays and Western blot analysis were conducted in the oral squamous cell carcinoma (OSCC) cell lines.
RESULTS: We found that the expression of miR-143 was significantly decreased in the OSCC cell lines (SCC-4, Tca-8113, CAL-27) and tumor tissues. Meanwhile, miR-143 was significantly correlated with the migration and invasion in OSCC cell lines. Further investigation revealed that the expression level of miR-143 was opposite to that of its potential target gene-CD44 v3 and was also related to phospho-c-Met activation.
CONCLUSIONS: miR-143 could exert significantly suppressive effects on the ability of migration and invasion in OSCC cell lines, and the mechanism of this might be related to the activity of phospho-c-met though the CD44 v3/HGF signal. miR-143 could thus provide new applications for the treatment of OSCC.

Ong CC, Gierke S, Pitt C, et al.
Small molecule inhibition of group I p21-activated kinases in breast cancer induces apoptosis and potentiates the activity of microtubule stabilizing agents.
Breast Cancer Res. 2015; 17:59 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Breast cancer, the most common cause of cancer-related deaths worldwide among women, is a molecularly and clinically heterogeneous disease. Extensive genetic and epigenetic profiling of breast tumors has recently revealed novel putative driver genes, including p21-activated kinase (PAK)1. PAK1 is a serine/threonine kinase downstream of small GTP-binding proteins, Rac1 and Cdc42, and is an integral component of growth factor signaling networks and cellular functions fundamental to tumorigenesis.
METHODS: PAK1 dysregulation (copy number gain, mRNA and protein expression) was evaluated in two cohorts of breast cancer tissues (n=980 and 1,108). A novel small molecule inhibitor, FRAX1036, and RNA interference were used to examine PAK1 loss of function and combination with docetaxel in vitro. Mechanism of action for the therapeutic combination, both cellular and molecular, was assessed via time-lapse microscopy and immunoblotting.
RESULTS: We demonstrate that focal genomic amplification and overexpression of PAK1 are associated with poor clinical outcome in the luminal subtype of breast cancer (P=1.29×10(-4) and P=0.015, respectively). Given the role for PAK1 in regulating cytoskeletal organization, we hypothesized that combination of PAK1 inhibition with taxane treatment could be combined to further interfere with microtubule dynamics and cell survival. Consistent with this, administration of docetaxel with either a novel small molecule inhibitor of group I PAKs, FRAX1036, or PAK1 small interfering RNA oligonucleotides dramatically altered signaling to cytoskeletal-associated proteins, such as stathmin, and induced microtubule disorganization and cellular apoptosis. Live-cell imaging revealed that the duration of mitotic arrest mediated by docetaxel was significantly reduced in the presence of FRAX1036, and this was associated with increased kinetics of apoptosis.
CONCLUSIONS: Taken together, these findings further support PAK1 as a potential target in breast cancer and suggest combination with taxanes as a viable strategy to increase anti-tumor efficacy.

Antonova O, Yossifova L, Staneva R, et al.
Changes in the gene expression profile of the bladder cancer cell lines after treatment with Helix lucorum and Rapana venosa hemocyanin.
J BUON. 2015 Jan-Feb; 20(1):180-7 [PubMed] Related Publications
PURPOSE: The purpose of this study was to elucidate the mechanism of action of the Helix lucorum hemocyanin (HlH), b-HlH-h, and RvH2-g hemocyanins as potential agents against bladder cancer.
METHODS: We evaluated the viability of 647-V, T-24, and CAL-29 bladder cancer cell lines after treatment with the tested hemocyanins. The cell viability was measured at 72 hrs with MTT and WST-1 assays. Acridine orange/propidium iodide double staining was used to discriminate between apoptotic and necrotic cells. Gene expression profiling of the 168 genes from human inflammatory cytokines and signal transduction pathways were performed on the tumor cells before and after hemocyanins' treatment.
RESULTS: The results showed decreased survival of cancer cells in the presence of HlH and two functional units: b-HlH-h and RvH2-g. Acridine orange/propidium iodide double staining revealed that the decreased viability was due to apoptosis. The gene expression data showed upregulation of genes involved in the apoptosis as well as of the immune system activation, and downregulation of the CCL2, CCL17, CCL21, CXCL1, and ABCF1 genes.
CONCLUSIONS: The present study is the first to report gene expression in human cells under the influence of hemocyanins. The mechanism of antitumor activity of the HlH, b-HlH-h, and RvH2-g hemocyanins includes induction of apoptosis. In addition to the antiproliferative effect, downregulation of the genes with metastatic potential was observed. Together with the already known immunogenic effect, these findings support further studies on hemocyanins as potential therapeutic agents against bladder cancer.

Haluskova J, Lachvac L, Nagy V
The investigation of GSTP1, APC and RASSF1 gene promoter hypermethylation in urine DNA of prostate-diseased patients.
Bratisl Lek Listy. 2015; 116(2):79-82 [PubMed] Related Publications
OBJECTIVES: Prostate cancer (PCa) represents one of the most complicated human tumors and, like many others malignancies, arises from progressive genetic and epigenetic alterations. Among all recognized epigenetic alterations, aberrant DNA methylation (hypo- and hypermethylation) is the most important and the best characterized change in PCa.
BACKGROUND: We analyzed GSTP1, APC and RASSF1 gene promoter hypermethylation in urine DNA of ten previously non-treated prostate-diseased patients.
METHODS: For the purpose, the quantitative real-time methylation specific PCR (MSP) with primers designed for amplification of methylated bisulfite-converted human DNA, followed by melting procedure, was currently optimized.
RESULTS: GSTP1 gene promoter hypermethylation was detected in 2 and 1 out of 5 patients with biopsy-confirmed PCa using the primers covering the 3´ and 5´ CpG regions of the promoter, respectively. The APC gene promoter hypermethylation was found in neither of PCa or non-PCa patients and the RASSFI gene promoter hypermethylation was found in some non-PCa and not in all PCa patients.
CONCLUSIONS: Our results suggest that GSTP1 gene promoter hypermethylation can be detected in urine DNA of PCa patients with real-time MSP followed by melting. This enables evaluation of its potential as a useful biomarker in the diagnosis and prognosis of PCa (Tab. 1, Fig. 1, Ref. 9).

Cal S, López-Otín C
ADAMTS proteases and cancer.
Matrix Biol. 2015 May-Jul; 44-46:77-85 [PubMed] Related Publications
ADAMTSs (A disintegrin and metalloprotease domains with thrombospondins motifs) are complex extracellular proteases that have been related to both oncogenic and tumor-protective functions. These enzymes can be secreted by cancer and stromal cells and may contribute to modify the tumor microenvironment by multiple mechanisms. Thus, ADAMTSs can cleave or interact with a wide range of extracellular matrix components or regulatory factors, and therefore affect cell adhesion, migration, proliferation and angiogenesis. The balance of protumor versus antitumor effects of ADAMTSs may depend on the nature of their substrates or interacting-partners upon secretion from the cell. Moreover, different ADAMTS genes have been found overexpressed, mutated or epigenetically silenced in tumors from different origins, suggesting the direct impact of these metalloproteases in cancer development. However, despite the important advances on the tumor biology of ADAMTSs in recent years, more mechanistic and functional studies are necessary to fully understand how these proteases can influence tumor microenvironment to potentiate cancer growth or to induce tumor regression. This review outlines current and emerging connections between ADAMTSs and cancer.

Disclaimer: This site is for educational purposes only; it can not be used in diagnosis or treatment.

Cite this page: Cotterill SJ. GOPC, Cancer Genetics Web: http://www.cancer-genetics.org/GOPC.htm Accessed:

Creative Commons License
This page in Cancer Genetics Web by Simon Cotterill is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Note: content of abstracts copyright of respective publishers - seek permission where appropriate.

 [Home]    Page last revised: 16 March, 2017     Cancer Genetics Web, Established 1999