Gene Summary

Gene:CAST; calpastatin
Aliases: BS-17, PLACK
Summary:The protein encoded by this gene is an endogenous calpain (calcium-dependent cysteine protease) inhibitor. It consists of an N-terminal domain L and four repetitive calpain-inhibition domains (domains 1-4), and it is involved in the proteolysis of amyloid precursor protein. The calpain/calpastatin system is involved in numerous membrane fusion events, such as neural vesicle exocytosis and platelet and red-cell aggregation. The encoded protein is also thought to affect the expression levels of genes encoding structural or regulatory proteins. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jun 2010]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 25 June, 2015


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 25 June 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.

Tag cloud generated 25 June, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

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: CAST (cancer-related)

Johnston SB, Raines RT
Conformational stability and catalytic activity of PTEN variants linked to cancers and autism spectrum disorders.
Biochemistry. 2015; 54(7):1576-82 [PubMed] Free Access to Full Article Related Publications
Phosphoinositides are membrane components that play critical regulatory roles in mammalian cells. The enzyme PTEN, which catalyzes the dephosphorylation of the phosphoinositide PIP3, is damaged in most sporadic tumors. Mutations in the PTEN gene have also been linked to autism spectrum disorders and other forms of delayed development. Here, human PTEN is shown to be on the cusp of unfolding under physiological conditions. Variants of human PTEN linked to somatic cancers and disorders on the autism spectrum are shown to be impaired in their conformational stability, catalytic activity, or both. Those variants linked only to autism have activity higher than the activity of those linked to cancers. PTEN-L, which is a secreted trans-active isoform, has conformational stability greater than that of the wild-type enzyme. These data indicate that PTEN is a fragile enzyme cast in a crucial role in cellular metabolism and suggest that PTEN-L is a repository for a critical catalytic activity.

Ahmed RK, Poiret T, Ambati A, et al.
TCR+CD4-CD8- T cells in antigen-specific MHC class I-restricted T-cell responses after allogeneic hematopoietic stem cell transplantation.
J Immunother. 2014; 37(8):416-25 [PubMed] Related Publications
Human TCRαβ(+) CD4(-)CD8(-) double-negative (DN) T cells represent a minor subset in peripheral blood, yet are important in infectious diseases and autoimmune responses. We examined the frequency of DN T cells in 17 patients after allogeneic hematopoietic stem cell transplantation (aHSCT) at 1, 2, 3, 6, and 12 months post-aHSCT and show that these cells increase early after aHSCT and decrease with time after aHSCT. DN T cells reside in the terminally differentiated effector (CD45RA(+)CCR7(-)) T-cell population and are polyclonal, determined by T-cell receptor Vβ CDR3 analysis. Gene expression analysis of ex vivo sorted DN T cells showed a distinct set of gene expression, including interleukin-8, as compared with CD4(+) or CD8(+) T cells. DN T cells contributed to MHC class I-restricted EBV-directed immune responses, defined by antigen-specific cytokine production and by detection of HLA-A*02:01-restricted EBV BMLF-1 (GLCTLVAML), LMP-2A (CLGGLLTMV), and HLA-A*24:02-restricted EBV BRLF-1 (DYCNVLNKEF) and EBNA3 (RYSIFFDY)-specific T cells. We created retroviral-transfected Jurkat cell lines with a Melan-A/MART-1-specific TCR(+) and the CD8α chain to study TCR(+) DN T cells in response to their nominal MHC class I/peptide ligand. We show that DN T cells exhibit increased TCRζ chain phosphorylation as compared with the TCR(+)CD8(+) transgenic T-cell line. DN T cells contribute to antigen-specific T-cell responses and represent an effector T-cell population that may be explored in immunotherapeutic approaches against viral infections or transformed cells.

Klammer M, Dybowski JN, Hoffmann D, Schaab C
Identification of significant features by the Global Mean Rank test.
PLoS One. 2014; 9(8):e104504 [PubMed] Free Access to Full Article Related Publications
With the introduction of omics-technologies such as transcriptomics and proteomics, numerous methods for the reliable identification of significantly regulated features (genes, proteins, etc.) have been developed. Experimental practice requires these tests to successfully deal with conditions such as small numbers of replicates, missing values, non-normally distributed expression levels, and non-identical distributions of features. With the MeanRank test we aimed at developing a test that performs robustly under these conditions, while favorably scaling with the number of replicates. The test proposed here is a global one-sample location test, which is based on the mean ranks across replicates, and internally estimates and controls the false discovery rate. Furthermore, missing data is accounted for without the need of imputation. In extensive simulations comparing MeanRank to other frequently used methods, we found that it performs well with small and large numbers of replicates, feature dependent variance between replicates, and variable regulation across features on simulation data and a recent two-color microarray spike-in dataset. The tests were then used to identify significant changes in the phosphoproteomes of cancer cells induced by the kinase inhibitors erlotinib and 3-MB-PP1 in two independently published mass spectrometry-based studies. MeanRank outperformed the other global rank-based methods applied in this study. Compared to the popular Significance Analysis of Microarrays and Linear Models for Microarray methods, MeanRank performed similar or better. Furthermore, MeanRank exhibits more consistent behavior regarding the degree of regulation and is robust against the choice of preprocessing methods. MeanRank does not require any imputation of missing values, is easy to understand, and yields results that are easy to interpret. The software implementing the algorithm is freely available for academic and commercial use.

Shinmei S, Sentani K, Hayashi T, et al.
Identification of PRL1 as a novel diagnostic and therapeutic target for castration-resistant prostate cancer by the Escherichia coli ampicillin secretion trap (CAST) method.
Urol Oncol. 2014; 32(6):769-78 [PubMed] Related Publications
OBJECTIVES: Although chemotherapy for castration-resistant prostate cancer (CRPC) has been applied clinically in recent years, the effects are not sufficient. It is urgently necessary to develop novel therapeutics for CRPC. We previously generated Escherichia coli ampicillin secretion trap libraries of 2 prostate cancer (PCa) cell lines and normal prostate. By comparing the E. coli ampicillin secretion trap libraries of CRPC cell lines with those of androgen-sensitive PCa cell lines and normal prostate, we focused on the protein-tyrosine-phosphatase of regenerating liver 1 (PRL1) gene and analyzed its expression and biological function.
MATERIALS AND METHODS: The expression of PRL1 was examined by quantitative reverse transcription polymerase chain reaction and immunohistochemistry in clinical PCa samples. The effects of PRL1 on PCa cells were evaluated by cell growth, migration, and invasion assays. To investigate the effect of PRL1 on epidermal growth factor receptor (EGFR) signaling, PRL1 knockdown PC3 cells were examined by Western blot and immunohistochemical analyses.
RESULTS: Quantitative reverse transcription polymerase chain reaction revealed that PRL1 was expressed much more highly in PCa than in nonneoplastic prostate samples. High expression of PRL1 detected by immunohistochemistry correlated with poor prognosis after prostatectomy and combined androgen blockade therapy. Functional analysis indicated that PRL1 stimulated cell growth, migration, and invasion in PCa cell lines. Expression EGFR and matrix metalloproteinase 9 was reduced by knockdown of PRL1 in the PC3 cell line.
CONCLUSIONS: PRL1 regulates expression of EGFR and modulates downstream targets. PRL1 has potential as a therapeutic target in PCa including CRPC.

Oo HZ, Sentani K, Sakamoto N, et al.
Overexpression of ZDHHC14 promotes migration and invasion of scirrhous type gastric cancer.
Oncol Rep. 2014; 32(1):403-10 [PubMed] Related Publications
Scirrhous type gastric cancer is highly aggressive and has a poorer prognosis than many other types of gastric carcinoma, due to its characteristic rapid cancer cell infiltration and proliferation, extensive stromal fibrosis, and frequent peritoneal dissemination. The aim of the present study was to identify novel prognostic markers or therapeutic targets for scirrhous type gastric cancer. We reviewed a list of genes with upregulated expression in scirrhous type gastric cancer and compared their expression with that in normal stomach from our previous Escherichia coli (E. coli) ampicillin secretion-trap (CAST) analysis. We focused on the ZDHHC14 gene, which encodes zinc finger, DHHC-type containing 14 protein. qRT-PCR analysis of ZDHHC14 in 41 gastric cancer cases revealed that compared to mRNA levels in normal non-neoplastic gastric mucosa, ZDHHC14 mRNA was overexpressed in 27% of gastric cancer tissue samples. The overexpression of ZDHHC14 was significantly associated with depth of tumor invasion, undifferentiated histology and scirrhous pattern. The invasiveness of ZDHHC14-knockdown HSC-44PE and 44As3 gastric cancer cells was decreased in comparison with that of the negative control siRNA-transfected cells, together with downregulation of MMP-17 mRNA. Integrins α5 and β1 were also downregulated in ZDHHC14-knockdown 44As3 cells. Forced expression of ZDHHC14 activated gastric cancer cell migration and invasion in vitro. These results indicate that ZDHHC14 is involved in tumor progression in patients with scirrhous type gastric cancer.

Oo HZ, Sentani K, Sakamoto N, et al.
Identification of novel transmembrane proteins in scirrhous-type gastric cancer by the Escherichia coli ampicillin secretion trap (CAST) method: TM9SF3 participates in tumor invasion and serves as a prognostic factor.
Pathobiology. 2014; 81(3):138-48 [PubMed] Related Publications
OBJECTIVE: Scirrhous-type gastric cancer (GC) is highly aggressive and has a poor prognosis due to rapid cancer cell infiltration accompanied by extensive stromal fibrosis. The aim of this study is to identify genes that encode transmembrane proteins frequently expressed in scirrhous-type GC.
METHODS: We compared Escherichia coli ampicillin secretion trap (CAST) libraries from 2 human scirrhous-type GC tissues with a normal stomach CAST library. By sequencing 2,880 colonies from scirrhous CAST libraries, we identified a list of candidate genes.
RESULTS: We focused on the TM9SF3 gene because it has the highest clone count, and immunohistochemical analysis demonstrated that 46 (50%) of 91 GC cases were positive for TM9SF3, which was observed frequently in scirrhous-type GC. TM9SF3 expression showed a significant correlation with the depth of invasion, tumor stage and undifferentiated GC. There was a strong correlation between TM9SF3 expression and poor patient outcome, which was validated in two separate cohorts by immunostaining and quantitative RT-PCR, respectively. Transient knockdown of the TM9SF3 gene by siRNA showed decreased tumor cell-invasive capacity.
CONCLUSION: Our results indicate that TM9SF3 might be a potential diagnostic and therapeutic target for scirrhous-type GC.

Li P, Yang R, Gao WQ
Contributions of epithelial-mesenchymal transition and cancer stem cells to the development of castration resistance of prostate cancer.
Mol Cancer. 2014; 13:55 [PubMed] Free Access to Full Article Related Publications
An important clinical challenge in prostate cancer therapy is the inevitable transition from androgen-sensitive to castration-resistant and metastatic prostate cancer. Albeit the androgen receptor (AR) signaling axis has been targeted, the biological mechanism underlying the lethal event of androgen independence remains unclear. New emerging evidences indicate that epithelial-to-mesenchymal transition (EMT) and cancer stem cells (CSCs) play crucial roles during the development of castration-resistance and metastasis of prostate cancer. Notably, EMT may be a dynamic process. Castration can induce EMT that may enhance the stemness of CSCs, which in turn results in castration-resistance and metastasis. Reverse of EMT may attenuate the stemness of CSCs and inhibit castration-resistance and metastasis. These prospective approaches suggest that therapies target EMT and CSCs may cast a new light on the treatment of castration-resistant prostate cancer (CRPC) in the future. Here we review recent progress of EMT and CSCs in CRPC.

Kuo CH, Liu CJ, Lu CY, et al.
17β-estradiol inhibits mesenchymal stem cells-induced human AGS gastric cancer cell mobility via suppression of CCL5- Src/Cas/Paxillin signaling pathway.
Int J Med Sci. 2014; 11(1):7-16 [PubMed] Free Access to Full Article Related Publications
Gender differences in terms of mortality among many solid organ malignancies have been proved by epidemiological data. Estrogen has been suspected to cast a protective effect against cancer because of the lower mortality of gastric cancer in females and the benefits of hormone replacement therapy (HRT) in gastric cancer. Hence, it suggests that 17β-estradiol (E2) may affect the behavior of cancer cells. One of the key features of cancer-related mortality is metastasis. Accumulating evidences suggest that human bone marrow mesenchymal stem cells (HBMMSCs) and its secreted CCL-5 have a role in enhancing the metastatic potential of breast cancer cells. However, it is not clear whether E2 would affect HBMMSCs-induced mobility in gastric cancer cells. In this report, we show that CCL-5 secreted by HBMMSCs enhanced mobility in human AGS gastric cancer cells via activation of Src/Cas/Paxillin signaling pathway. Treatment with specific neutralizing antibody of CCL-5 significantly inhibited HBMMSCs-enhanced mobility in human AGS gastric cancer cells. We further observe that 17β-estradiol suppressed HBMMSCs-enhanced mobility by down-regulating CCL5-Src/Cas/paxillin signaling pathway in AGS cells. Collectively, these results suggest that 17β-estradiol treatment significantly inhibits HBMMSCS-induced mobility in human AGS gastric cancer cells.

Wolf J, Müller-Decker K, Flechtenmacher C, et al.
An in vivo RNAi screen identifies SALL1 as a tumor suppressor in human breast cancer with a role in CDH1 regulation.
Oncogene. 2014; 33(33):4273-8 [PubMed] Related Publications
The gold standard for determining the tumorigenic potential of human cancer cells is a xenotransplantation into immunodeficient mice. Higher tumorigenicity of cells is associated with earlier tumor onset. Here, we used xenotransplantation to assess the tumorigenic potential of human breast cancer cells following RNA interference-mediated inhibition of over 5000 genes. We identify 16 candidate tumor suppressors, one of which is the zinc-finger transcription factor SALL1. Analyzing this particular molecule in more detail, we show that inhibition of SALL1 correlates with reduced levels of CDH1, an important contributor to epithelial-to-mesenchymal transition. Furthermore, SALL1 expression led to an increased migration and more than twice as many cells expressing a cancer stem cell signature. Also, SALL1 expression correlates with the survival of breast cancer patients. These findings cast new light on a gene that has previously been described to be relevant during embryogenesis, but not carcinogenesis.

Bond WS, Akinfenwa PY, Perlaky L, et al.
Tumorspheres but not adherent cells derived from retinoblastoma tumors are of malignant origin.
PLoS One. 2013; 8(6):e63519 [PubMed] Free Access to Full Article Related Publications
Verification that cell lines used for cancer research are derived from malignant cells in primary tumors is imperative to avoid invalidation of study results. Retinoblastoma is a childhood ocular tumor that develops from loss of functional retinoblastoma protein (pRb) as a result of genetic or epigenetic changes that affect both alleles of the RB1 gene. These patients contain unique identifiable genetic signatures specifically present in malignant cells. Primary cultures derived from retinoblastoma tumors can be established as non-adherent tumorspheres when grown in defined media or as attached monolayers when grown in serum-containing media. While the RB1 genotypes of tumorspheres match those of the primary tumor, adherent cultures have the germline RB1 genotype. Tumorspheres derived from pRb-negative tumors do not express pRb and express the neuroendocrine tumor markers synaptophysin and microtubule-associated protein 2 (MAP2). Adherent cells are synaptophysin-negative and express pRb, the epithelial cell marker cytokeratin that is expressed in the retinal pigmented epithelium and the vascular endothelial cell marker CD34. While tumorspheres are of malignant origin, our results cast doubt on the assumption that adherent tumor-derived cultures are always valid in vitro models of malignant cells and emphasize the need for validation of primary tumor cultures.

Tang Y, Xu L
Superiority and clinical significance of Lunx mRNA in the diagnosis of malignant pleural effusion caused by pulmonary carcinoma.
J Exp Clin Cancer Res. 2013; 32:37 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Pulmonary carcinoma is the main cause of malignant pleural effusions (MPEs). However, there is no satisfactory marker for diagnosing MPEs caused by pulmonary carcinoma. The purpose of this study is to assess the clinical significance of Lunx mRNA detection in diagnosing MPEs caused by pulmonary carcinoma.
METHODS: A total of 209 patients with pleural effusions were recruited. The patients were diagnosed by cast-off cells, bronchoscopy, and pleural biopsy. The levels of Lunx mRNA in the pleural effusions were determined by real-time PCR. The levels of PH, LDH, glucose, albumin, and CEA were also determined. Patients who accepted chemotherapy underwent Lunx mRNA detection before and after the first chemotherapy session. The patients were divided into four groups according the effect of chemotherapy: complete remission (CR), partial remission (PR), no change (NC), and progressive disease (PD). The patients were also divided into two groups according the change in direction of Lunx mRNA expression after chemotherapy: increased group and decreased group. The patients were followed up to determine survival.
RESULTS: Lunx mRNA was positive in 89 of 106 patients with pleural effusions caused by pulmonary carcinoma. The specificity and sensitivity were 95.9% and 84.9%. The area under the ROC curve was 0.922. Lunx mRNA detection was better than detection using cast-off cells and CEA. All of the Lunx-positive patients with MPEs were diagnosed with pulmonary carcinoma, and all extrapulmonary carcinoma patients were Lunx-negative. The positive predictive value of Lunx mRNA for the source of tumor cells was 100%. Lunx mRNA expression decreased after the first session of chemotherapy in the CR and PR groups, increased in the PD group, there was no change in the NC group. Further analysis indicated the change in direction of Lunx mRNA expression was associated with the overall survival of patients. The patients in the increased group had longer overall survival times than those in the decreased group.
CONCLUSION: Lunx mRNA is a specific tumor gene that is highly expressed in MPEs caused by pulmonary carcinoma. The changes in Lunx mRNA levels after chemotherapy can predict the prognosis of patients with MPEs caused by pulmonary carcinoma.

Patel SJ, Molinolo AA, Gutkind S, Crawford NP
Germline genetic variation modulates tumor progression and metastasis in a mouse model of neuroendocrine prostate carcinoma.
PLoS One. 2013; 8(4):e61848 [PubMed] Free Access to Full Article Related Publications
Neuroendocrine (NE) differentiation has gained increased attention as a prostate cancer (PC) prognostic marker. The aim of this study is to determine whether host germline genetic variation influences tumor progression and metastasis in C57BL/6-Tg(TRAMP)8247Ng/J (TRAMP) mouse model of aggressive NEPC. TRAMP mice were crossed to the eight progenitor strains of the Collaborative Cross recombinant inbred panel to address this. Tumor growth and metastasis burden were quantified in heterozygous transgene positive F1 male mice at 30 weeks of age. Compared to wild-type C57BL/6J-Tg(TRAMP)824Ng/J males, TRAMP x CAST/EiJ, TRAMP x NOD/ShiLtJ and TRAMP x NZO/HlLtJ F1 males displayed significant increases in tumor growth. Conversely, TRAMP x WSB/EiJ and TRAMP x PWK/PhJ F1 males displayed significant reductions in tumor growth. Interestingly, despite reduced tumor burden, TRAMP x WSB/EiJ males had an increased nodal metastasis burden. Patterns of distant pulmonary metastasis tended to follow the same patterns as that of local dissemination in each of the strains. All tumors and metastases displayed positive staining for NE markers, synaptophysin, and FOXA2. These experiments conclusively demonstrate that the introduction of germline variation by breeding modulates tumor growth, local metastasis burden, and distant metastasis frequency in this model of NEPC. These strains will be useful as model systems to facilitate the identification of germline modifier genes that promote the development of aggressive forms of PC.

Smith KN, Halfyard SJ, Yaskowiak ES, et al.
Fine map of the Gct1 spontaneous ovarian granulosa cell tumor locus.
Mamm Genome. 2013; 24(1-2):63-71 [PubMed] Free Access to Full Article Related Publications
The spontaneous development of juvenile-onset, ovarian granulosa cell (GC) tumors in the SWR/Bm (SWR) inbred mouse strain is a model for juvenile-type GC tumors that appear in infants and young girls. GC tumor susceptibility is supported by multiple Granulosa cell tumor (Gct) loci, but the Gct1 locus on Chr 4 derived from SWR strain background is fundamental for GC tumor development and uniquely responsive to the androgenic precursor dehydroepiandrosterone (DHEA). To resolve the location of Gct1 independently from other susceptibility loci, Gct1 was isolated in a congenic strain that replaces the distal segment of Chr 4 in SWR mice with a 47 × 10(6)-bp genomic segment from the Castaneus/Ei (CAST) strain. SWR females homozygous for the CAST donor segment were confirmed to be resistant to DHEA- and testosterone-induced GC tumorigenesis, indicating successful exchange of CAST alleles (Gct1 ( CA )) for SWR alleles (Gct1 ( SW )) at this tumor susceptibility locus. A series of nested, overlapping, congenic sublines was created to fine-map Gct1 based on GC tumor susceptibility under the influence of pubertal DHEA treatment. Twelve informative lines have resolved the Gct1 locus to a 1.31 × 10(6)-bp interval on mouse Chr 4, a region orthologous to human Chr 1p36.22.

Suzuki K
Diagnosis and treatment of multiple myeloma and AL amyloidosis with focus on improvement of renal lesion.
Clin Exp Nephrol. 2012; 16(5):659-71 [PubMed] Free Access to Full Article Related Publications
Multiple myeloma (MM) and AL amyloidosis are caused by the expansion of monoclonal plasma cells and secretion of dysproteinemia (Bence Jones protein and free light chain) and some patients require the hemodialysis. Myeloma kidney is mainly caused by the cast nephropathy of the distal tubuli, whereas, AL amyloid-protein is mainly deposited in glomeruli with massive fibrillar involvement. Therefore, almost MM patients presents a symptom of renal insufficiency, whereas, almost patients of AL amyloidosis present a nephrotic syndrome with severe hypoalbuminemia. These two diseases have some similar characteristics such as up-regulation of cyclin D1 gene by 11:14 chromosomal translocation. High-dose chemotherapy supported with autologous peripheral blood stem cells is effective for these two diseases. However, they are still difficult to be cured and require long-term disease control. In recent years, introduction of novel agents has changed their treatment strategies from the palliation therapy to the clinical cure.

Hayashi T, Sentani K, Oue N, et al.
The search for secreted proteins in prostate cancer by the Escherichia coli ampicillin secretion trap: expression of NBL1 is highly restricted to the prostate and is related to cancer progression.
Pathobiology. 2013; 80(2):60-9 [PubMed] Related Publications
AIMS: Genes expressed only in cancer tissue or specific organs will be useful molecular markers. To identify genes that encode secreted proteins present in prostate cancer (PCa), we generated Escherichia coli ampicillin secretion trap (CAST) libraries from PCa and normal prostate (NP).
METHODS AND RESULTS: We identified 15 candidate genes that encode secreted proteins present in PCa and NP. Quantitative RT-PCR analysis revealed that MSMB, NBL1 and AZGP1 were expressed with much higher specificity in PCa and NP than in 14 other kinds of normal tissue. We focused on NBL1, which was originally identified as a putative tumor suppressor gene. Western blot analysis revealed that NBL1 protein was highly expressed in both cell lysate and culture media of the DU145 PCa cell line. Immunohistochemical analysis showed that NBL1 expression was highly detected in and restricted to NP and PCa and was significantly down-regulated in PCa. NBL1 expression was significantly reduced according to the tumor stage, Gleason grade and preoperative prostate-specific antigen (PSA) value.
CONCLUSION: NBL1 is a secreted protein that is highly restricted to the prostate. Underexpression of NBL1 correlated with PCa progression. NBL1 might be a candidate tumor marker for PCa in addition to PSA.

Fang Y, Yu Y, Hou Q, et al.
The Chinese herb isolate isorhapontigenin induces apoptosis in human cancer cells by down-regulating overexpression of antiapoptotic protein XIAP.
J Biol Chem. 2012; 287(42):35234-43 [PubMed] Free Access to Full Article Related Publications
Although the Chinese herb Gnetum cleistostachyum has been used as a remedy for cancers for hundred years, the active compounds and molecular mechanisms underlying its anti-cancer activity have not been explored. Recently a new derivative of stilbene compound, isorhapontigenin (ISO), was isolated from this Chinese herb. In the present study, we examined the potential of ISO in anti-cancer activity and the mechanisms involved in human cancer cell lines. We found that ISO exhibited significant inhibitory effects on human bladder cancer cell growth that was accompanied by marked apoptotic induction as well as down-regulation of the X-linked inhibitor of apoptosis protein (XIAP). Further studies have shown that ISO down-regulation of XIAP protein expression was only observed in endogenous XIAP, but not in constitutionally exogenously expressed XIAP in the same cells, excluding the possibility of ISO regulating XIAP expression at the level of protein degradation. We also identified that ISO down-regulated XIAP gene transcription via inhibition of Sp1 transactivation. There was no significant effect of ISO on apoptosis and colony formation of cells transfected with exogenous HA-tagged XIAP. Collectively, current studies, for the first time to the best of our knowledge, identify ISO as a major active compound for the anti-cancer activity of G. cleistostachyum by down-regulation of XIAP expression and induction of apoptosis through specific targeting of a SP1 pathway, and cast new light on the treatment of the cancer patients with XIAP overexpression.

Waaler J, Machon O, Tumova L, et al.
A novel tankyrase inhibitor decreases canonical Wnt signaling in colon carcinoma cells and reduces tumor growth in conditional APC mutant mice.
Cancer Res. 2012; 72(11):2822-32 [PubMed] Related Publications
Increased nuclear accumulation of β-catenin, a mediator of canonical Wnt signaling, is found in numerous tumors and is frequently associated with tumor progression and metastasis. Inhibition of Wnt/β-catenin signaling therefore is an attractive strategy for anticancer drugs. In this study, we have identified a novel small molecule inhibitor of the β-catenin signaling pathway, JW55, that functions via inhibition of the PARP domain of tankyrase 1 and tankyrase 2 (TNKS1/2), regulators of the β-catenin destruction complex. Inhibition of TNKS1/2 poly(ADP-ribosyl)ation activity by JW55 led to stabilization of AXIN2, a member of the β-catenin destruction complex, followed by increased degradation of β-catenin. In a dose-dependent manner, JW55 inhibited canonical Wnt signaling in colon carcinoma cells that contained mutations in either the APC (adenomatous polyposis coli) locus or in an allele of β-catenin. In addition, JW55 reduced XWnt8-induced axis duplication in Xenopus embryos and tamoxifen-induced polyposis formation in conditional APC mutant mice. Together, our findings provide a novel chemotype for targeting canonical Wnt/β-catenin signaling through inhibiting the PARP domain of TNKS1/2.

Nilsson LM, Forshell TZ, Rimpi S, et al.
Mouse genetics suggests cell-context dependency for Myc-regulated metabolic enzymes during tumorigenesis.
PLoS Genet. 2012; 8(3):e1002573 [PubMed] Free Access to Full Article Related Publications
c-Myc (hereafter called Myc) belongs to a family of transcription factors that regulates cell growth, cell proliferation, and differentiation. Myc initiates the transcription of a large cast of genes involved in cell growth by stimulating metabolism and protein synthesis. Some of these, like those involved in glycolysis, may be part of the Warburg effect, which is defined as increased glucose uptake and lactate production in the presence of adequate oxygen supply. In this study, we have taken a mouse-genetics approach to challenge the role of select Myc-regulated metabolic enzymes in tumorigenesis in vivo. By breeding λ-Myc transgenic mice, Apc(Min) mice, and p53 knockout mice with mouse models carrying inactivating alleles of Lactate dehydrogenase A (Ldha), 3-Phosphoglycerate dehydrogenase (Phgdh) and Serine hydroxymethyltransferase 1 (Shmt1), we obtained offspring that were monitored for tumor development. Very surprisingly, we found that these genes are dispensable for tumorigenesis in these genetic settings. However, experiments in fibroblasts and colon carcinoma cells expressing oncogenic Ras show that these cells are sensitive to Ldha knockdown. Our genetic models reveal cell context dependency and a remarkable ability of tumor cells to adapt to alterations in critical metabolic pathways. Thus, to achieve clinical success, it will be of importance to correctly stratify patients and to find synthetic lethal combinations of inhibitors targeting metabolic enzymes.

Karkucak M, Yakut T, Baytan B, et al.
The variant translocation of ABL1 gene t(2;9)(q21;q34) in a childhood T-cell acute lymphoblastic leukemia.
Bratisl Lek Listy. 2012; 113(1):19-20 [PubMed] Related Publications
We present the case of the childhood ALL that was identified by the translocation of the ABL1 gene to the q21 band of chromosome 2 without t(9;22)(q34;q11) translocation. The observation of a poor clinical course of the case may contribute to explanation of the action of t(9;22)(q34;q11) translocation, of which poor prognostic action is known on ALL's, in terms of ABL1 gene, independent of the BCR gene. On the other hand, the prognostic significance of this variant ABL1 translocation detection, which is very rarely observed, will cast a light on future cases (Tab. 1, Fig. 1, Ref. 11).

Wu W, Li J, Liu Y, et al.
Comparative proteomic studies of serum from patients with hepatocellular carcinoma.
J Invest Surg. 2012; 25(1):37-42 [PubMed] Related Publications
BACKGROUND: Human hepatocellular carcinoma (HCC) is one of the most common solid tumors. It is always associated with prolonged hospital stay, increased attributable mortality, and greater hospitalization cost. To identify new biomarkers that could improve the early diagnosis in hepatocellular carcinoma, we performed a proteomic study.
METHODS: Two-dimensional gel electrophoresis (2-DE) and mass spectrometry (MS) were used to compare the serum protein profiles between patients with hepatocellular carcinoma and healthy volunteers.
RESULTS: Eight protein spots were found significantly changed in patients with hepatocellular carcinoma. Among them, four proteins were successfully identified, including MYH2 protein, mitochondrial ATP synthase, sulfated glycoprotein-2 (SGP-2), and Glial fibrillary acidic protein (GFAP). The increased levels of SGP-2 were further confirmed by Western blot analysis from independent series of serum samples.
CONCLUSIONS: These results indicate that MYH2 protein, mitochondrial ATP synthase, SGP-2, and GFAP may be potential molecular biomarkers for hepatocellular carcinoma, and special attention should be cast on MYH2 protein.

Bouaynaya N, Shterenberg R, Schonfeld D
Robustness of inverse perturbation for discrete event control.
Conf Proc IEEE Eng Med Biol Soc. 2011; 2011:2422-5 [PubMed] Free Access to Full Article Related Publications
We study the robustness of the inverse perturbation solution in discrete-time systems modeled by homogeneous Markov chains. We cast the optimal inverse perturbation control as a strictly convex optimization problem, which admits a unique global solution. We show that the optimal inverse perturbation control is robust to estimation errors in the original network. The derived results are applied to the Human melanoma gene regulatory network, where the aim is to force the network to converge to a desired steady-state distribution of gene regulation.

Azarova AM, Gautam G, George RE
Emerging importance of ALK in neuroblastoma.
Semin Cancer Biol. 2011; 21(4):267-75 [PubMed] Free Access to Full Article Related Publications
Since the original descriptions of gain-of function mutations in anaplastic lymphoma kinase (ALK), interest in the role of this receptor tyrosine kinase in neuroblastoma development and as a potential therapeutic target has escalated. As a group, the activating point mutations in full-length ALK, found in approximately 8% of all neuroblastoma tumors, are distributed evenly across different clinical stages. However, the most frequent somatic mutation, F1174L, is associated with amplification of the MYCN oncogene. This combination of features appears to confer a worse prognosis than MYCN amplification alone, suggesting a cooperative effect on neuroblastoma formation by these two proteins. Indeed, F1174L has shown more potent transforming activity in vivo than the second most common activating mutation, R1275Q, and is responsible for innate and acquired resistance to crizotinib, a clinically relevant ALK inhibitor that will soon be commercially available. These advances cast ALK as a bona fide oncoprotein in neuroblastoma and emphasize the need to understand ALK-mediated signaling in this tumor. This review addresses many of the current issues surrounding the role of ALK in normal development and neuroblastoma pathogenesis, and discusses the prospects for clinically effective targeted treatments based on ALK inhibition.

Lorenzo PI, Jimenez Moreno CM, Delgado I, et al.
Immunohistochemical assessment of Pax8 expression during pancreatic islet development and in human neuroendocrine tumors.
Histochem Cell Biol. 2011; 136(5):595-607 [PubMed] Free Access to Full Article Related Publications
The paired box transcription factor Pax8 is critical for development of the eye, thyroid gland as well as the urinary and reproductive organs. In adult, Pax8 overexpression is associated with kidney, ovarian and thyroid tumors and has emerged as a specific marker for these cancers. Recently, Pax8 expression was also reported in human pancreatic islets and in neuroendocrine tumors, identifying Pax8 as a novel member of the Pax family expressed in the pancreas. Herein, we sought to provide a comprehensive analysis of Pax8 expression during pancreogenesis and in adult islets. Immunohistochemical analysis using the most employed Pax8 polyclonal antibody revealed strong nuclear staining in the developing mouse pancreas and in mature human and mouse islets. Astonishingly, Pax8 mRNA in mouse islets was undetectable while human islets exhibited low levels. These discrepancies raised the possibility of antibody cross-reactivity. This premise was confirmed by demonstrating that the polyclonal Pax8 antibody also recognized the islet-enriched Pax6 protein both by Western blotting and immunohistochemistry. Thus, in islets polyclonal Pax8 staining corresponds mainly to Pax6. In order to circumvent this caveat, a novel Pax8 monoclonal antibody was used to re-evaluate whether Pax8 was indeed expressed in islets. Surprisingly, Pax8 was not detected in neither the developing pancreas or in mature islets. Reappraisal of pancreatic neuroendocrine tumors using this Pax8 monoclonal antibody exhibited no immunostaining as compared to the Pax8 polyclonal antibody. In conclusion, Pax8 is not expressed in the pancreas and cast doubts on the value of Pax8 as a pancreatic neuroendocrine tumor marker.

Hayashi T, Oue N, Sakamoto N, et al.
Identification of transmembrane protein in prostate cancer by the Escherichia coli ampicillin secretion trap: expression of CDON is involved in tumor cell growth and invasion.
Pathobiology. 2011; 78(5):277-84 [PubMed] Related Publications
AIMS: Prostate cancer (PCa) is one of the most common malignancies worldwide. Genes expressed only in cancer tissue, and especially related to proteins located on the cell membrane, will be useful molecular markers for diagnosis and may also be good therapeutic targets. The aim of this study was to identify genes that encode transmembrane proteins present in PCa.
METHODS AND RESULTS: We generated Escherichia coli ampicillin secretion trap (CAST) libraries from 2 PCa cell lines and normal prostate tissues. By sequencing 3,264 colonies from CAST libraries, we identified 18 candidate genes that encode transmembrane proteins present in PCa. Quantitative RT-PCR analysis of these candidates revealed that STEAP1, ADAM9 and CDON were expressed much more highly in PCa than in 15 kinds of normal tissues. Among the candidates, CDON encodes the CDO protein, which is an orphan cell surface receptor of the immunoglobulin superfamily. Additional quantitative RT-PCR revealed that 83% of PCa tissues showed CDON overexpression. Knockdown of CDON in DU145 cells induced 5-fluorouracil-induced apoptosis and inhibited invasion ability.
CONCLUSION: These results suggest that CDON has a high potential as a therapeutic target for PCa.

Chowdhury SA, Nibbe RK, Chance MR, Koyutürk M
Subnetwork state functions define dysregulated subnetworks in cancer.
J Comput Biol. 2011; 18(3):263-81 [PubMed] Free Access to Full Article Related Publications
Emerging research demonstrates the potential of protein-protein interaction (PPI) networks in uncovering the mechanistic bases of cancers, through identification of interacting proteins that are coordinately dysregulated in tumorigenic and metastatic samples. When used as features for classification, such coordinately dysregulated subnetworks improve diagnosis and prognosis of cancer considerably over single-gene markers. However, existing methods formulate coordination between multiple genes through additive representation of their expression profiles and utilize fast heuristics to identify dysregulated subnetworks, which may not be well suited to the potentially combinatorial nature of coordinate dysregulation. Here, we propose a combinatorial formulation of coordinate dysregulation and decompose the resulting objective function to cast the problem as one of identifying subnetwork state functions that are indicative of phenotype. Based on this formulation, we show that coordinate dysregulation of larger subnetworks can be bounded using simple statistics on smaller subnetworks. We then use these bounds to devise an efficient algorithm, Crane, that can search the subnetwork space more effectively than existing algorithms. Comprehensive cross-classification experiments show that subnetworks identified by Crane outperform those identified by additive algorithms in predicting metastasis of colorectal cancer (CRC).

Hertig A, Bonnard G, Ulinski T, et al.
Tubular nuclear accumulation of Snail and epithelial phenotypic changes in human myeloma cast nephropathy.
Hum Pathol. 2011; 42(8):1142-8 [PubMed] Related Publications
The transcription factor Snail is an important repressor of E-cadherin gene expression. It plays a key role in the induction of epithelial-mesenchymal transition, an essential process important not only in embryonic development and tumor progression but also in organ fibrogenesis. We studied the expression of Snail by immunohistochemistry, along with several epithelial phenotypic changes suggestive of epithelial-mesenchymal transition, in 14 patients with multiple myeloma cast nephropathy. This nephropathy is characterized by a rapid progression toward fibrosis. As controls, we used normal kidneys and kidneys from patients displaying an idiopathic nephrotic syndrome, a syndrome unassociated with renal fibrosis. We discovered that, in all patients with multiple myeloma nephropathy, a drastic accumulation of Snail is seen in the nuclei from tubular epithelial cells showing epithelial phenotypic changes. In contrast, normal and idiopathic nephrotic syndrome kidneys did not exhibit either of these markers. Snail, a major player in the process of epithelial-to-mesenchymal transition, is highly expressed by tubular epithelial cells during multiple myeloma nephropathy. It is, therefore, a potential target to prevent multiple myeloma kidneys from fibrosing. Intranuclear accumulation of Snail is a characteristic in phenotypically altered tubular cells from multiple myeloma kidneys. The epithelial-mesenchymal transition pathway could, therefore, be involved in the rapid renal fibrogenesis observed in this setting.

Mullighan C, Petersdorf E, Davies SM, DiPersio J
From trees to the forest: genes to genomics.
Biol Blood Marrow Transplant. 2011; 17(1 Suppl):S52-7 [PubMed] Related Publications
Crick, Watson, and colleagues revealed the genetic code in 1953, and since that time, remarkable progress has been made in understanding what makes each of us who we are. Identification of single genes important in disease, and the development of a mechanistic understanding of genetic elements that regulate gene function, have cast light on the pathophysiology of many heritable and acquired disorders. In 1990, the human genome project commenced, with the goal of sequencing the entire human genome, and a "first draft" was published with astonishing speed in 2001. The first draft, although an extraordinary achievement, reported essentially an imaginary haploid mix of alleles rather than a true diploid genome. In the years since 2001, technology has further improved, and efforts have been focused on filling in the gaps in the initial genome and starting the huge task of looking at normal variation in the human genome. This work is the beginning of understanding human genetics in the context of the structure of the genome as a complete entity, and as more than simply the sum of a series of genes. We present 3 studies in this review that apply genomic approaches to leukemia and to transplantation to improve and extend therapies.

Bouaynaya N, Shterenberg R, Schonfeld D
Inverse perturbation for optimal intervention in gene regulatory networks.
Bioinformatics. 2011; 27(1):103-10 [PubMed] Free Access to Full Article Related Publications
MOTIVATION: Analysis and intervention in the dynamics of gene regulatory networks is at the heart of emerging efforts in the development of modern treatment of numerous ailments including cancer. The ultimate goal is to develop methods to intervene in the function of living organisms in order to drive cells away from a malignant state into a benign form. A serious limitation of much of the previous work in cancer network analysis is the use of external control, which requires intervention at each time step, for an indefinite time interval. This is in sharp contrast to the proposed approach, which relies on the solution of an inverse perturbation problem to introduce a one-time intervention in the structure of regulatory networks. This isolated intervention transforms the steady-state distribution of the dynamic system to the desired steady-state distribution.
RESULTS: We formulate the optimal intervention problem in gene regulatory networks as a minimal perturbation of the network in order to force it to converge to a desired steady-state distribution of gene regulation. We cast optimal intervention in gene regulation as a convex optimization problem, thus providing a globally optimal solution which can be efficiently computed using standard toolboxes for convex optimization. The criteria adopted for optimality is chosen to minimize potential adverse effects as a consequence of the intervention strategy. We consider a perturbation that minimizes (i) the overall energy of change between the original and controlled networks and (ii) the time needed to reach the desired steady-state distribution of gene regulation. Furthermore, we show that there is an inherent trade-off between minimizing the energy of the perturbation and the convergence rate to the desired distribution. We apply the proposed control to the human melanoma gene regulatory network.
AVAILABILITY: The MATLAB code for optimal intervention in gene regulatory networks can be found online:

Lizardi PM
As we bring demethylating drugs to the clinic, we better know the DICE being cast.
Oncogene. 2010; 29(43):5772-4 [PubMed] Related Publications
In this issue, Weber and coworkers report that DNA-demethylating drugs alter the transcriptional expression of the cMet proto-oncogene. Abnormal transcription is driven by the antisense promoter of a Line-1 repetitive element present within an intron. The element is a recent addition to the genome and is absent in animal models of cancer.

Anami K, Oue N, Noguchi T, et al.
Search for transmembrane protein in gastric cancer by the Escherichia coli ampicillin secretion trap: expression of DSC2 in gastric cancer with intestinal phenotype.
J Pathol. 2010; 221(3):275-84 [PubMed] Related Publications
Gastric cancer (GC) is one of the most common malignancies worldwide. Genes expressed only in cancer tissue, and especially on the cell membrane, will be useful molecular markers for diagnosis and may also be good therapeutic targets. To identify genes that encode transmembrane proteins present in GC, we generated Escherichia coli ampicillin secretion trap (CAST) libraries from two GC cell lines and normal stomach. By sequencing 4320 colonies from CAST libraries, we identified 30 candidate genes that encode transmembrane proteins present in GC. Quantitative reverse transcription-polymerase chain reaction analysis of these candidates revealed that ZDHHC14, BST2, DRAM2, and DSC2 were expressed much more highly in GC than in 14 kinds of normal tissues. Among these, DSC2 encodes desmocollin 2, which is one of three known desmocollins. Immunohistochemical analysis demonstrated that 22 (28%) of 80 GC cases were positive for desmocollin 2, and desmocollin 2 expression was observed frequently in GC with the intestinal mucin phenotype. Furthermore, desmocollin 2 expression was correlated with CDX2 expression. These results suggest that expression of desmocollin 2, induced by CDX2, may be a key regulator for GC with the intestinal mucin phenotype. Our results provide a list of genes that have high potential as a diagnostic and therapeutic target for GC.

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