HINT1

Gene Summary

Gene:HINT1; histidine triad nucleotide binding protein 1
Aliases: HINT, NMAN, PKCI-1, PRKCNH1
Location:5q23.3
Summary:This gene encodes a protein that hydrolyzes purine nucleotide phosphoramidates substrates, including AMP-morpholidate, AMP-N-alanine methyl ester, AMP-alpha-acetyl lysine methyl ester, and AMP-NH2. The encoded protein interacts with these substrates via a histidine triad motif. This gene is considered a tumor suppressor gene. In addition, mutations in this gene can cause autosomal recessive neuromyotonia and axonal neuropathy. There are several related pseudogenes on chromosome 7. Several transcript variants have been observed. [provided by RefSeq, Dec 2015]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:histidine triad nucleotide-binding protein 1
Source:NCBIAccessed: 16 March, 2017

Ontology:

What does this gene/protein do?
Show (8)

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.

  • Immunohistochemistry
  • Apoptosis
  • ROC Curve
  • Vesicular Transport Proteins
  • beta Catenin
  • Gene Expression Profiling
  • Cancer Gene Expression Regulation
  • Colorectal Cancer
  • Transcription Factor AP-1
  • Gene Silencing
  • Phosphorylation
  • RTPCR
  • Nerve Tissue Proteins
  • beta-Transducin Repeat-Containing Proteins
  • Staging
  • Transcription
  • Cytogenetic Analysis
  • Transcriptome
  • Ubiquitin-Protein Ligases
  • Lymphatic Metastasis
  • Hep G2 Cells
  • Immunoenzyme Techniques
  • Messenger RNA
  • Base Sequence
  • HINT1
  • Chromosome 5
  • Skin Cancer
  • HEK293 Cells
  • Promoter Regions
  • Epigenetics
  • Western Blotting
  • Transcription Factors
  • RT-PCR
  • Chronic Myelogenous Leukemia
  • Helicobacter Infections
  • Hepatocellular Carcinoma
  • Liver Cancer
  • Fusion Proteins, bcr-abl
  • Stomach Cancer
  • NIH 3T3 Cells
  • DNA Methylation
  • Polymerase Chain Reaction
Tag cloud generated 16 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

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

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

Latest Publications: HINT1 (cancer-related)

Wu XS, Bao TH, Ke Y, et al.
Hint1 suppresses migration and invasion of hepatocellular carcinoma cells in vitro by modulating girdin activity.
Tumour Biol. 2016; 37(11):14711-14719 [PubMed] Related Publications
Histidine triad nucleotide-binding protein 1 (Hint1) is a haploinsufficient tumor suppressor gene. Its role in cancer cell migration has not been previously speculated. In the current study, we examined the expression of Hint1 in metastatic and non-metastatic lymph nodes of hepatocellular carcinoma (HCC) patients and further elucidated the effect of Hint1 expression on girdin expression and phosphorylation of AKT and ERK1/2 and on the migration of HCC cells in vitro. Expression of Hint1 and girdin in primary HCC tissues and metastatic and non-metastatic lymph nodes was determined by RT-PCR assays. HepG2 cells were transfected with plasmid vectors overexpressing Hint1 or small interfering RNA (siRNA) targeting Hint1, girdin, Hint1 plus girdin, or the scrambled RNA. Migration and invasion of HCC cells were examined by wound and Transwell assays. Protein expression was detected by immunofluorescence and immunoblotting assays. RT-PCR assays revealed that the messenger RNA (mRNA) transcript levels of Hint1 were markedly lower than those of primary HCC tissues and non-metastatic lymph nodes (P < 0.01). By contrast, the mRNA transcript levels of girdin were significantly higher than non-metastatic lymph nodes (P < 0.05). Furthermore, siRNA knockdown of HINT1 resulted in a significant increase in the mRNA transcript levels of girdin in HepG2 cells (P < 0.05). Wound assays and Transwell assays showed that Hint1 knockdown by siRNA significantly enhanced the migration and invasion of HepG2 cells compared to HepG2 cells transfected with scrambled siRNA. Hint1 knockdown also led to significantly increased phosphorylation of girdin and AKT in HepG2 cells (P < 0.05), which, however, was effectively aborted by girdin knockdown by siRNA (P < 0.05). Hint1 is downregulated in metastatic lymph nodes and is implicated in migration and invasion of HCC cells in vitro by modulating girdin and AKT expression and phosphorylation. The Hint1-girdin-AKT signaling axis should be further dissected for its role in HCC migration and invasion and may be therapeutically targeted to suppress tumor growth and metastasis.

Qian H, Xuan J, Liu Y, Shi G
Function of G-Protein-Coupled Estrogen Receptor-1 in Reproductive System Tumors.
J Immunol Res. 2016; 2016:7128702 [PubMed] Free Access to Full Article Related Publications
The G-protein-coupled estrogen receptor-1 (GPER-1), also known as GPR30, is a novel estrogen receptor mediating estrogen receptor signaling in multiple cell types. The progress of estrogen-related cancer is promoted by GPER-1 activation through mitogen-activated protein kinases (MAPK), phosphoinositide 3-kinase (PI3K), and phospholipase C (PLC) signaling pathways. However, this promoting effect of GPER-1 is nonclassic estrogen receptor (ER) dependent manner. In addition, clinical evidences revealed that GPER-1 is associated with estrogen resistance in estrogen-related cancer patients. These give a hint that GPER-1 may be a novel therapeutic target for the estrogen-related cancers. However, preclinical studies also found that GPER-1 activation of its special agonist G-1 inhibits cancer cell proliferation. This review aims to summarize the characteristics and complex functions of GPER-1 in cancers.

Lynce F, Isaacs C
How Far Do We Go With Genetic Evaluation? Gene, Panel, and Tumor Testing.
Am Soc Clin Oncol Educ Book. 2016; 35:e72-8 [PubMed] Related Publications
The traditional model by which an individual was identified as harboring a hereditary susceptibility to cancer was to test for a mutation in a single gene or a finite number of genes associated with a particular syndrome (e.g., BRCA1 and BRCA2 for hereditary breast and ovarian cancer or mismatch repair genes for Lynch syndrome). The decision regarding which gene or genes to test for was based on a review of the patient's personal medical history and their family history. With advances in next-generation DNA sequencing technology, offering simultaneous testing for multiple genes associated with a hereditary susceptibility to cancer is now possible. These panels typically include high-penetrance genes, but they also often include moderate- and low-penetrance genes. A number of the genes included in these panels have not been fully characterized either in terms of their cancer risks or their management options. Another way some patients are unexpectedly identified as carrying a germline mutation in a cancer susceptibility gene is at the time they undergo molecular profiling of their tumor, which typically has been carried out to guide treatment choices for their cancer. This article first focuses on the issues that need to be considered when deciding between recommending more targeted testing of a single or a small number of genes associated with a particular syndrome (single/limited gene testing) versus performing a multigene panel. This article also reviews the issues regarding germline risk that occur within the setting of ordering molecular profiling of tumors.

Tonduti D, Orcesi S, Jenkinson EM, et al.
Clinical, radiological and possible pathological overlap of cystic leukoencephalopathy without megalencephaly and Aicardi-Goutières syndrome.
Eur J Paediatr Neurol. 2016; 20(4):604-10 [PubMed] Related Publications
BACKGROUND: Cystic leukoencephalopathy without megalencephaly is a disorder related in some cases to RNASET2 mutations and characterized by bilateral anterior temporal subcortical cysts and multifocal lobar white matter lesions with sparing of central white matter structures. This phenotype significantly overlaps with the sequelae of in utero cytomegalovirus (CMV) infection, including the presence of intracranial calcification in some cases. Aicardi-Goutières syndrome (AGS) is another inherited leukodystrophy with cerebral calcification mimicking congenital infection. Clinical, radiological and biochemical criteria for the diagnosis of AGS have been established, although the breadth of phenotype associated with mutations in the AGS-related genes is much greater than previously envisaged.
PATIENTS AND METHODS: We describe the clinical, biochemical and radiological findings of five patients demonstrating a phenotype reminiscent of AGS.
RESULTS: All patients were found to carry biallelic mutations of RNASET2.
CONCLUSIONS: Our patients illustrate the clinical and radiological overlap that can be seen between RNASET2-related leukodystrophy and AGS in some cases. Our data highlight the need to include both disorders in the same differential diagnosis, and hint at possible shared pathomechanisms related to auto-inflammation which are worthy of further investigation.

Yang M, Xu X, Cai J, et al.
NSCLC harboring EGFR exon-20 insertions after the regulatory C-helix of kinase domain responds poorly to known EGFR inhibitors.
Int J Cancer. 2016; 139(1):171-6 [PubMed] Related Publications
Anecdote clinical observations hint that non-small cell lung cancer (NSCLC) with exon-20 insertions might respond poorly to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), contrasting to those with classic mutations. Lack of patient-derived experimental models has been a major hurdle for the discovery of new treatment for the diseases. We established two NSCLC-PDXs harboring two different exon-20 insertions, LU0387-adenocarcinoma (ADC) with a nine-base insertion at 2319 (H773-V774insNPH) and LU3075-squamous cell carcinoma (SCC) with a nine-base insertion at 2316 (P772-H773insDNP). Both insertions immediately follow the regulatory C-helix of the kinase domain. Contrary to the generally good responses to EGFR inhibitors observed in PDXs with classic mutations, both exon-20 insertions are largely resistant to cetuximab and TKIs in vivo, suggesting fundamental difference from the classic EGFR mutations, consistent with the poor response rate to TKI seen in anecdotal clinic reports. It is worth noting that although responses are generally poor, they differ between the two exon-20 mutants depending on the type of TKI. In vitro drug sensitivity assays using established primary cell lines from our two PDXs largely confirmed the in vivo data. Our data from patient-derived experimental models confirmed that exon-20 insertions in domain immediately following the C-helix confer poor response to all known EGFR inhibitors, and suggested that these models can be utilized to facilitate the discovery of new therapies targeting NSCLC harboring exon-20 insertions.

Sfakianakis S, Bei ES, Zervakis M, Kafetzopoulos D
A network-based approach to enrich gene signatures for the prediction of breast cancer metastases.
Conf Proc IEEE Eng Med Biol Soc. 2015; 2015:6497-500 [PubMed] Related Publications
Despite the multiplicity of the gene expression analysis studies for the identification of genomics based origins of cancerous diseases, the presented gene signatures have generally little overlap. The genes do not function in isolation and therefore a more holistic approach that takes into account the interactions among them is needed. In this study we present a stepwise refinement methodology where starting from some initial set of biomarkers we expand and enrich this set taking into account existing biological information. In particular, we start with a 27 gene signature previously identified as indicative of the presence of circulating tumor cells (CTCs) in peripheral blood of breast cancer patients. We use the manually curated HINT database of protein-protein interactions as the background biological network to locate the network-based similarity of the input genes and how they connect to each other. The result is an enriched connected set of genes that is subsequently expanded to form an even bigger network based on the ability of the surrounding genes to strongly correlate with the phenotypes of a training set of breast cancer patient cases. The induced network is then used as a new gene signature for the classification of breast brain metastases in an independent dataset. The results are encouraging for the validity of this method.

Shi Z, Wu X, Ke Y, Wang L
Hint1 Up-Regulates IκBα by Targeting the β-TrCP Subunit of SCF E3 Ligase in Human Hepatocellular Carcinoma Cells.
Dig Dis Sci. 2016; 61(3):785-94 [PubMed] Related Publications
BACKGROUND AND AIM: There is increasing evidence that histidine triad nucleotide-binding protein 1 (HINT1) is a novel tumor suppressor. In the present study, we investigated the mechanism by which HINT1 promotes the stability of inhibitor of NF-κB α (IκBα) in the cytoplasm of hepatocellular carcinoma (HCC) cells, which was observed in our previous study (Wang et al. in Int J Cancer 124:1526-1534, 2009).
METHODS: We examined HINT1 and IκBα expression in HCC cell lines and determined the effect of HINT1 overexpression and knockdown on IκBα protein and mRNA expression in these cell lines. Then, ubiquitination assays were performed to investigate the effects of HINT1 expression plasmid transfection on IκBα ubiquitination. Next, the interaction between HINT1 and β-TrCP was investigated in immunoprecipitation and immunofluorescence assays.
RESULTS: Our data showed that increased HINT1 expression in HepG2 and SMMC7702 cells markedly increased IκBα protein levels, while decreased HINT1 expression markedly decreased them. Overexpression or knockdown of HINT1 did not alter the transcription of IκBα, but HINT1 inhibited proteasomal IκBα degradation and reduced its ubiquitination levels. This inhibition might occur because HINT1 is a component of the SCF(β-TrCP) E3 ligase, which is responsible for IκBα ubiquitination and degradation.
CONCLUSION: This study provides new evidence that HINT1 is a regulator of IκBα through SCF(β-TrCP) E3 ligase. These findings help to clarify the mechanism underlying the anticancer effects of HINT1.

Bi J, Li P, Li C, et al.
The SDF-1/CXCR4 chemokine axis in uveal melanoma cell proliferation and migration.
Tumour Biol. 2016; 37(3):4175-82 [PubMed] Related Publications
The stromal-cell-derived factor 1 (SDF-1)/chemokine receptor 4 (CXCR4) chemokine axis plays a key role in tumor migration. Here, we analyzed the axis in uveal melanoma (UM) proliferation and migration and investigated the effect of a chemical inhibitor of CXCR4, AMD3100, on UM. We found that CXCR4 was expressed in all five UM cell lines tested as well as the retinal pigment epithelium cell line ARPE-19 cells, while CXCR7 was only detected in OM290 and VUP cell lines. SDF-1 promotes the proliferation and migration of OCM-1 and OCM431 cell lines, while AMD3100 weakens this function. Taken together, our results show that the SDF-1/CXCR4 chemokine axis plays a key role in UM cell proliferation and migration and that AMD3100 can alleviate this function, which may offer a hint for UM treatment.

Čokić VP, Mojsilović S, Jauković A, et al.
Gene expression profile of circulating CD34(+) cells and granulocytes in chronic myeloid leukemia.
Blood Cells Mol Dis. 2015; 55(4):373-81 [PubMed] Free Access to Full Article Related Publications
PURPOSE: We compared the gene expression profile of peripheral blood CD34(+) cells and granulocytes in subjects with chronic myeloid leukemia (CML), with the accent on signaling pathways affected by BCR-ABL oncogene.
METHODS: The microarray analyses have been performed in circulating CD34(+) cells and granulocytes from peripheral blood of 7 subjects with CML and 7 healthy donors. All studied BCR-ABL positive CML patients were in chronic phase, with a mean value of 2012±SD of CD34(+)cells/μl in peripheral blood.
RESULTS: The gene expression profile was more prominent in CML CD34(+) cells (3553 genes) compared to granulocytes (2701 genes). The 41 and 39 genes were significantly upregulated in CML CD34(+) cells (HINT1, TXN, SERBP1) and granulocytes, respectively. BCR-ABL oncogene activated PI3K/AKT and MAPK signaling through significant upregulation of PTPN11, CDK4/6, and MYC and reduction of E2F1, KRAS, and NFKBIA gene expression in CD34(+) cells. Among genes linked to the inhibition of cellular proliferation by BCR-ABL inhibitor Imatinib, the FOS and STAT1 demonstrated significantly decreased expression in CML.
CONCLUSION: The presence of BCR-ABL fusion gene doubled the expression quantity of genes involved in the regulation of cell cycle, proliferation and apoptosis of CD34(+) cells. These results determined the modified genes in PI3K/AKT and MAPK signaling of CML subjects.

Nik-Zainal S, Kucab JE, Morganella S, et al.
The genome as a record of environmental exposure.
Mutagenesis. 2015; 30(6):763-70 [PubMed] Free Access to Full Article Related Publications
Whole genome sequencing of human tumours has revealed distinct patterns of mutation that hint at the causative origins of cancer. Experimental investigations of the mutations and mutation spectra induced by environmental mutagens have traditionally focused on single genes. With the advent of faster cheaper sequencing platforms, it is now possible to assess mutation spectra in experimental models across the whole genome. As a proof of principle, we have examined the whole genome mutation profiles of mouse embryo fibroblasts immortalised following exposure to benzo[a]pyrene (BaP), ultraviolet light (UV) and aristolochic acid (AA). The results reveal that each mutagen induces a characteristic mutation signature: predominantly G→T mutations for BaP, C→T and CC→TT for UV and A→T for AA. The data are not only consistent with existing knowledge but also provide additional information at higher levels of genomic organisation. The approach holds promise for identifying agents responsible for mutations in human tumours and for shedding light on the aetiology of human cancer.

Read J, Wadt KA, Hayward NK
Melanoma genetics.
J Med Genet. 2016; 53(1):1-14 [PubMed] Related Publications
Approximately 10% of melanoma cases report a relative affected with melanoma, and a positive family history is associated with an increased risk of developing melanoma. Although the majority of genetic alterations associated with melanoma development are somatic, the underlying presence of heritable melanoma risk genes is an important component of disease occurrence. Susceptibility for some families is due to mutation in one of the known high penetrance melanoma predisposition genes: CDKN2A, CDK4, BAP1, POT1, ACD, TERF2IP and TERT. However, despite such mutations being implicated in a combined total of approximately 50% of familial melanoma cases, the underlying genetic basis is unexplained for the remainder of high-density melanoma families. Aside from the possibility of extremely rare mutations in a few additional high penetrance genes yet to be discovered, this suggests a likely polygenic component to susceptibility, and a unique level of personal melanoma risk influenced by multiple low-risk alleles and genetic modifiers. In addition to conferring a risk of cutaneous melanoma, some 'melanoma' predisposition genes have been linked to other cancers, with cancer clustering observed in melanoma families at rates greater than expected by chance. The most extensively documented association is between CDKN2A germ line mutations and pancreatic cancer, and a cancer syndrome including cutaneous melanoma, uveal melanoma and mesothelioma has been proposed for BAP1 germ line mutations. Other medium to high penetrance melanoma predisposition genes have been associated with renal cell carcinoma (MITF, BAP1) and glioma (POT1). These associations between melanoma and other cancers hint at the possibility of common pathways for oncogenesis, and better knowledge of these pathways may improve understanding of the genetic basis underpinning familial melanoma. It is likely that 'melanoma' risk genes will impact on mutation screening and genetic counselling not only for melanoma but also a range of other cancers.

Lynce F, Smith KL, Stein J, et al.
Deleterious BRCA1/2 mutations in an urban population of Black women.
Breast Cancer Res Treat. 2015; 153(1):201-9 [PubMed] Related Publications
Information on the prevalence of deleterious BRCA1 and BRCA2 (BRCA1/2) mutations in clinic-based populations of Black women is limited. In order to address this gap, we performed a retrospective study to determine the prevalence of deleterious BRCA1/2 mutations, predictors of having a mutation, and acceptance of risk-reducing surgeries in Black women. In an urban unselected clinic-based population, we evaluated 211 self-identified Black women who underwent genetic counseling for hereditary breast-ovarian cancer syndrome. BRCA1/2 mutations were identified in 13.4% of the participants who received genetic testing. Younger age at diagnosis, higher BRCAPRO score, significant family history, and diagnosis of triple-negative breast cancer were associated with identification of a BRCA1/2 mutation. Of the affected patients found to have a deleterious mutation, almost half underwent prophylactic measures. In our study population, 1 in 7 Black women who underwent genetic testing harbored a deleterious BRCA1/2 mutation independent of age at diagnosis or family history.

Joubert B, Honnorat J
Autoimmune channelopathies in paraneoplastic neurological syndromes.
Biochim Biophys Acta. 2015; 1848(10 Pt B):2665-76 [PubMed] Related Publications
Paraneoplastic neurological syndromes and autoimmune encephalitides are immune neurological disorders occurring or not in association with a cancer. They are thought to be due to an autoimmune reaction against neuronal antigens ectopically expressed by the underlying tumour or by cross-reaction with an unknown infectious agent. In some instances, paraneoplastic neurological syndromes and autoimmune encephalitides are related to an antibody-induced dysfunction of ion channels, a situation that can be labelled as autoimmune channelopathies. Such functional alterations of ion channels are caused by the specific fixation of an autoantibody upon its target, implying that autoimmune channelopathies are usually highly responsive to immuno-modulatory treatments. Over the recent years, numerous autoantibodies corresponding to various neurological syndromes have been discovered and their mechanisms of action partially deciphered. Autoantibodies in neurological autoimmune channelopathies may target either directly ion channels or proteins associated to ion channels and induce channel dysfunction by various mechanisms generally leading to the reduction of synaptic expression of the considered channel. The discovery of those mechanisms of action has provided insights on the regulation of the synaptic expression of the altered channels as well as the putative roles of some of their functional subdomains. Interestingly, patients' autoantibodies themselves can be used as specific tools in order to study the functions of ion channels. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers.

Bendris N, Lemmers B, Blanchard JM
Cell cycle, cytoskeleton dynamics and beyond: the many functions of cyclins and CDK inhibitors.
Cell Cycle. 2015; 14(12):1786-98 [PubMed] Free Access to Full Article Related Publications
While targeting experiments carried out on the genes encoding many cell cycle regulators have challenged our views of cell cycle control, they also suggest that redundancy might not be the only explanation for the observed perplexing phenotypes. Indeed, several observations hint at functions of cyclins and CDK inhibitors that cannot be accounted for by their sole role as kinase regulators. They are found involved in many cellular transactions, depending or not on CDKs that are not directly linked to cell cycle control, but participating to general mechanisms such as transcription, DNA repair or cytoskeleton dynamics. In this review we discuss the roles that these alternative functions might have in cancer cell proliferation and migration that sometime even challenge their definition as proliferation markers.

Othman MA, Vujić D, Zecević Z, et al.
A cryptic three-way translocation t(10;19;11)(p12.31;q13.31;q23.3) with a derivative Y-chromosome in an infant with acute myeloblastic leukemia (M5b).
Gene. 2015; 563(2):115-9 [PubMed] Related Publications
Acute myeloid leukemia (AML) is a heterogeneous disease characterized by the malignant transformation of hematopoietic precursors to a pathogenic cell clone. Chromosomal band 11q23 harboring MLL (=mixed lineage leukemia) gene is known to be involved in rearrangements with variety of genes as activating partners of MLL in different AML subtypes. Overall, an unfavorable prognosis is associated with MLL abnormalities. Here we investigated an 11-month-old male presenting with hyperleukocytosis being diagnosed with AML subtype FAB-M5b. In banding cytogenetics a der(19)t(19;?)(q13.3;?) and del(Y)(q11.23) were found as sole aberrations. Molecular cytogenetics revealed that the MLL gene was disrupted and even partially lost due to a t(10;19;11)(p12.31;q13.31;q23.3), an MLL/MLLT10 fusion appeared, and the der(Y) was an asymmetric inverted duplication with breakpoints in Yp11.2 and Yq11.23. The patient got hematopoietic stem cell transplantation from his haploidentical mother. Still three months afterwards 15% of blasts were detected in bone marrow and later the patient was lost during follow-up. The present case highlights the necessity to exclude MLL rearrangements, even when there seems to be no actual hint from banding cytogenetics.

Galal AM, Walker LA, Khan IA
Induction of GST and related events by dietary phytochemicals: sources, chemistry, and possible contribution to chemoprevention.
Curr Top Med Chem. 2015; 14(24):2802-21 [PubMed] Related Publications
This review provides an overview of the chemical constituents of regularly consumed plants that increase the activity or induce expression of glutathione S-transferases (GSTs), a major family of detoxification/ cytoprotective enzymes of ubiquitous occurrence in the body. Since induction of phase II (cytoprotective) enzymes, essentially GSTs, is a principal strategy in deactivation of potential carcinogens, it is reasonable to conclude that phytochemicals that enhance the activity/expression of GST isoforms/isoenzymes may play a role in cancer prevention. In this respect, classes of natural products that exhibit this ability are presented. In addition, their possible contribution to chemoprevention is discussed. GSTs constitute a large family of detoxification enzymes in nature. GSTs has been long known to deactivate electrophilic xenobiotics or metabolites, reactive oxygen species as well as certain endogenous substrates. However, there is a growing appreciation that GSTs may have an even wider relevance to cancer, in that they can directly modulate the activity of a number of protein targets, including other enzymes in redox pathways and in signaling networks of cell division and cell cycle control. The following aspects will be treated herein: botanical sources, phytochemical classes, chemical structures of these natural products, bioactivity relevant to chemoprevention, and their influence on induction of GST in vitro and in animal models. A hint on the SAR of organosulfur compounds, isothiocyanates, and limonoids as GST inducers, is added. The few clinical and/or epidemiological studies that associate GST induction with prevention of carcinogenesis are also reviewed.

Shao H, Kirkwood JM, Wells A
Tenascin-C Signaling in melanoma.
Cell Adh Migr. 2015; 9(1-2):125-30 [PubMed] Free Access to Full Article Related Publications
Tenascin-C (TNC), a multifunctional matricellular glyco-protein, is highly expressed in the majority of melanoma cell lines and has been implicated in the progression of melanoma. A growing body of evidence has implicated the role of TNC in the process of invasion and metastasis for melanoma. However, the mechanism and individual signaling pathways by which TNC drives melanoma progression have not been illuminated. Herein we provide perspectives from the investigation of TNC in other settings that may hint at the mechanistic role of TNC in this disease.

Kuwabara S, Misawa S
Acquired and genetic channelopathies: in vivo assessment of axonal excitability.
Exp Neurol. 2015; 263:368-71 [PubMed] Related Publications
Neuronal or axonal ion channel function can be impaired or altered in a number of disorders, such as acquired (autoantibody-mediated, toxic, and metabolic) and genetic channelopathies, and even neurodegenerative (motor neuron disease) or inflammatory diseases (multiple sclerosis, immune-mediated neuropathies). When specific channels are affected, axonal/neuronal excitability primarily alters according to original function of the corresponding channels. Separately, in the 1990s, axonal excitability testing was developed to assess ion channel function, membrane potential, and passive membrane properties non-invasively in human subjects. Using this technique, numerous papers on altered axonal excitability in a variety of disorders have been published since 2000. In a recent issue of Experimental Neurology, Park et al. demonstrated changes in peripheral axonal excitability in limbic encephalitis and acquired neuromyotonia with anti-voltage gated potassium channel antibodies. Unexpectedly, the results were not consistent with those caused by simple potassium channel blockade, suggesting that multiple other factors contribute to altered axonal excitability. In contrast it was reported that patients with episodic ataxia type 1 (genetic channelopathy with mutation of Kv1.1 channel gene) show prominent excitability changes exactly compatible with fast potassium channel blockade. This commentary aims to highlight findings of this study in a broader context, and provides possible explanations for the discrepancy of patterns of axonal excitability changes in acquired and genetic potassium channelopathies.

Moccia F, Poletto V
May the remodeling of the Ca²⁺ toolkit in endothelial progenitor cells derived from cancer patients suggest alternative targets for anti-angiogenic treatment?
Biochim Biophys Acta. 2015; 1853(9):1958-73 [PubMed] Related Publications
Endothelial progenitor cells (EPCs) may be recruited from bone marrow to sustain the metastatic switch in a number of solid cancers, including breast cancer (BC) and renal cellular carcinoma (RCC). Preventing EPC mobilization causes tumor shrinkage. Novel anti-angiogenic treatments have been introduced in therapy to inhibit VEGFR-2 signaling; unfortunately, these drugs blocked tumor angiogenesis in pre-clinical murine models, but resulted far less effective in human patients. Understanding the molecular mechanisms driving EPC proliferation and tubulogenesis in cancer patients could outline novel targets for alternative anti-angiogenic treatments. Store-operated Ca²⁺ entry (SOCE) regulates the growth of human EPCs, and it is mediated by the interaction between the endoplasmic reticulum Ca²⁺-sensor, Stim1, and the plasmalemmal Ca²⁺ channels, Orai1 and TRPC1. EPCs do not belong to the neoplastic clone: thus, unlike tumor endothelium and neoplastic cells, they should not remodel their Ca²⁺ toolkit in response to tumor microenvironment. However, our recent work demonstrated that EPCs isolated from naïve RCC patients (RCC-EPCs) undergo a dramatic remodeling of their Ca²⁺ toolkit by displaying a remarkable drop in the endoplasmic reticulum Ca²⁺ content, by down-regulating the expression of inositol-1,4,5-receptors (InsP3Rs), and by up-regulating Stim1, Orai1 and TRPC1. Moreover, EPCs are dramatically less sensitive to VEGF stimulation both in terms of Ca²⁺ signaling and of gene expression when isolated from tumor patients. Conversely, the pharmacological abolition of SOCE suppresses proliferation in these cells. These results question the suitability of VEGFR-2 as a therapeutically relevant target for anti-angiogenic treatments and hint at Orai1 and TRPC1 as more promising alternatives. This article is part of a Special Issue entitled: 13th European Symposium on Calcium.

Butrick M, Kelly S, Peshkin BN, et al.
Disparities in uptake of BRCA1/2 genetic testing in a randomized trial of telephone counseling.
Genet Med. 2015; 17(6):467-75 [PubMed] Free Access to Full Article Related Publications
PURPOSE: As genetic counseling and testing become more fully integrated into clinical care, alternative delivery models are increasingly prominent. This study examines predictors of genetic testing for hereditary breast/ovarian cancer among high-risk women in a randomized trial of in-person versus telephone-based genetic counseling.
METHODS: Methods include multivariable logistic regression and interaction analyses.
RESULTS: Of the 669 participants, 600 completed counseling and 523 received test results. As previously reported, participants randomized to telephone counseling were significantly less likely to be tested. In intention-to-treat analyses, completion of counseling and testing was associated with: race/ethnicity (odds ratio (OR) = 1.96, 95% confidence interval (CI): 1.20-3.20), perceived stress (OR = 0.89, 95% CI: 0.81-0.98), knowledge (OR = 1.12, 95% CI: 1.02-1.23), and randomization group (OR = 1.48, 95% CI: 1.01-2.16). Further, race/ethnicity moderated the association between randomization group and testing; minority women receiving telephone counseling were least likely to complete testing.
CONCLUSION: Evidence for logistical and communication-based explanations for this interaction is presented. The overall increased access made possible with telephone genetic counseling should be considered in light of the possibility that this may also lead to lower rates of testing among high-risk minority women. Additional care should be taken to assess and address potential barriers when services are delivered by telephone.Genet Med 17 6, 467-475.

Plönes T, Beckers F, Engel-Riedel W, et al.
Absence of amplification of the FGFR1-gene in human malignant mesothelioma of the pleura: a pilot study.
BMC Res Notes. 2014; 7:549 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Mesothelioma (MPM) is a rare malignant disease with a worse outcome. Fibroblast growth factor 1 (FGFR1) may be an interesting target for selective tyrosine kinases inhibitors (TKI) in MPM. The aim of this study was to evaluate the amplification of the FGFR1 gene in patients suffering from MPM.
FINDINGS: We identified nineteen male patients treated in our department between August 2008 and July 2010 matching the inclusion criteria. Mean age was 68 years. Histopathological examination confirmed thirteen patients with epitheloid subtype, five with biphasic and one patient with sarcomatoid. Fluorescence in situ hybridization analysis revealed no polysomy nor an amplification of the FGFR gene copy number in any case.
CONCLUSION: Regarding that also EGFR amplifications in MPM are absolute rarities, our findings may be a hint that TKI's will not satisfy the hope for a new era in the treatment of MPM.

Chuang HC, Yang LP, Fitzgerald AL, et al.
The p53-reactivating small molecule RITA induces senescence in head and neck cancer cells.
PLoS One. 2014; 9(8):e104821 [PubMed] Free Access to Full Article Related Publications
TP53 is the most commonly mutated gene in head and neck cancer (HNSCC), with mutations being associated with resistance to conventional therapy. Restoring normal p53 function has previously been investigated via the use of RITA (reactivation of p53 and induction of tumor cell apoptosis), a small molecule that induces a conformational change in p53, leading to activation of its downstream targets. In the current study we found that RITA indeed exerts significant effects in HNSCC cells. However, in this model, we found that a significant outcome of RITA treatment was accelerated senescence. RITA-induced senescence in a variety of p53 backgrounds, including p53 null cells. Also, inhibition of p53 expression did not appear to significantly inhibit RITA-induced senescence. Thus, this phenomenon appears to be partially p53-independent. Additionally, RITA-induced senescence appears to be partially mediated by activation of the DNA damage response and SIRT1 (Silent information regulator T1) inhibition, with a synergistic effect seen by combining either ionizing radiation or SIRT1 inhibition with RITA treatment. These data point toward a novel mechanism of RITA function as well as hint to its possible therapeutic benefit in HNSCC.

Khoo KH, Hoe KK, Verma CS, Lane DP
Drugging the p53 pathway: understanding the route to clinical efficacy.
Nat Rev Drug Discov. 2014; 13(3):217-36 [PubMed] Related Publications
The tumour suppressor p53 is the most frequently mutated gene in human cancer, with more than half of all human tumours carrying mutations in this particular gene. Intense efforts to develop drugs that could activate or restore the p53 pathway have now reached clinical trials. The first clinical results with inhibitors of MDM2, a negative regulator of p53, have shown efficacy but hint at on-target toxicities. Here, we describe the current state of the development of p53 pathway modulators and new pathway targets that have emerged. The challenge of targeting protein-protein interactions and a fragile mutant transcription factor has stimulated many exciting new approaches to drug discovery.

Symes AJ, Eilertsen M, Millar M, et al.
Quantitative analysis of BTF3, HINT1, NDRG1 and ODC1 protein over-expression in human prostate cancer tissue.
PLoS One. 2013; 8(12):e84295 [PubMed] Free Access to Full Article Related Publications
Prostate carcinoma is the most common cancer in men with few, quantifiable, biomarkers. Prostate cancer biomarker discovery has been hampered due to subjective analysis of protein expression in tissue sections. An unbiased, quantitative immunohistochemical approach provided here, for the diagnosis and stratification of prostate cancer could overcome this problem. Antibodies against four proteins BTF3, HINT1, NDRG1 and ODC1 were used in a prostate tissue array (> 500 individual tissue cores from 82 patients, 41 case pairs matched with one patient in each pair had biochemical recurrence). Protein expression, quantified in an unbiased manner using an automated analysis protocol in ImageJ software, was increased in malignant vs non-malignant prostate (by 2-2.5 fold, p<0.0001). Operating characteristics indicate sensitivity in the range of 0.68 to 0.74; combination of markers in a logistic regression model demonstrates further improvement in diagnostic power. Triple-labeled immunofluorescence (BTF3, HINT1 and NDRG1) in tissue array showed a significant (p<0.02) change in co-localization coefficients for BTF3 and NDRG1 co-expression in biochemical relapse vs non-relapse cancer epithelium. BTF3, HINT1, NDRG1 and ODC1 could be developed as epithelial specific biomarkers for tissue based diagnosis and stratification of prostate cancer.

Chuang WY, Ströbel P, Bohlender-Willke AL, et al.
Late-onset myasthenia gravis - CTLA4(low) genotype association and low-for-age thymic output of naïve T cells.
J Autoimmun. 2014; 52:122-9 [PubMed] Related Publications
Late-onset myasthenia gravis (LOMG) has become the largest MG subgroup, but the underlying pathogenetic mechanisms remain mysterious. Among the few etiological clues are the almost unique serologic parallels between LOMG and thymoma-associated MG (TAMG), notably autoantibodies against acetylcholine receptors, titin, ryanodine receptor, type I interferons or IL-12. This is why we checked LOMG patients for two further peculiar features of TAMG - its associations with the CTLA4(high/gain-of-function) +49A/A genotype and with increased thymic export of naïve T cells into the blood, possibly after defective negative selection in AIRE-deficient thymomas. We analyzed genomic DNA from 116 Caucasian LOMG patients for CTLA4 alleles by PCR/restriction fragment length polymorphism, and blood mononuclear cells for recent thymic emigrants by quantitative PCR for T cell receptor excision circles. In sharp contrast with TAMG, we now find that: i) CTLA4(low) +49G(+) genotypes were more frequent (p = 0.0029) among the 69 LOMG patients with age at onset ≥60 years compared with 172 healthy controls; ii) thymic export of naïve T cells from the non-neoplastic thymuses of 36 LOMG patients was lower (p = 0.0058) at diagnosis than in 77 age-matched controls. These new findings are important because they suggest distinct initiating mechanisms in TAMG and LOMG and hint at aberrant immuno-regulation in the periphery in LOMG. We therefore propose alternate defects in central thymic or peripheral tolerance induction in TAMG and LOMG converging on similar final outcomes. In addition, our data support a 60-year-threshold for onset of 'true LOMG' and an LOMG/early-onset MG overlapping group of patients between 40 and 60.

Spaniel C, Honda M, Selitsky SR, et al.
microRNA-122 abundance in hepatocellular carcinoma and non-tumor liver tissue from Japanese patients with persistent HCV versus HBV infection.
PLoS One. 2013; 8(10):e76867 [PubMed] Free Access to Full Article Related Publications
Mechanisms of hepatic carcinogenesis in chronic hepatitis B and hepatitis C are incompletely defined but often assumed to be similar and related to immune-mediated inflammation. Despite this, several studies hint at differences in expression of miR-122, a liver-specific microRNA with tumor suppressor properties, in hepatocellular carcinoma (HCC) associated with hepatitis B virus (HBV) versus hepatitis C virus (HCV) infection. Differences in the expression of miR-122 in these cancers would be of interest, as miR-122 is an essential host factor for HCV but not HBV replication. To determine whether the abundance of miR-122 in cancer tissue is influenced by the nature of the underlying virus infection, we measured miR-122 by qRT-PCR in paired tumor and non-tumor tissues from cohorts of HBV- and HCV-infected Japanese patients. miR-122 abundance was significantly reduced from normal in HBV-associated HCC, but not in liver cancer associated with HCV infection. This difference was independent of the degree of differentiation of the liver cancer. Surprisingly, we also found significant differences in miR-122 expression in non-tumor tissue, with miR-122 abundance reduced from normal in HCV- but not HBV-infected liver. Similar differences were observed in HCV- vs. HBV-infected chimpanzees. Among HCV-infected Japanese subjects, reductions in miR-122 abundance in non-tumor tissue were associated with a single nucleotide polymorphism near the IL28B gene that predicts poor response to interferon-based therapy (TG vs. TT genotype at rs8099917), and correlated negatively with the abundance of multiple interferon-stimulated gene transcripts. Reduced levels of miR-122 in chronic hepatitis C thus appear to be associated with endogenous interferon responses to the virus, while differences in miR-122 expression in HCV- versus HBV-associated HCC likely reflect virus-specific mechanisms contributing to carcinogenesis. The continued expression of miR-122 in HCV-associated HCC may signify an important role for HCV replication late in the progression to malignancy.

Fu Y, Fesler M, Mahmud G, et al.
Narrowing down the common deleted region of 5q to 6.0 Mb in blastic plasmacytoid dendritic cell neoplasms.
Cancer Genet. 2013 Jul-Aug; 206(7-8):293-8 [PubMed] Related Publications
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy. Simple and complex recurrent cytogenetic abnormalities have been reported, which demonstrate predominantly genomic losses, of which deletions of 5q are the most frequent aberrations in BPDCN with or without cutaneous manifestation; however, the gene responsible for the disease remains unknown. Using microarray-based molecular characterization, a recent study on several cases of BPDCN with the 5q deletion identified a large, common deleted region (CDR) of 29 Mb that contains several possible candidate genes. We report on a 67-year-old female patient who presented with leukemic BPDCN without skin involvement and had a deletion of 5q and a t(6;8)(p21;q24). By oligo-array-comparative genome hybridization (a-CGH) method, the genomic coordinations of the 5q deletion demonstrated unique breakpoints reported for the first time. Through mapping with those published cases using the same a-CGH method, the CDR was reduced from 29 Mb to 6 Mb, which excluded the previous candidate genes and highlighted an excellent biological gene: the HINT1 gene. Moreover, a molecular cytogenetic characterization of the translocation t(6;8) was performed in search for a novel gene fusion that could be associated with tumor progression.

Li J, Lu X
The emerging roles of 3' untranslated regions in cancer.
Cancer Lett. 2013; 337(1):22-5 [PubMed] Related Publications
Accumulating evidence suggests that 3' untranlated regions (3' UTRs) are critical for spatial and temporal gene expression in both physiological and pathological conditions. The reprogramming of 3' UTRs by various means is a common phenomenon in cancer; disturbances of 3' UTRs significantly increase the risk of cancer susceptibility by acting both in cis and in trans. In this manuscript, we provide an update and perspective on recent advances made in understanding the emerging roles for 3' UTRs in cancer development and hint at the potential future applications of 3' UTRs in cancer diagnosis and therapy.

Wiestler B, Claus R, Hartlieb SA, et al.
Malignant astrocytomas of elderly patients lack favorable molecular markers: an analysis of the NOA-08 study collective.
Neuro Oncol. 2013; 15(8):1017-26 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The number of patients age >65 years with malignant gliomas is increasing. Prognosis of these patients is worse compared with younger patients. To determine biological differences among malignant gliomas of different age groups and help to explain the survival heterogeneity seen in the NOA-08 trial, the prevalence and impact of recently established biomarkers for outcome in younger patients were characterized in elderly patients.
METHODS: Prevalences of mutations of isocitrate dehydrogenase 1 (IDH1) and histone H3.3 (H3F3A), the glioma cytosine-phosphate-guanine island methylator phenotype (G-CIMP), and methylation of alkylpurine DNA N-glycosylase (APNG) and peroxiredoxin 1 (PRDX1) promoters were determined in a representative biomarker subset (n = 126 patients with anaplastic astrocytoma or glioblastoma) from the NOA-08 trial.
RESULTS: IDH1 mutations (R132H) were detected in only 3/126 patients, precluding determination of an association between IDH mutation and outcome. These 3 patients also displayed the G-CIMP phenotype. None of the IDH1 wild-type tumors were G-CIMP positive. Mutations in H3F3A were absent in all 103 patients sequenced for H3F3A. MassARRAY analysis of the APNG promoter revealed generally low methylation levels and failed to confirm any predictive properties for benefit from alkylating chemotherapy. Neither did PRDX1 promoter methylation show differential methylation or association with outcome in this cohort. In a 170-patient cohort from The Cancer Genome Atlas database matched for relevant prognostic factors, age ≥65 years was strongly associated with shorter survival.
CONCLUSIONS: Despite an age-independent stable frequency of O(6)-methylguanine-DNA methyltransferase (MGMT) promoter hypermethylation, tumors in this age group largely lack prognostically favorable markers established in younger glioblastoma patients, which likely contributes to the overall worse prognosis of elderly patients. However, the survival differences hint at fundamental further differences among malignant gliomas of different age groups.

Lee NP
The blood-biliary barrier, tight junctions and human liver diseases.
Adv Exp Med Biol. 2012; 763:171-85 [PubMed] Related Publications
Tight junction (TJ) composes of an intriguing class of cell junction molecules, for which these molecules share similar organizations and structure features among different organs. Fourtypes of transmembrane molecules namely occludins, claudins, junctional adhesion molecules and coxsackievirus and adenovirus receptors act as core units and each link directly and indirectly with a panel of peripheral molecules and underlying cytoskeletons to constitute the functional protein complexes at TJs. Individual TJ complex alone or in co-operation with other complexes via cross-talk mediated by peripheral molecules activate signaling pathways pertinent to various physiological and pathological processes in livers. In human livers, TJs are located at two regions in association with hepatocytes and cholangiocytes and perform major roles in controlling bile flow and metabolism. Apart from this physiological function, the other functions of TJs relating to liver diseases of hepatitis and liver cancer are gradually uncovered. The understanding of how TJs are involved in these clinical conditions hint for the development of new treatments at the molecular level.

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