Tumor gene polymorphisms are often associated with individual susceptibility to genetic diseases. Cytochrome P4501A1 (CYP1A1) and glutathione S-transferase mu 1 (GSTM1) gene polymorphisms are closely related to the susceptibility of the body to chemical carcinogens in the environment. Therefore, we explored the relationship between CYP1A1 and GSTM1 gene polymorphisms and susceptibility to bone tumors. Multiplex-polymerase chain reaction (PCR), allelic-specific PCR, and PCR-restriction fragment length polymorphism techniques were used to analyze CYP1A1 and GSTM1 gene polymorphisms in 52 bone tumor patients and 100 healthy subjects. The allelic variation frequency of the CYP1A1 gene at exon 7 (Ile 462 Val) in bone tumor patients was 0.462, which was significantly higher than that in the normal controls (0.223). The frequency of the absence of the GSTM1 homozygous genotype in the patients (0.65) was also markedly higher than that in the control group (0.41). Subjects with CYP1A1 Val/Val homozygous mutations and absence of the GSTM1 homozygous genotype were at markedly increased risk of developing bone tumors [ORs 4.15 (95%CI: 1.268-13.30) and 2.35 (95%CI: 1.15-4.85), respectively]. The OR for the combined effect of the CYP1A1 and GSTM1 gene polymorphisms was 8.55 (95%CI: 1.75-41.50). CYP1A1 and GSTM1 polymorphisms are genetic risk factors in patients with bone tumors, and the allelic variation of these genes increases the risk of bone tumor occurrence.

Endocytosis is differentially regulated by hypoxia-inducible factor-1α (HIF-1α) and phospholipase D (PLD). However, the relationship between HIF-1α and PLD in endocytosis is unknown. HIF-1α is degraded through the prolyl hydroxylase (PHD)/von Hippel-Lindau (VHL) ubiquitination pathway in an oxygen-dependent manner. Here, we show that PLD1 recovers the decrease in epidermal growth factor receptor (EGFR) endocytosis induced by HIF-1α independent of lipase activity via the Rab5-mediated endosome fusion pathway. EGF-induced interaction of PLD1 with HIF-1α, PHD and VHL may contribute to EGFR endocytosis. The pleckstrin homology domain (PH) of PLD1 itself promotes degradation of HIF-1α, then accelerates EGFR endocytosis via upregulation of rabaptin-5 and suppresses tumor progression. These findings reveal a novel role of the PLD1-PH domain as a positive regulator of endocytosis and provide a link between PLD1 and HIF-1α in the EGFR endocytosis pathway.

Triple negative breast cancers (TNBC) are a more aggressive subset of breast cancer. A better understanding of its biology could allow the rational development of targeted therapies.

Lung cancer ranks as the first most common cancer and the first leading cause of cancer-related death in China and worldwide. Due to the difficulty in early diagnosis and the onset of cancer metastasis, the 5-year survival rate of lung cancer remains extremely low. Long noncoding RNAs (lncRNAs), which lacking protein-coding ability, have recently emerged as pivotal participants in biological processes, often dysregulated in a range of cancers, including lung cancer. In this review, we highlight the recent findings of lncRNAs in lung cancer pathogenesis. While our understanding of lncRNAs in the onset and progression of lung cancer is still in its infancy, there is no doubt that understanding the activities of lncRNAs will certainly secure strong biomarkers and improve treatment options for lung cancer patients.

Microsatellite instability (MSI) is a frequent and clinically relevant molecular phenotype in colorectal cancer. MSI cancers have favorable survival compared with microsatellite stable cancers (MSS), possibly due to the pronounced tumor-infiltrating lymphocytes observed in MSI cancers. Consistent with the strong immune response that MSI cancers trigger in the host, previous transcriptome expression studies have identified mRNA signatures characteristic of immune response in MSI cancers. However, proteomics features of MSI cancers and the extent to which the mRNA signatures are reflected at the protein level remain largely unknown. Here, we performed a comprehensive comparison of global proteomics profiles between MSI and MSS colorectal cancers in The Cancer Genome Atlas (TCGA) cohort. We found that protein signatures of MSI are also associated with increased immunogenicity. To reliably quantify post-transcription regulation in MSI cancers, we developed a resampling-based regression method by integrative modeling of transcriptomics and proteomics data sets. Compared with the popular simple method, which detects post-transcriptional regulation by either identifying genes differentially expressed at the mRNA level but not at the protein level or vice versa, our method provided a quantitative, more sensitive, and accurate way to identify genes subject to differential post-transcriptional regulation. With this method, we demonstrated that post-transcriptional regulation, coordinating protein expression with key players, initiates de novo and enhances protective host response in MSI cancers.

Anaplastic thyroid carcinoma is the most undifferentiated form of thyroid cancer and one of the deadliest of all adult solid malignancies. Here we report the first genomic and transcriptomic profile of anaplastic thyroid cancer including those of several unique cell lines and outline novel potential drivers of malignancy and targets of therapy.

Thirteen adult patients with temozolomide, surgery and radiation refractory ganglioglioma were screened for the BRAF V600E mutation. Three (23%) were found positive for the presence of the BRAF mutation and were treated with the BRAF inhibitor dabrafenib. Dabrafenib was well tolerated with no grade 3 or higher toxicity. The median number of cycles was 7 (a cycle was defined as 1 month of daily dabrafenib) and best response was stable disease in two patients and a partial response in one patient. Median progression-free survival was 7 months with a range of 4-10 months.

The activation of hepatic kinase mechanistic target of rapamycin complex 1 (mTORC1) is implicated in the development of obesity-related metabolic disorders. This study investigated the metabolic sequelae of mTORC1 hyperactivation in human hepatoma cells and the lipid-regulating mechanisms of two short-chain fatty acids: 4-phenylbutyric acid (PBA) and (R)-α-lipoic acid (LA). We created three stable cell lines that exhibit low, normal, or high mTORC1 activity. mTORC1 hyperactivation induced the expression of lipogenic (DGAT1 and DGAT2) and lipoprotein assembly (MTP and APOB) genes, thereby raising cellular triacylglyceride (TG) and exacerbating secretion of apoB-containing TG-rich lipoproteins. LYS6K2, a specific inhibitor of the p70 S6 kinase branch of mTORC1 signaling, reversed these effects. PBA and LA decreased secreted TG through distinct mechanisms. PBA repressed apoB expression (both mRNA and protein) and lowered secreted TG without mitigation of mTORC1 hyperactivity or activation of AMPK. LA decreased cellular and secreted TG by attenuating mTORC1 signaling in an AMPK-independent manner. LA did not regulate apoB expression but led to the secretion of apoB-containing TG-poor lipoproteins by repressing the expression of lipogenic genes, FASN, DGAT1, and DGAT2. Our studies provide new mechanistic insight into the hypolipidemic activity of PBA and LA in the context of mTORC1 hyperactivation and suggest that the short-chain fatty acids may aid in the prevention and treatment of hypertriglyceridemia.

The MexTAg transgenic mouse model of mesothelioma replicates many aspects of human mesothelioma, including induction by asbestos, pathogenicity and response to cytotoxic chemotherapy, despite high levels of the SV40 large T Antigen (TAg) in the mesothelial compartment. This model enables analysis of the molecular events associated with asbestos induced mesothelioma and is utilised here to investigate the molecular dynamics of tumours induced in these mice, using gene expression patterns as a read out.

BRCA1-interacting protein 1 (BRIP1), a DNA-dependent ATPase and a DNA helicase, is critical for BRCA-associated DNA damage repair functions and may be associated with the tumourigenesis and aggressiveness of various cancers. Here, we constructed a BRIP1 recombinant plasmid, overexpressed it in a cervical cancer cell line (HeLa) and found that ectopic expression of BRIP1 could remarkably enhance the antitumor activity of cisplatin, as demonstrated by decreased cell viability, colony formation and tumour xenografts' weight. Moreover, BRIP1 promoted cisplatin-mediated cell apoptosis and suppressed tumour angiogenesis. We also found that the synergistic inhibition effect of BRIP1 might be partially attributed to attenuation of Rac1 GTPase activation and that Rac1 GTPase re-activation could reverse the sensitizing effect induced by BRIP1. Our study suggested that up-regulation of BRIP1 could enhance chemosensitivity of HeLa cells to cisplatin through inhibiting Rac1 GTPase activation, and it provides a new insight into the essential role of BRIP1 in cervical cancer chemotherapy.

Breast cancer is more common in European Americans (EAs) than in African Americans (AAs) but mortality from breast cancer is higher among AAs. While there are racial differences in DNA methylation and gene expression in breast tumors, little is known whether such racial differences exist in breast tissues of healthy women. Genome-wide DNA methylation and gene expression profiling was performed in histologically normal breast tissues of healthy women. Linear regression models were used to identify differentially-methylated CpG sites (CpGs) between EAs (n = 61) and AAs (n = 22). Correlations for methylation and expression were assessed. Biological functions of the differentially-methylated genes were assigned using the Ingenuity Pathway Analysis. Among 485 differentially-methylated CpGs by race, 203 were hypermethylated in EAs, and 282 were hypermethylated in AAs. Promoter-related differentially-methylated CpGs were more frequently hypermethylated in EAs (52%) than AAs (27%) while gene body and intergenic CpGs were more frequently hypermethylated in AAs. The differentially-methylated CpGs were enriched for cancer-associated genes with roles in cell death and survival, cellular development, and cell-to-cell signaling. In a separate analysis for correlation in EAs and AAs, different patterns of correlation were found between EAs and AAs. The correlated genes showed different biological networks between EAs and AAs; networks were connected by Ubiquitin C. To our knowledge, this is the first comprehensive genome-wide study to identify differences in methylation and gene expression between EAs and AAs in breast tissues from healthy women. These findings may provide further insights regarding the contribution of epigenetic differences to racial disparities in breast cancer.

Both 5-methylcytosine (5mC) and its oxidized form 5-hydroxymethylcytosine (5hmC) have been proposed to be involved in tumorigenesis. Because the readout of the broadly used 5mC mapping method, bisulfite sequencing (BS-seq), is the sum of 5mC and 5hmC levels, the 5mC/5hmC patterns and relationship of these two modifications remain poorly understood. By profiling real 5mC (BS-seq corrected by Tet-assisted BS-seq, TAB-seq) and 5hmC (TAB-seq) levels simultaneously at single-nucleotide resolution, we here demonstrate that there is no global loss of 5mC in kidney tumors compared with matched normal tissues. Conversely, 5hmC was globally lost in virtually all kidney tumor tissues. The 5hmC level in tumor tissues is an independent prognostic marker for kidney cancer, with lower levels of 5hmC associated with shorter overall survival. Furthermore, we demonstrated that loss of 5hmC is linked to hypermethylation in tumors compared with matched normal tissues, particularly in gene body regions. Strikingly, gene body hypermethylation was significantly associated with silencing of the tumor-related genes. Downregulation of IDH1 was identified as a mechanism underlying 5hmC loss in kidney cancer. Restoring 5hmC levels attenuated the invasion capacity of tumor cells and suppressed tumor growth in a xenograft model. Collectively, our results demonstrate that loss of 5hmC is both a prognostic marker and an oncogenic event in kidney cancer by remodeling the DNA methylation pattern.

The characteristics of a cellular calcium signal (calcium signature) are determined, at least partly, by the expression of a subset of genes encoding proteins involved in calcium entry, calcium uptake and calcium modulation. Our aim in the present work was to characterize the set of genes involved in calcium signal generation that are differentially expressed in normal brain tissues versus brain tumor and/or glioma stem cells. Public datasets were analyzed according to a four step methodology consisting of: 1. detecting the outliers by using principal component analysis of the whole transcriptome; 2. building a calcium toolbox composed of 260 genes involved in the generation and modulation of the calcium signal; 3. analyzing the calcium toolbox transcriptome of different human brain areas and 4. detecting genes from the calcium toolbox preferentially expressed in tumor tissues or tumor cells compared to normal brain tissues. Our approach was validated on normal brain tissue. Tumor sample analysis allowed us to disclose a set of eighteen genes characteristic of glioblastoma tissues or glioma stem cells. Interpreting the set of genes highlighted in the study led us to propose that i) the mechanism of store operated calcium entry is strongly perturbed in cancer cells and tissues, ii) the process of calcium reuptake into mitochondria is more important in cancer cells and tissues than in their normal counterparts and iii) these two mechanisms may be coupled in at least one subgroup of the glioblastoma stem cells.

Despite the intensive research of the last three decades into Transient Receptor Potential (TRP) cation channels, no precise and complete profiling of these channels is yet available regarding their involvement in physiopathology and carcinogenesis in particular. TRP channel activity is crucial for all the essential hallmarks of carcinogenesis such as proliferation, apoptosis, migration and angiogenesis, which is the reason why these channels have been proposed not only as clinical markers, but also as promising targets for anti-cancer therapy. However, in the majority of studies, each channel has been considered as a separate molecular entity and studied independently from the other TRPs, while a complete "transportome" of the specific stages of carcinogenesis is required for the effective use of these targets. This review focuses on the partial TRP expression profiles found in the literature and the means by which a full TRP signature could be achieved.

Current therapeutic strategies for sickle cell anemia are aimed at reactivating fetal hemoglobin. Pomalidomide, a third-generation immunomodulatory drug, was proposed to induce fetal hemoglobin production by an unknown mechanism. Here, we report that pomalidomide induced a fetal-like erythroid differentiation program, leading to a reversion of γ-globin silencing in adult human erythroblasts. Pomalidomide acted early by transiently delaying erythropoiesis at the burst-forming unit-erythroid/colony-forming unit-erythroid transition, but without affecting terminal differentiation. Further, the transcription networks involved in γ-globin repression were selectively and differentially affected by pomalidomide including BCL11A, SOX6, IKZF1, KLF1, and LSD1. IKAROS (IKZF1), a known target of pomalidomide, was degraded by the proteasome, but was not the key effector of this program, because genetic ablation of IKZF1 did not phenocopy pomalidomide treatment. Notably, the pomalidomide-induced reprogramming was conserved in hematopoietic progenitors from individuals with sickle cell anemia. Moreover, multiple myeloma patients treated with pomalidomide demonstrated increased in vivo γ-globin levels in their erythrocytes. Together, these data reveal the molecular mechanisms by which pomalidomide reactivates fetal hemoglobin, reinforcing its potential as a treatment for patients with β-hemoglobinopathies.

Melanoma can switch between proliferative and invasive states, which have identifying gene expression signatures that correlate with good and poor prognosis, respectively. However, the mechanisms controlling these signatures are poorly understood. In this study, we identify BMI1 as a key determinant of melanoma metastasis by which its overexpression enhanced and its deletion impaired dissemination. Remarkably, in this tumor type, BMI1 had no effect on proliferation or primary tumor growth but enhanced every step of the metastatic cascade. Consistent with the broad spectrum of effects, BMI1 activated widespread gene expression changes, which are characteristic of melanoma progression and also chemoresistance. Accordingly, we showed that up-regulation or down-regulation of BMI1 induced resistance or sensitivity to BRAF inhibitor treatment and that induction of noncanonical Wnt by BMI1 is required for this resistance. Finally, we showed that our BMI1-induced gene signature encompasses all of the hallmarks of the previously described melanoma invasive signature. Moreover, our signature is predictive of poor prognosis in human melanoma and is able to identify primary tumors that are likely to become metastatic. These data yield key insights into melanoma biology and establish BMI1 as a compelling drug target whose inhibition would suppress both metastasis and chemoresistance of melanoma.

CIAPIN1 (cytokine-induced apoptosis inhibitor 1) was recently identified as an essential downstream effector of the Ras signaling pathway. However, its potential role in regulating myeloid leukemia cells sensitivity to Imatinib remains unclear. In this study, we found depletion of CIAPIN1 inhibited proliferation and triggered more apoptosis of K562CML (chronic myeloid leukemia) cells with or without Imatinib treatment. Meanwhile, CIAPIN1 depletion decreased ERK5 phosphorylation and NF-κB activity. Importantly, treating CIAPIN1-depleted K562 cells with ERK5 signaling pathway specific inhibitor, XMD8-92, further inhibited proliferation and promoted apoptosis with or without Imatinib treatment. Treatment with the NF-κB specific inhibitor, Bay 11-7082, induced nearly the same inhibition of proliferation and promotion of apoptosis conferred by CIAPIN1 depletion as was observed with XMD8-92 treatment. Further, XMD8-92 and Bay 11-7082 synergistically inhibited proliferation and promoted apoptosis of CIAPIN1-depleted K562 cells with or without Imatinib treatment. The nude mice transplantation model was also performed to confirm the enhanced sensitivity of CIAPIN1-depleted K562 cells to Imatinib. Thus, our results provided a potential management by which CIAPIN1 knock-down might have a crucial impact on enhancing sensitivity of K562 cells to Imatinib in the therapeutic approaches, indicating that CIAPIN1 knock-down might serve as a combination with chemotherapeutical agents in leukemia diseases therapy.

Mammaglobin is a glycoprotein exhibiting homology to uteroglobin gene family. Although the biological function of the protein is not yet known it has been reported to act as marker for breast cancer in women. This study reports the expression of mammaglobin gene in canine mammary tumor condition. The gene was cloned, sequenced and heterologously expressed in Escherichia coli host system as 12 kDa (approx.) recombinant fusion protein. The expressed protein was further purified to homogeneity and confirmed by western blotting. Hyperimmune sera were raised against the expressed protein in rabbits and mice to standardize sandwich ELISA for relative quantification of circulating protein in the sera of dogs with mammary tumors. Based on receiver-operating characteristics analysis, the test was found to be 90% sensitive and 95% specific for a cut-off value of 0.177 with respect to histopathological staining in diagnosing canine mammary tumors and the protein level was not elevated in other diseased conditions. These findings indicate that it can act as a novel molecular marker for detecting mammary tumors in canines.

Breast cancer 1, early onset (BRCA1) is one of the most important genes in human familial breast cancer, which also plays an important role in canine mammary tumors. The objectives of this study were to determine the promoter sequence of canine BRCA1, to investigate its promoter mutation status and to describe BRCA1 expression pattern in canine mammary tumors. The promoter sequence of canine BRCA1 was acquired by aligning human BRCA1 promoter sequence with canine genomic sequence and confirmed by standard promoter activity analysis. Same as human BRCA1 promoter, the CAAT box and G/C box were found in canine BRCA1 promoter. In order to explore the mutation status of the promoter region and to investigate the expression pattern of this gene, 10 normal canine mammary tissues, 15 benign mammary tumors and 15 malignant mammary tumors were used. By sequencing, 46.7% of the malignant mammary tumors were found with a deletion of one cytosine in the promoter region. The mRNA expression of BRCA1 was significantly reduced in benign and malignant mammary tumors (P<0.05), and the protein expression of BRCA1 was significantly reduced in malignant mammary tumors (P<0.05). This study is the first time to determine the canine BRCA1 promoter sequence and to describe the promoter mutation status in canine mammary tumors.

Fifty-four canine mammary lesions (15 hyperplasias, 7 adenomas and 32 carcinomas) were submitted to immunohistochemical analysis for the evaluation of PTEN and E-cadherin co-expression. Subjects bearing mammary carcinomas were also submitted to a 2-year follow-up study to compare immunohistochemical results with overall survival. All the hyperplastic samples stained positive for both markers, 100% of adenomas were positive for PTEN and 86% for E-cadherin, and 69% and 34% of carcinomas were positive for PTEN and E-cadherin, respectively. Statistical analysis showed a positive correlation between these two proteins both considering all (p b 0.01) or malignant tumors (p < 0.05). The female dogs bearing tumors positively-stained for both markers had a longer overall survival (p < 0.05) and absence of lymphatics invasion (p < 0.05). Simultaneous double immunofluorescence confirmed the co-localization of the two proteins in neoplastic cells. Results reported in this study confirm the tumor suppressor effect of these two molecules.