Autoantibodies against tumor-associated antigens are very attractive biomarkers for the development of noninvasive serological tests for the early detection of cancer because of their specificity and stability in the sera. In our study, we applied T7 phage display-based serological analysis of recombinant cDNA expression libraries technique to identify a representative set of antigens eliciting humoral responses in patients with gastric cancer (GC), produced phage-antigen microarrays and exploited them for the survey of autoantibody repertoire in patients with GC and inflammatory diseases. We developed procedures for data normalization and cutoff determination to define sero-positive signals and ranked them by the signal intensity and frequency of reactivity. To identify autoantibodies with the highest diagnostic value, a 1,150-feature microarray was tested with sera from 100 patients with GC and 100 cancer-free controls, and then the top-ranked 86 antigens were used for the production of focused array that was tested with an independent validation set comprising serum samples from 235 patients with GC, 154 patients with peptic ulcer and gastritis and 213 healthy controls. The receiver operating characteristic curve analysis showed that 45-autoantibody signature could discriminate GC and healthy controls with area under the curve (AUC) of 0.79 (59% sensitivity and 90% specificity), GC and peptic ulcer with AUC of 0.76 and GC and gastritis with AUC of 0.64. Moreover, it could detect early GC with equal sensitivity than advanced GC. Interestingly, the autoantibody production did not correlate with histological type, H. pylori status, grade, localization and size of the primary tumor, whereas it appeared to be associated with the metastatic disease.Despite the overall global decrease in incidence, gastric cancer (GC) with the estimated $989,600 new cases and $738,000 deaths per year remains the fourth most common type of cancer and the second most common cause of cancer-related death worldwide. 1 The high mortality rate in GC is mostly due to its detection at advanced stage (IIIA-IV), when the estimated 5-year survival rate ranges from 4 to 20% and the median overall survival is around 8-12 months. Only less than 20% of cases are detected at an early localized stage when the complete, curative resection is possible and the 5-year survival rate reaches 75%. 2,3 The early detection of GC is hampered by the lack of specific symptoms before it has spread beyond the original site and the lack of reliable noninvasive screening tests. Currently, the diagnosis is based on endoscopic examination followed by the histological analysis of gastric biopsy, which is an invasive technique not applicable for the screening of asymptomatic population. Hence, the identification and validation of GC biomarkers that could be detected in body fluids such as plasma, serum or urine and that are suitable for the development of noninvasive or minimally invasive tests applicable for screening high-risk groups would represent a significant ste...
Lung cancer is the most common cancer worldwide, accounting for over 1.37 million deaths annually. The clinical outcome and management of lung cancer patients could be substantially improved by the implementation of non-invasive biomarker assays for the early detection, prognosis as well as prediction and monitoring of treatment response. MicroRNAs (miRNAs) have been implicated in the regulation of virtually all signaling circuits within a cell and their dysregulation has been shown to play an essential role in the development and progression of cancer. Recently, miRNAs were found to be released into the circulation and to exist there in a remarkably stable form. Furthermore, various cancers were shown to leave specific miRNA fingerprints in the blood of patients suggesting that cell-free miRNAs could serve as non-invasive biomarkers for the detection or monitoring of cancer and putative therapeutic targets. Since that, a considerable effort has been devoted to decode the information carried by circulating miRNAs. In the current review, we give an insight into the mechanisms of miRNA release into the bloodstream, their putative functional significance and systematically review the studies focused on the identification of cell-free miRNAs with the diagnostic, prognostic, and predictive significance in lung cancer and discuss their potential clinical utility.
Highlights d LDH upregulation is required for the transition from hyperplasia to neoplasia d LDH expression drives tumor formation in the context of EGFR overexpression d Increased sugar uptake drives tumor formation in the Drosophila EGFR model d Synergy between EGFR and LDHA correlates with poor outcome in human cancer
Myotonic dystrophy type 1 (DM1) is caused by CUG triplet expansions in the 3′ UTR of dystrophia myotonica protein kinase (DMPK) messenger ribonucleic acid (mRNA). The etiology of this multi-systemic disease involves pre-mRNA splicing defects elicited by the ability of the CUG-expanded mRNA to ‘sponge’ splicing factors of the muscleblind family. Although nuclear aggregation of CUG-containing mRNPs in distinct foci is a hallmark of DM1, the mechanisms of their homeostasis have not been completely elucidated. Here we show that a DEAD-box helicase, DDX6, interacts with CUG triplet-repeat mRNA in primary fibroblasts from DM1 patients and with CUG–RNA in vitro. DDX6 overexpression relieves DM1 mis-splicing, and causes a significant reduction in nuclear DMPK-mRNA foci. Conversely, knockdown of endogenous DDX6 leads to a significant increase in DMPK-mRNA foci count and to increased sequestration of MBNL1 in the nucleus. While the level of CUG-expanded mRNA is unaffected by increased DDX6 expression, the mRNA re-localizes to the cytoplasm and its interaction partner MBNL1 becomes dispersed and also partially re-localized to the cytoplasm. Finally, we show that DDX6 unwinds CUG-repeat duplexes in vitro in an adenosinetriphosphate-dependent manner, suggesting that DDX6 can remodel and release nuclear DMPK messenger ribonucleoprotein foci, leading to normalization of pathogenic alternative splicing events.
The Hippo pathway has been identified as a key barrier for tumorigenesis, acting through downregulation of YAP/TAZ activity. Elevated YAP/TAZ activity has been documented in many human cancers. Ubiquitylation has been shown to play a key role in regulating YAP/TAZ activity through downregulation of a number of Hippo pathway components. Several ubiquitin ligase complexes have been implicated in this process, however, little is known about the deubiquitylating enzymes that counteract these activities to regulate YAP/TAZ. Here we identify the deubiquitylating enzyme USP9x as a regulator of YAP/TAZ activity. We demonstrate that USPx regulates ubiquitin-mediated turnover of the YAP inhibitor, Angiomotin. USP9x acts to deubiquitylate Angiomotin at lysine 496, resulting in stabilization of Angiomotin and lower YAP/TAZ activity. USP9x mRNA levels were reduced in several cancers. Clinically, USP9x mRNA levels were reduced in several cancers with low USPx expression correlating with poor prognosis in renal clear cell carcinoma. Our data indicate that USP9x may be a useful biomarker for renal clear cell carcinoma.
BackgroundChanges in cellular metabolism are now recognized as potential drivers of cancer development, rather than as secondary consequences of disease. Here, we explore the mechanism by which metabolic changes dependent on aldehyde dehydrogenase impact cancer development.MethodsALDH7A1 was identified as a potential cancer gene using a Drosophila in vivo metastasis model. The role of the human ortholog was examined using RNA interference in cell-based assays of cell migration and invasion. 1H-NMR metabolite profiling was used to identify metabolic changes in ALDH7A1-depleted cells. Publically available cancer gene expression data was interrogated to identify a gene-expression signature associated with depletion of ALDH7A1. Computational pathway and gene set enrichment analysis was used to identify signaling pathways and cellular processes that were correlated with reduced ALDH7A1 expression in cancer. A variety of statistical tests used to evaluate these analyses are described in detail in the methods section. Immunohistochemistry was used to assess ALDH7A1 expression in tissue samples from cancer patients.ResultsDepletion of ALDH7A1 increased cellular migration and invasiveness in vitro. Depletion of ALDH7A1 led to reduced levels of metabolites identified as ligands for Peroxisome proliferator-activated receptor (PPARα). Analysis of publically available cancer gene expression data revealed that ALDH7A1 mRNA levels were reduced in many human cancers, and that this correlated with poor survival in kidney and liver cancer patients. Using pathway and gene set enrichment analysis, we establish a correlation between low ALDH7A1 levels, reduced PPAR signaling and reduced patient survival. Metabolic profiling showed that endogenous PPARα ligands were reduced in ALDH7A1-depleted cells. ALDH7A1-depletion led to reduced PPAR transcriptional activity. Treatment with a PPARα agonist restored normal cellular behavior. Low ALDH7A1 protein levels correlated with poor clinical outcome in hepatocellular and renal clear cell carcinoma patients.ConclusionsWe provide evidence that low ALDH7A1 expression is a useful prognostic marker of poor clinical outcome for hepatocellular and renal clear cell carcinomas and hypothesize that patients with low ALDH7A1 might benefit from therapeutic approaches addressing PPARα activity.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-5061-7) contains supplementary material, which is available to authorized users.
BackgroundCurrently the cytological examination of fine needle aspiration (FNA) biopsies is the standard technique for the pre-operative differential diagnosis of thyroid nodules. However, the results may be non-informative in ~20% of cases due to an inadequate sampling and the lack of highly specific, measurable cytological criteria, therefore ancillary biomarkers that could aid in these cases are clearly needed. The aim of our study was to evaluate the mRNA expression levels of 8 candidate marker genes as the diagnostic biomarkers for the discrimination of benign and malignant thyroid nodules and to find a combination of biomarkers with the highest diagnostic value.Materials and methodsmRNA expression levels of eight candidate marker genes - BIRC5, CCND1, CDH1, CITED1, DPP4, LGALS3, MET and TFF3 was measured by real-time RT-PCR in paired nodular and surrounding normal thyroid tissue specimens of 105 consecutive patients undergoing thyroid surgery and compared between different types of thyroid lesions.ResultsSignificant differences in the mRNA expression levels between the normal and malignant thyroid tissues and between benign and malignant nodules were found for BIRC5, CCND1, CITED1, DPP4, LGALS3, MET and TFF3, but not CDH1. On a single gene basis, relative quantity (RQ) of LGALS3 had the highest diagnostic value for the discrimination of malignant and benign thyroid nodules (AUC = 0.832, P < 0.0001 and 90.9% sensitivity and 65.6% specificity at the optimal cut-off on ROC curve). The only two-marker set that outperformed LGALS3 was RQ sum of LGALS3 and BIRC5 (AUC = 0.841, P < 0.0001). An application of multivariate logistic regression analysis resulted in the generation of a multiplex biomarker model based on LGALS3, BIRC5, TFF3, CCND1, MET and CITED1 that had considerably higher specificity than a single marker or two marker gene-based models (AUC = 0.895, P < 0.0001, 70.5% sensitivity and 93.4% specificity).ConclusionsThis study confirmed that mRNA expression levels of 7 out of 8 candidate genes analysed have a diagnostic value for the distinction of benign and malignant thyroid nodules. The multiplex biomarker model based on 6 genes outperformed a single marker or two marker-based models and warrants feasibility studies on FNA biopsies and the validation in a larger cohort of patients.
Trefoil factor 3 (TFF3) is overexpressed in a variety of solid epithelial cancers, where it has been shown to promote migration, invasion, proliferation, survival and angiogenesis. On the contrary, in the majority of thyroid tumors, it is downregulated, yet its role in the development of thyroid cancer remains unknown. Here we show that TFF3 exhibits strong cytoplasmic staining of normal thyroid follicular cells and colloid and the staining is increased in hyperfunctioning thyroid nodules, while it is decreased in all thyroid cancers of follicular cell origin. By meta-analysis of gene expression datasets, we found that in the thyroid cancer, conversely to the breast cancer, the expression of TFF3 mRNA was downregulated by estrogen signaling and confirmed this by treating thyroid cancer cells with estradiol. Forced expression of TFF3 in anaplastic thyroid cancer cells resulted in decreased cell proliferation, clonal spheroid formation and entry into the S phase. Furthermore, it induced acquisition of epithelial-like cell morphology and expression of the differentiation markers of thyroid follicular cells and transcription factors implicated in the thyroid morphogenesis and function. Taken together, this study provides the first evidence that TFF3 may act as a tumor suppressor or an oncogene depending on the cellular context.
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