Dataset Information

PTBP1-associated microRNA-1 and -133b suppress the Warburg effect in colorectal tumors.

ABSTRACT: It is known that pyruvate kinase in muscle (PKM), which is a rate-limiting glycolytic enzyme, has essential roles in the Warburg effect and that expression of cancer-dominant PKM2 is increased by polypyrimidine tract-binding protein 1 (PTBP1), which is a splicer of the PKM gene. In other words, PKM2 acts as a promoter of the Warburg effect. Previously, we demonstrated that the Warburg effect was partially established by down-regulation of several microRNAs (miRs) that bind to PTBP1 and that ectopic expression of these miRs suppressed the Warburg effect. In this study, we investigated the functions of miR-1 and -133b, which are well known as muscle-specific miRs, from the viewpoint of the Warburg effect in colorectal tumors. The expression levels of miR-1 and -133b were relatively high in colon tissue except muscle and very frequently down-regulated in 75 clinical colorectal tumors samples, even in adenomas, compared with those of the adjacent normal tissue samples. The ectopic expression of these miRs induced growth suppression and autophagic cell death through the switching of PKM isoform expression from PKM2 to PKM1 by silencing PTBP1 expression both in vitro and in vivo. Also, we showed that the resultant increase in the intracellular level of reactive oxygen species (ROS) was involved in this mechanism. Furthermore, PTBP1 was highly expressed in most of the 30 clinical colorectal tumor samples examined, even in adenomas. Our results suggested that PTBP1 and PTBP1-associated miR-1 and -133b are crucial molecules for the maintenance of the Warburg effect in colorectal tumors.

SUBMITTER: Taniguchi K

PROVIDER: S-EPMC4951342 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

PTBP1-associated microRNA-1 and -133b suppress the Warburg effect in colorectal tumors.

Taniguchi Kohei K Sakai Miku M Sugito Nobuhiko N Kumazaki Minami M Shinohara Haruka H Yamada Nami N Nakayama Tatsushi T Ueda Hiroshi H Nakagawa Yoshihito Y Ito Yuko Y Futamura Manabu M Uno Bunji B Otsuki Yoshinori Y Yoshida Kazuhiro K Uchiyama Kazuhisa K Akao Yukihiro Y

Oncotarget 20160401 14

It is known that pyruvate kinase in muscle (PKM), which is a rate-limiting glycolytic enzyme, has essential roles in the Warburg effect and that expression of cancer-dominant PKM2 is increased by polypyrimidine tract-binding protein 1 (PTBP1), which is a splicer of the PKM gene. In other words, PKM2 acts as a promoter of the Warburg effect. Previously, we demonstrated that the Warburg effect was partially established by down-regulation of several microRNAs (miRs) that bind to PTBP1 and that ecto ...[more]

PMID: 26980745

Similar Datasets

Project description:Testicular Germ Cell Tumors (TGCTs) are a rare group of neoplasms and the most common solid malignancy arising in young male adults. Despite the good response of these tumors to platinum-based chemotherapy, some patients are refractory to treatment and present poor clinical outcomes. During carcinogenesis and tumor development, cancer cells reprogram energy metabolism toward a hyper-glycolytic phenotype, an emerging hallmark of cancer. This phenomenon, known as the Warburg effect or aerobic glycolysis, involves overexpression of metabolism-related proteins, like glucose and monocarboxylate transporters, pH regulators and intracellular glycolytic enzymes. The metabolic profile of TGCTs is very little explored and, recently, this metabolic rewiring of cancer cells has been associated with aggressive clinicopathological characteristics of these tumors. The overexpression of monocarboxylate transporter 4 (MCT4) in TGCTs has been pointed out as a poor prognostic factor, as well as a promising therapeutic target. As a result, the main aim of the present study was to evaluate the prognostic value of key metabolism-related proteins in TGCTs. The immunohistochemical expressions of CD44 (as a monocarboxylate transporter chaperone), glucose transporter 1 (GLUT1), carbonic anhydrase IX (CAIX), hexokinase II (HKII) and lactate dehydrogenase V (LDHV) were evaluated in a series of 148 adult male patients with TGCTs and associated with clinicopathological parameters. In addition, paired normal tissues were also evaluated. The sample included 75 seminoma and 73 non-seminoma tumors. GLUT1 and CD44 expression was significantly increased in malignant samples when compared to paired normal samples. Conversely, HKII and LDHV expressions were significantly decreased in malignant samples. Concerning the clinicopathological values, CAIX expression was significantly associated with disease recurrence, while HKII expression was significantly associated with aggressive characteristics of TGCTs, including higher staging and non-seminoma histology. In conclusion, this study brings new insights on the metabolic characteristics of TGCTs, showing alterations in the expression of proteins related with the Warburg effect, as well as associations of the hyper-glycolytic and acid-resistant phenotype with aggressive clinicopathological parameters.

Project description:Cancer metabolism has received renewed interest as a potential target for cancer therapy. In this study, we use a multi-scale modeling approach to interrogate the implications of three metabolic scenarios of potential clinical relevance: the Warburg effect, the reverse Warburg effect and glutamine addiction. At the intracellular level, we construct a network of central metabolism and perform flux balance analysis (FBA) to estimate metabolic fluxes; at the cellular level, we exploit this metabolic network to calculate parameters for a coarse-grained description of cellular growth kinetics; and at the multicellular level, we incorporate these kinetic schemes into the cellular automata of an agent-based model (ABM), iDynoMiCS. This ABM evaluates the reaction-diffusion of the metabolites, cellular division and motion over a simulation domain. Our multi-scale simulations suggest that the Warburg effect provides a growth advantage to the tumor cells under resource limitation. However, we identify a non-monotonic dependence of growth rate on the strength of glycolytic pathway. On the other hand, the reverse Warburg scenario provides an initial growth advantage in tumors that originate deeper in the tissue. The metabolic profile of stromal cells considered in this scenario allows more oxygen to reach the tumor cells in the deeper tissue and thus promotes tumor growth at earlier stages. Lastly, we suggest that glutamine addiction does not confer a selective advantage to tumor growth with glutamine acting as a carbon source in the tricarboxylic acid (TCA) cycle, any advantage of glutamine uptake must come through other pathways not included in our model (e.g., as a nitrogen donor). Our analysis illustrates the importance of accounting explicitly for spatial and temporal evolution of tumor microenvironment in the interpretation of metabolic scenarios and hence provides a basis for further studies, including evaluation of specific therapeutic strategies that target metabolism.

Project description:BackgroundCleft palate (CP) is the second most common congenital birth defect; however, the relationship between CP-associated genes and epigenetic regulation remains largely unknown. In this study, we investigated the contribution of microRNAs (miRNAs) to cell proliferation and regulation of genes involved in CP development.MethodsIn order to identify all genes for which mutations or association/linkage have been found in individuals with CP, we conducted a systematic literature search, followed by bioinformatics analyses for these genes. We validated the bioinformatics results experimentally by conducting cell proliferation assays and miRNA-gene regulatory analyses in cultured human palatal mesenchymal cells treated with each miRNA mimic.ResultsWe identified 131 CP-associated genes in the systematic review. The bioinformatics analysis indicated that the CP genes were associated with signaling pathways, microRNAs (miRNAs), metabolic pathways, and cell proliferation. A total 17 miRNAs were recognized as potential modifiers of human CP genes. To validate miRNA function in cell proliferation, a main cause of CP, we conducted cell proliferation/viability assays for the top 11 candidate miRNAs from our bioinformatics analysis. Overexpression of miR-133b, miR-374a-5p, and miR-4680-3p resulted in a more than 30% reduction in cell proliferation activity in human palatal mesenchymal cell cultures. We found that several downstream target CP genes predicted by the bioinformatics analyses were significantly downregulated through induction of these miRNAs (FGFR1, GCH1, PAX7, SMC2, and SUMO1 by miR-133b; ARNT, BMP2, CRISPLD1, FGFR2, JARID2, MSX1, NOG, RHPN2, RUNX2, WNT5A and ZNF236 by miR-374a-5p; and ERBB2, JADE1, MTHFD1 and WNT5A by miR-4680-3p) in cultured cells.ConclusionsOur results indicate that miR-374a-5p, miR-4680-3p, and miR-133b regulate expression of genes that are involved in the etiology of human CP, providing insight into the association between CP-associated genes and potential targets of miRNAs in palate development.

Dataset Information

PTBP1-associated microRNA-1 and -133b suppress the Warburg effect in colorectal tumors.

Publications

PTBP1-associated microRNA-1 and -133b suppress the Warburg effect in colorectal tumors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets