Research IndicatorsGraph generated 27 February 2015 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 27 February, 2015 using data from PubMed, MeSH and CancerIndex
Specific Cancers (3)
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).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
Search the Epigenomics database and view relevant gene tracks of samples.
Latest Publications: UCP2 (cancer-related)
Esteves P, Pecqueur C, Ransy C, et al.Mitochondrial retrograde signaling mediated by UCP2 inhibits cancer cell proliferation and tumorigenesis.
Cancer Res. 2014; 74(14):3971-82 [PubMed
] Related Publications
Cancer cells tilt their energy production away from oxidative phosphorylation (OXPHOS) toward glycolysis during malignant progression, even when aerobic metabolism is available. Reversing this phenomenon, known as the Warburg effect, may offer a generalized anticancer strategy. In this study, we show that overexpression of the mitochondrial membrane transport protein UCP2 in cancer cells is sufficient to restore a balance toward oxidative phosphorylation and to repress malignant phenotypes. Altered expression of glycolytic and oxidative enzymes mediated the effects of this metabolic shift. Notably, UCP2 overexpression increased signaling from the master energy-regulating kinase, adenosine monophosphate-activated protein kinase, while downregulating expression of hypoxia-induced factor. In support of recent new evidence about UCP2 function, we found that UCP2 did not function in this setting as a membrane potential uncoupling protein, but instead acted to control routing of mitochondria substrates. Taken together, our results define a strategy to reorient mitochondrial function in cancer cells toward OXPHOS that restricts their malignant phenotype.
Du GJ, Li JH, Liu WJ, et al.The combination of TRPM8 and TRPA1 expression causes an invasive phenotype in lung cancer.
Tumour Biol. 2014; 35(2):1251-61 [PubMed
] Related Publications
Our recent studies have shown that hypothermic microenvironment promotes tumor progression and that the molecular sensors for cold are the transient receptor potential (TRP) channels TRPM8 and TRPA1. To evaluate the contribution of TRPM8 and TRPA1 to cancer malignancy, we screened cell subpopulations from Lewis lung cancer (LLC) using limiting dilutions and Western blotting. We identified that LLC-1 cells express 3-fold more TRPM8 than TRPA1, LLC-2 cells express TRPM8 at levels similar to TRPA1, and LLC-3 cells express TRPM8 at one-third the level of TRPA1. LLC-2 cells showed greater adhesion, migration, invasiveness and resistance to hypothermia than LLC-1 and LLC-3 cells, although LLC-2 cells had a longer doubling time. TRPM8 or TRPA1 knockdown using siRNA promoted cell proliferation and decreased adhesion and invasiveness in LLC-2 cells. When assessed for UCP2 staining, LLC-1 cells showed increased staining compared to LLC-2 cells, both of which had more UCP2-positive cells than the LLC-3 subpopulation. In an autophagy assay, hypothermia induced substantially less autophagy in LLC-1 cells than in LLC-2 cells, which displayed decreased autophagy compared to LLC-3 cells. Moreover, mice injected with LLC-2 cells had significantly more spontaneous and experimental lung metastases and a shorter overall survival time than mice injected with LLC-1 or LLC-3 cells. Importantly, LLC-2 cells were also more resistant to activated spleen CTL and the chemotherapeutic drug doxorubicin than LLC-1 and LLC-3 cells in vitro. Collectively, our data suggest that TRPM8 induces UCP2 to trigger metabolic transformation, whereas TRPA1 induces autophagy during adverse conditions, and the combination of both genes contributes directly to an invasive phenotype in lung cancer.
Hossein-Nezhad A, Mirzaei K, Keshavarz SA, et al.Evidences of dual role of vitamin D through cellular energy homeostasis and inflammation pathway in risk of cancer in obese subjects.
Minerva Med. 2013; 104(3):295-307 [PubMed
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AIM: The underlying molecular mechanisms of the role obesity plays in increasing the risk of cancer are not well illuminated. Several mechanisms are proposed for vitamin D as an anti-cancer agent in various malignancies which may be attributed to both its both its anti-inflammatory characteristics as well as its mediatory role in cellular energy homeostasis. This study evaluates the expression of PBMCs' genes which are involved in cellular energy homeostasis such as VDR, PPARγ, PGC1a and UCP2. Moreover, considering the possible role of vitamin D in the inflammation mechanisms, we also aimed at measurement of some inflammatory mediators such as TNF-α, IL-1β, IL4, IL-6, IL10, IL13 and IL17 in inflammatory state in samples obtained from obese persons with and without positive family history of cancer. Moreover, to expand the study to a clinical context, we assessed the correlation of the resting metabolic rate with the evaluated gene.
METHODS: A total of 274 obese women were included in the current cross-sectional study. All of participants were class I obese. By constructing a pedigree that includes 3 generations, twenty-one subjects were at increased risk because of a positive family history of colorectal cancer. Accordingly, current study's analysis was based on positive and negative family history of colorectal cancer.
RESULTS: The concentration of Insulin and PTH were significantly high in group with positive history of cancer. 25 (OH) vitamin D, REE/kg and REE/FFM statuses in two groups; the level of mentioned terms were lower in group with positive history of cancer compared to group with negative history of cancer. We found significantly lower REE/kg in deficiency of vitamin D and higher REE/kg in sufficiency status. Our results demonstrated significant higher concentrations of IL1β, IL17, TNFα and IL6 in group with positive history of cancer compared to group with negative history of cancer. The concentrations of IL13, IL10 and IL4 were significantly lower in group with positive history of cancer compared to group with negative history of cancer. The relative expression of VDR, PGC1αand PPARγ gene was significantly lower in group with positive history of cancer. The relative expression of UCP2 was almost significantly lesser in group with positive history of cancer also.
CONCLUSION: The observed mutual alteration in the levels of inflammatory markers and relative expression of important gene in energy homeostasis may be caused by vitamin D deficiency among the obese subjects with positive history of colorectal cancer.
Liu Y, Jiang H, Xing FQ, et al.Uncoupling protein 2 expression affects androgen synthesis in polycystic ovary syndrome.
Endocrine. 2013; 43(3):714-23 [PubMed
] Related Publications
The roles of uncoupling protein-2 (UCP2) on the androgen synthesis of granulosa cells derived from patients with polycystic ovary syndrome (PCOS) and normal subjects were explored. Primary human granulosa cells from 18 patients who received in vitro fertilization (IVF) were examined; nine patients had PCOS with hyperandrogenism. Primary cultures were treated with genipin, a proton leak inhibitor, guanosine diphosphate (GDP), an UCP inhibitor, and triiodothyronine (T3), an inducer of UCP gene expression. Mitochondrial membrane potential was determined using the JC-1 assay. T3 induced P450scc and UCP2 expressions and testosterone synthesis in both normal and PCOS granulosa cells. Their expressions in response to T3 treatments were correlated in the PCOS group. Differences in testosterone synthesis were observed between normal and PCOS cells in response to genipin. Increased mitochondrial membrane potential was observed in response to genipin and GDP; while T3 decreased it. Increased ovarian UCP2 expression in response to T3 treatment in PCOS may alter pregnenolone synthesis by influencing P450scc expression, thus altering testosterone production. Further in vivo studies are necessary to fully elucidate the role of UCP2 in the hyperandrogenism commonly observed in PCOS.
Dalla Pozza E, Fiorini C, Dando I, et al.Role of mitochondrial uncoupling protein 2 in cancer cell resistance to gemcitabine.
Biochim Biophys Acta. 2012; 1823(10):1856-63 [PubMed
] Related Publications
Cancer cells exhibit an endogenous constitutive oxidative stress higher than that of normal cells, which renders tumours vulnerable to further reactive oxygen species (ROS) production. Mitochondrial uncoupling protein 2 (UCP2) can mitigate oxidative stress by increasing the influx of protons into the mitochondrial matrix and reducing electron leakage and mitochondrial superoxide generation. Here, we demonstrate that chemical uncouplers or UCP2 over-expression strongly decrease mitochondrial superoxide induction by the anticancer drug gemcitabine (GEM) and protect cancer cells from GEM-induced apoptosis. Moreover, we show that GEM IC(50) values well correlate with the endogenous level of UCP2 mRNA, suggesting a critical role for mitochondrial uncoupling in GEM resistance. Interestingly, GEM treatment stimulates UCP2 mRNA expression suggesting that mitochondrial uncoupling could have a role also in the acquired resistance to GEM. Conversely, UCP2 inhibition by genipin or UCP2 mRNA silencing strongly enhances GEM-induced mitochondrial superoxide generation and apoptosis, synergistically inhibiting cancer cell proliferation. These events are significantly reduced by the addition of the radical scavenger N-acetyl-l-cysteine or MnSOD over-expression, demonstrating a critical role of the oxidative stress. Normal primary fibroblasts are much less sensitive to GEM/genipin combination. Our results demonstrate for the first time that UCP2 has a role in cancer cell resistance to GEM supporting the development of an anti-cancer therapy based on UCP2 inhibition associated to GEM treatment.
The Crosstalk between a tumor and its hypoxic microenvironment has become increasingly important. However, the exact role of UCP2 function in cancer cells under hypoxia remains unknown. In this study, UCP2 showed anti-apoptotic properties in A549 cells under hypoxic conditions. Over-expression of UCP2 in A549 cells inhibited reactive oxygen species (ROS) accumulation (P<0.001) and apoptosis (P<0.001) compared to the controls when the cells were exposed to hypoxia. Moreover, over-expression of UCP2 inhibited the release of cytochrome C and reduced the activation of caspase-9. Conversely, suppression of UCP2 resulted in the ROS generation (P = 0.006), the induction of apoptosis (P<0.001), and the release of cytochrome C from mitochondria to the cytosolic fraction, thus activating caspase-9. These data suggest that over-expression of UCP2 has anti-apoptotic properties by inhibiting ROS-mediated apoptosis in A549 cells under hypoxic conditions.
Uncoupling proteins (UCPs) belong to a family of mitochondrial carrier proteins that are present in the mitochondrial inner membrane. UCP1 was first identified followed by its two homologs, UCP2 and UCP3. The physiological functions of UCP include lowering mitochondrial membrane potential and dissipating metabolic energy as heat. However, UCP can be dysregulated and may contribute to the pathogenesis of metabolic disorders and obesity. Recent studies suggest that UCP also plays a role in neurodegenerative diseases and atherosclerosis. In addition, the widely expressed UCP, UCP2, has been shown to be upregulated in a number of aggressive human cancers. One mechanism of UCP2 upregulation in these cancers is due to oxidative stress, and elevated UCP2 in turn reduces oxidative stress, which provides a growth advantage for these cancers. Nevertheless, new studies suggest UCP2 may interact with oncogenes and tumor suppressor genes, providing a potential new mechanism of how UCP2 contributes to cancer development. In this review, the evidence supporting the role of UCPs in diseases other than diabetes and obesity, the reports on how UCP is regulated in cancer cells, and how UCP may regulate p53 will be discussed.
The Warburg Effect is characterized by an irreversible injury to mitochondrial oxidative phosphorylation (OXPHOS) and an increased rate of aerobic glycolysis. In this study, we utilized a breast epithelial cell line lacking mitochondrial DNA (rho(0)) that exhibits the Warburg Effect associated with breast cancer. We developed a MitoExpress array for rapid analysis of all known nuclear genes encoding the mitochondrial proteome. The gene-expression pattern was compared among a normal breast epithelial cell line, its rho(0) derivative, breast cancer cell lines and primary breast tumors. Among several genes, our study revealed that over-expression of mitochondrial uncoupling protein UCP2 in rho(0) breast epithelial cells reflects gene expression changes in breast cancer cell lines and in primary breast tumors. Furthermore, over-expression of UCP2 was also found in leukemia, ovarian, bladder, esophagus, testicular, colorectal, kidney, pancreatic, lung and prostate tumors. Ectopic expression of UCP2 in MCF7 breast cancer cells led to a decreased mitochondrial membrane potential and increased tumorigenic properties as measured by cell migration, in vitro invasion and anchorage independent growth. Consistent with in vitro studies, we demonstrate that UCP2 over-expression leads to development of tumors in vivo in an orthotopic model of breast cancer. Genipin, a plant derived small molecule, suppressed the UCP2 led tumorigenic properties, which were mediated by decreased reactive oxygen species and down-regulation of UCP2. However, UCP1, 3, 4 and 5 gene expression was unaffected. UCP2 transcription was controlled by SMAD4. Together, these studies suggest a tumor-promoting function of UCP2 in breast cancer. In summary, our studies demonstrate that i) the Warburg Effect is mediated by UCP2; ii) UCP2 is over-expressed in breast and many other cancers; iii) UCP2 promotes tumorigenic properties in vitro and in vivo and iv) genipin suppresses the tumor promoting function of UCP2.
Kim JH, Li L, Yun JH, et al.Association study between the -866G/A polymorphism in the promoter of uncoupling protein-2 gene and polycystic ovary syndrome.
Mol Med Rep. 2011 Jul-Aug; 4(4):747-51 [PubMed
] Related Publications
Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, chronic oligoanovulation and insulin resistance. A number of women with PCOS are obese and exhibit abnormal phenotypes, including high levels of androgens, an irregular menstrual cycle and increased hair growth. Studies on obese PCOS patients have proven the crucial role that obesity plays in insulin resistance and hyperinsulinemia. The uncoupling protein (UCP) gene is one of the genes known to have a strong association with obesity and insulin resistance. Thus, we analyzed the association between the -866G/A polymorphism in the promoter of UCP2 and PCOS. Genotyping was performed by polymerase chain reaction along with restriction fragment length polymorphism analysis, followed by an analysis of the genotype of the UCP2 polymorphism in PCOS and control subjects using HapAnalyzer. The study included samples from 277 PCOS patients and 152 healthy controls. P<0.05 was considered to be statistically significant. In conclusion, no association was found between the -866G/A single nucleotide polymorphism and PCOS (P=0.7168, OR=1.07, 95% CI). The present study showed that -866G/A, a UCP2 gene polymorphism, is not associated with the pathogenesis of PCOS.
The histological manifestation of growth-regulating and differentiation-inducing signals in cancer cells is considered as a key component for clinical outcome prediction and commonly defined as tumor differentiation grade. However, the molecular and functional framework underlying this clinical parameter remains poorly understood. Our correlative data display a significant association (P>0.001) between mitochondrial uncoupling protein 2 (UCP2) and tumor grade in primary breast cancer (n=234). Through mechanistic analyses, we show a synergistic link between UCP2 and established cellular pathways in conferring grade-associated functional phenotypes. Here, the application of well to moderately differentiated primary tumor cell lines has enabled direct observation of SMAD recruitment to the UCP2 promoter underlying repression of gene transcription. In contrast, poorly differentiated tumor cells, known to be TGFβ resistant, displayed aberrant UCP2 regulation, and consequently, gene overexpression, which reduced mitochondrial calcium and facilitated the maintenance of mitochondrial membrane potential, thereby significantly decreasing oxidative stress and inhibiting cell death. Conversely, UCP2 silencing in such cells rapidly led to the induction of apoptosis and cell differentiation, concurrent with reduced cell survival and proliferation, confirming gene-specific effects. Demonstration of a biologically driven role for UCP2 dysregulation in promoting multiple characteristics of tumor aggressiveness strongly endorses assessment of gene expression at clinical presentation to augment therapeutic decision-making and improve patient outcome through personalized targeting approaches.
There is a known inverse association between type 2 diabetes (T2D) and prostate cancer (PrCa) that is poorly understood. Genetic studies of the T2D-PrCa association may provide insight into the underlying mechanisms of this association. We evaluated associations in the Atherosclerosis Risk in Communities study between PrCa and nine T2D single nucleotide polymorphisms from genome-wide association studies of T2D (in CDKAL1, CDKN2A/B, FTO, HHEX, IGF2BP2, KCNJ11, PPARG, SLC30A8, and TCF7L2) and four T2D single nucleotide polymorphisms from pre-genome-wide association studies (in ADRB2, CAPN10, SLC2A2, and UCP2). From 1987 to 2000, there were 397 incident PrCa cases among 6,642 men ages 45 to 64 years at baseline. We used race-adjusted Cox proportional hazards models to estimate associations between PrCa and increasing number of T2D risk-raising alleles. PrCa was positively associated with the CAPN10 rs3792267 G allele [hazard ratio (HR) 1.20; 95% confidence interval (CI), 1.00-1.44] and inversely associated with the SLC2A2 rs5400 Thr110 allele (HR, 0.85; 95% CI, 0.72, 1.00), the UCP2 rs660339 Val55 allele (HR, 0.84; 95% CI, 0.73, 0.97) and the IGF2BP2 rs4402960 T allele (HR, 0.79; 95% CI, 0.61-1.02; blacks only). The TCF7L2 rs7903146 T allele was inversely associated with PrCa using a dominant genetic model (HR, 0.79; 95% CI, 0.65-0.97). Further knowledge of T2D gene-PrCa mechanisms may improve understanding of PrCa etiology.
Cancer cells respond to unfavorable microenvironments such as nutrient limitation, hypoxia, oxidative stress, and host defense by comprehensive metabolic reprogramming. Mitochondria are linked to this complex adaptive response and emerging evidence indicates that uncoupling protein-2 (UCP2), a mitochondrial inner membrane anion carrier, may contribute to this process. Effects of UCP2 on mitochondrial bioenergetics, redox homeostasis, and oxidant production in cancer cells may modulate molecular pathways of macromolecular biosynthesis, antioxidant defense, apoptosis, cell growth and proliferation, enhancing robustness and promoting chemoresistance. Elucidation of these interactions may identify novel anti-cancer strategies.
Mitochondrial dysfunction is involved in the pathogenesis of neurodegenerative diseases, including Parkinson's disease (PD). Uncoupling proteins (UCPs) delink ATP production from biofuel oxidation in mitochondria to reduce oxidative stress. UCP2 is expressed in brain, and has neuroprotective effects under various toxic insults. We observed induction of UCP2 expression by leptin in neuronal cultures, and hypothesize that leptin may preserve neuronal survival via UCP2. We showed that leptin preserved cell survival in neuronal SH-SY5Y cells against MPP+ toxicity (widely used in experimental Parkinsonian models) by maintaining ATP levels and mitochondrial membrane potential (MMP); these effects were accompanied by increased UCP2 expression. Leptin had no effect in modulating reactive oxygen species levels. Stable knockdown of UCP2 expression reduced ATP levels, and abolished leptin protection against MPP+-induced mitochondrial depolarization, ATP deficiency, and cell death, indicating that UCP2 is critical in mediating these neuroprotective effects of leptin against MPP+ toxicity. Interestingly, UCP2 knockdown increased UCP4 expression, but not of UCP5. Our findings show that leptin preserves cell survival by maintaining MMP and ATP levels mediated through UCP2 in MPP+-induced toxicity.
Affourtit C, Brand MDMeasuring mitochondrial bioenergetics in INS-1E insulinoma cells.
Methods Enzymol. 2009; 457:405-24 [PubMed
] Related Publications
Pancreatic beta cells secrete insulin in response to raised blood glucose levels. This glucose-stimulated insulin secretion (GSIS) depends on mitochondrial function and is regulated by the efficiency with which oxidative metabolism is coupled to ATP synthesis. Uncoupling protein-2 (UCP2) affects this coupling efficiency and is therefore a plausible pathological and physiological regulator of GSIS. In this respect, it is important to be able to measure coupling efficiencies accurately. Here, we describe experimental protocols to determine the coupling efficiency of trypsinized INS-1E cells, a popular beta cell model, and we present practical details of our RNA interference studies to probe the effect of UCP2 knockdown on this efficiency. We also introduce a method to determine coupling efficiencies noninvasively in attached cells and discuss theoretical and practical aspects of a modular-kinetic approach to describe and understand cellular bioenergetics.
Cancer cells acquire drug resistance as a result of selection pressure dictated by unfavorable microenvironments. This survival process is facilitated through efficient control of oxidative stress originating from mitochondria that typically initiates programmed cell death. We show this critical adaptive response in cancer cells to be linked to uncoupling protein-2 (UCP2), a mitochondrial suppressor of reactive oxygen species (ROS). UCP2 is present in drug-resistant lines of various cancer cells and in human colon cancer. Overexpression of UCP2 in HCT116 human colon cancer cells inhibits ROS accumulation and apoptosis after exposure to chemotherapeutic agents. Tumor xenografts of UCP2-overexpressing HCT116 cells retain growth in nude mice receiving chemotherapy. Augmented cancer cell survival is accompanied by altered NH(2)-terminal phosphorylation of the pivotal tumor suppressor p53 and induction of the glycolytic phenotype (Warburg effect). These findings link UCP2 with molecular mechanisms of chemoresistance. Targeting UCP2 may be considered a novel treatment strategy for cancer.
Galamb O, Gyõrffy B, Sipos F, et al.Helicobacter pylori and antrum erosion-specific gene expression patterns: the discriminative role of CXCL13 and VCAM1 transcripts.
Helicobacter. 2008; 13(2):112-26 [PubMed
] Related Publications
BACKGROUND AND AIMS: Chronic Helicobacter pylori infection affects approximately half of the world, leads to chronic gastritis and peptic ulceration, and is linked to gastric carcinoma. Our aims were to compare the gene expression profile (GEP) of H. pylori-positive and H. pylori-negative gastric erosions and adjacent mucosa to explain the possible role and response to H. pylori infection and to get erosion-related mRNA expression patterns.
METHODS: Total RNA was extracted, amplified, and biotinylated from gastric biopsies of patients with H. pylori-positive and H. pylori-negative antrum erosions (ER) (8/8) and adjacent macroscopically normal mucosae (8/8). The GEP was evaluated using HGU133plus2.0 microarrays. Two independent normalizations (MAS5.0, RMA), PAM feature selection, hierarchical cluster analysis, and discriminant analysis were done. The expression of 14 genes was also measured by real-time-polymerase chain reaction. VCAM-1 and CXCL13 immunohistochemistry (IHC) was done.
RESULTS: In H. pylori infection, significant overexpression of MHC class II antigen-presenting genes, interleukin-7 receptor, ubiquitin-D, CXCR4, lactoferrin immune response-related genes, CXCL-2 and -13, CCL18 chemokine ligand, and VCAM-1 genes were established. In erosive gastritis, increased proliferation (MET) and transport (UCP2, SCFD1, KPNA4) were found, while genes associated with adhesion (SIGLEC11), transcription regulation (ESRRG), and electron and ion transport (ACADM, CLIC6) were down-regulated. Discriminant analysis successfully classified all samples into four groups (HP+ER-, HP+ER+, HP-ER+, HP-ER-) using a reduced gene set (20). Significant overexpression of VCAM-1 and CXC13 protein was detected by IHC in HP+ samples (p < .05).
CONCLUSIONS: Whole genomic microarray analysis yielded new H. pylori infection and erosion-related gene expression changes. Discriminative genes can be used in mRNA-based diagnostic classification of gastric biopsies.
DeJong CH, Busquets S, Moses AG, et al.Systemic inflammation correlates with increased expression of skeletal muscle ubiquitin but not uncoupling proteins in cancer cachexia.
Oncol Rep. 2005; 14(1):257-63 [PubMed
] Related Publications
Muscle wasting in experimental cancer cachexia has been associated with increased ubiquitin proteasome proteolytic system activity and increased uncoupling protein (UCP) expression. Increased ubiquitin proteasome pathway activity has also been found in gastric, but not lung, cancer patients. It therefore remains unclear in which patients modulation of this proteolytic system could be a therapeutic target. We investigated markers of systemic inflammation, hypermetabolism and expression of ubiquitin and uncoupling proteins 2 and 3 in muscle of pancreatic cancer patients. Rectus abdominis muscle was sampled from 15 weight-losing pancreatic cancer patients and 11 controls. UCP2 and 3, and ubiquitin mRNA expression were measured by Northern blots and UCP3 protein by Western blotting. Resting energy expenditure and plasma IL-6, sTNF-R and C-reactive protein (CRP) were also measured. Cancer patients had lost 18% of pre-illness stable weight, but were not significantly hypermetabolic compared with controls. IL-6, sTNF-R and CRP levels and ubiquitin 2.4 kb, but not 1.2 kb, mRNA expression were increased in cancer patients. UCP-2 and 3 mRNA and UCP-3 protein were similar in both groups. Weight loss correlated with systemic inflammation and ubiquitin 1.2 and 2.4 kb mRNA expression. Weight loss in pancreatic cancer is associated with systemic inflammation and increased mRNA expression for ubiquitin but not uncoupling proteins in skeletal muscle. The pro-inflammatory network and ubiquitin proteasome pathway may be targets for intervention in pancreatic cancer cachexia.
Ostrowski J, Klimek-Tomczak K, Wyrwicz LS, et al.Heterogeneous nuclear ribonucleoprotein K enhances insulin-induced expression of mitochondrial UCP2 protein.
J Biol Chem. 2004; 279(52):54599-609 [PubMed
] Related Publications
The uncoupling protein 2, UCP2, is a member of a family of inner mitochondrial membrane ion carriers involved in a host of metabolic processes. UCP2 protein is encoded by nuclear genome, but the protein is found exclusively in the mitochondria. The heterogeneous nuclear ribonucleoprotein K (hnRNPK) is an RNA-binding protein involved in many processes that compose gene expression, including mRNA processing and translation. The yeast three-hybrid screen revealed K protein bound to ucp2 mRNA through sites located in the 3'-untranslated region of the transcript. ucp2 mRNA-K protein complexes were associated with polysome-coated mitochondria. Expression of exogenous K protein augmented the insulin-induced mitochondrial level of UCP2 protein that was not accompanied by a corresponding increase in ucp2 mRNA. These results suggest the insulin stimulates translation of ucp2 mRNA in a process that involves K protein.
Tan MG, Ooi LL, Aw SE, Hui KMCloning and identification of hepatocellular carcinoma down-regulated mitochondrial carrier protein, a novel liver-specific uncoupling protein.
J Biol Chem. 2004; 279(43):45235-44 [PubMed
] Related Publications
We report the identification of a novel cDNA fragment that shows significantly reduced expression in cancerous tissue compared with paired non-cancerous liver tissue in patients with hepatocellular carcinoma (HCC). The full-length transcript of 1733 bp encodes a protein of 308 amino acids that has all the hallmark features of mitochondrial carrier proteins. We designate the novel protein as HDMCP (HCC-down-regulated mitochondrial carrier protein). The HDMCP orthologs in human, mouse, and rat are found to exhibit close similarity in protein sequence and gene organization, as well as exclusive expression in the liver. Moreover, conserved syntenic regions have been demonstrated at the HDMCP gene locus in the human, mouse, and rat genome. Taken together, we suggest that HDMCP might have a conserved and unique biological function in the liver. Overexpression of HDMCP in transiently transfected cancer cells results in the loss of staining by MitoTracker dye, indicating that HDMCP could induce the dissipation of mitochondrial membrane potential (DeltaPsim). However, HDMCP-mediated disruption of DeltaPsim is not related to mitochondrial permeability transition or apoptosis. In addition, we further demonstrate that the dissipation of DeltaPsim is accompanied by significant reduction of cellular ATP in 293T cells overexpressing HDMCP or uncoupling protein 2 (UCP2). Our present findings suggest that HDMCP might be one of the long postulated uncoupling proteins that catalyze the physiological "proton leak" in the liver. The down-regulation of HDMCP in HCC cancer cells might result in the elevation of DeltaPsim, a common phenomenon found in cancer cells.
Savagner F, Franc B, Guyetant S, et al.Defective mitochondrial ATP synthesis in oxyphilic thyroid tumors.
J Clin Endocrinol Metab. 2001; 86(10):4920-5 [PubMed
] Related Publications
Oxyphilic tumors (oncocytomas or Hürthle cell tumors) form a rare subgroup of thyroid tumors characterized by cells containing abundant mitochondria. The relationship between the mitochondrial proliferation and the pathogenesis of these tumors is unknown. We have assessed the expression of the mitochondrial ND2 and ND5 (subunits of the nicotinamide adenine dinucleotide dehydrogenase complex) genes and the nuclear UCP2 (uncoupling protein 2) gene in 22 oxyphilic thyroid tumors and matched controls. The consumption of oxygen in mitochondria from tumors was determined by polarography. ATP assays were used to explore the mitochondrial respiratory chain activity and the oxidative phosphorylation coupling in seven fresh thyroid tumors and controls. Adenosine triphosphate synthesis was significantly lower in all the tumors, compared with controls, suggesting that a coupling defect in oxidative phosphorylation may be a cause of mitochondrial hyperplasia in oxyphilic thyroid tumors.
Carretero MV, Torres L, Latasa U, et al.Transformed but not normal hepatocytes express UCP2.
FEBS Lett. 1998; 439(1-2):55-8 [PubMed
] Related Publications
Uncoupling protein 2 (UCP2) expression in liver is restricted to non-parenchymal cells. By means of differential display screening between normal rat liver and H4IIE hepatoma cells we have isolated a cDNA clone encompassing part of UCP2 cDNA. Northern blot analysis revealed that UCP2 is expressed in some hepatocarcinoma cell lines, while it is absent in adult hepatocytes. UCP2 mRNA in H4IIE cells was downregulated when cells were cultured for 36 h in 0.1% serum and its expression was restored upon addition of 10% serum or phorbol esters. Hypomethylation of UCP2 was observed in transformed UCP2 expressing cells. Our results indicate that UCP2 is expressed in some hepatocarcinoma cell lines and that serum components may participate in maintaining elevated UCP2 levels.