Research IndicatorsGraph generated 10 March 2017 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 09 March, 2017 using data from PubMed, MeSH and CancerIndex
Specific Cancers (4)
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.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: UCP2 (cancer-related)
Background. The most significant hallmarks of cancer are directly or indirectly linked to deregulated mitochondria. In this study, we sought to profile mitochondria associated genes in isogenic prostate cell lines with different tumorigenic phenotypes from the same patient. Results. Two isogenic human prostate cell lines RC77N/E (nonmalignant cells) and RC77T/E (malignant cells) were profiled for expression of mitochondrial biogenesis and energy metabolism genes by qRT-PCR using the Human Mitochondria and the Mitochondrial Energy Metabolism RT(2) PCR arrays. Forty-seven genes were differentially regulated between the two cell lines. The interaction and regulatory networks of these genes were generated by Ingenuity Pathway Analysis. UCP2 was the most significantly upregulated gene in primary adenocarcinoma cells in the current study. The overexpression of UCP2 upon malignant transformation was further validated using human prostatectomy clinical specimens. Conclusions. This study demonstrates the overexpression of multiple genes that are involved in mitochondria biogenesis, bioenergetics, and modulation of apoptosis. These genes may play a role in malignant transformation and disease progression. The upregulation of some of these genes in clinical samples indicates that some of the differentially transcribed genes could be the potential targets for therapeutic interventions.
Calgani A, Delle Monache S, Cesare P, et al.Leptin contributes to long-term stabilization of HIF-1α in cancer cells subjected to oxygen limiting conditions.
Cancer Lett. 2016; 376(1):1-9 [PubMed
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Leptin, a cytokine produced by the adipose tissue in response to food intake, is a key player in the regulation of energy balance and body weight control. Physiological action of leptin in modulating the metabolic adaptation of different peripheral tissues supports the hypothesis that it could also exert a direct effect on cancer cells. In vitro, treatment with leptin up-regulated HIF-1α and stimulated adhesion and invasion of prostate cancer cells cultured in hypoxia. Leptin action was effective in both low and high glycolytic cancer cell lines, and determined the up-regulation of lactate exporter MCT4 and its associated protein CD147. HIF-1α stabilization was oligomycin-independent and was associated with an important modulation of mitochondrial homeostasis. In fact, leptin treatment produced mitochondrial biogenesis, stabilization of mitochondrial membrane potential and increased uncoupled respiration through the up-regulation of UCP2. Furthermore, leptin counteracted the downmodulation of SIRT1 induced by hypoxia, and persistent high levels of SIRT1 were directly involved in HIF-1α stabilization. Leptin can sustain cancer progression in hypoxic environment and when mitochondrial respiration is impaired. Leptin signaling axis, including the new proposed intermediate SIRT1, could represent a new diagnostic and therapeutic target in prostate cancer.
Cox TR, Gartland A, Erler JTLysyl Oxidase, a Targetable Secreted Molecule Involved in Cancer Metastasis.
Cancer Res. 2016; 76(2):188-92 [PubMed
] Related Publications
Secondary metastatic cancer remains the single biggest cause of mortality and morbidity across most solid tumors. In breast cancer, 100% of deaths are attributed to metastasis. At present, there are no "cures" for secondary metastatic cancer of any form and there is an urgent unmet clinical need to improve the tools available in our arsenal against this disease, both in terms of treatment, but also prevention. Recently, we showed that hypoxic induction of the extracellular matrix modifying enzyme lysyl oxidase (LOX) correlates with metastatic dissemination to the bone in estrogen receptor negative breast cancer and is essential for the formation of premetastatic osteolytic lesions. We showed that in models of breast cancer metastasis, targeting LOX, or its downstream effects, significantly inhibited premetastatic niche formation and the resulting metastatic burden, offering preclinical validation of this enzyme as a therapeutic target for metastatic breast cancer. Our work is the latest in an emerging body of work supporting the targeting of LOX and calls for greater efforts in developing therapeutics against this extracellular secreted factor in the prevention of cancer progression across multiple solid tumor types.
BACKGROUND: Tamoxifen (TAM) and fulvestrant (FUL) are the major drugs for patients with estrogen receptor-positive (ER(+)) breast cancers. However, the development of endocrine resistance is the impediment for successful treatment. We aimed to explore the mechanisms of endocrine resistance and therapeutic strategy for overcoming resistance against TAM and FUL.
METHODS: Experiments were performed in ER(+) and estrogen/TAM-sensitive MCF7 cells and antiestrogen-resistant MCF7/LCC9 cells. The expression of miR-214 and uncoupling protein 2 (UCP2) was determined by RT-qPCR and Western blot in breast cancer cells and human breast cancer tissue specimens. Cell autophagy was examined by fluorescent probe monodansyl cadaverine (MDC) and GFP-LC3-II-positive punctate identified by confocal microscopy. Apoptotic cells were determined by Annexin V-FITC/PI staining. The potential regulatory target of miR-214 was determined by prediction tool, target protein expression and luciferase reporter assay.
RESULTS: 4-OHT/FUL treatment resulted in induction of apoptosis as well as autophagy in breast cancer cells. Autophagy might be the major cause of endocrine resistance to 4-OHT or FUL. MiR-214 increased the sensitivity of breast cancer cells to the 4-OHT/FUL-induced apoptosis through inhibition of autophagy. Importantly, a negative correlation was established between miR-214 and UCP2 in human breast cancer tissue specimens assayed by RT-qPCR. UCP2 was identified to be a direct target of miR-214. Further study in MCF7/LCC9 cells indicated that endocrine resistance might arise from activation of the PI3K-Akt-mTOR pathway, thereby inducing autophagy by overexpression of UCP2.
CONCLUSION: MiR-214 increased the sensitivity of breast cancer cells to TAM and FUL through inhibition of autophagy by targeting UCP2. MiR-214 shows potential as a novel therapeutic strategy for overcoming endocrine resistance in ER(+) breast cancers.
Hima S, Sreeja SRegulatory role of estrogen-induced reactive oxygen species in the modulatory function of UCP 2 in papillary thyroid cancer cells.
IUBMB Life. 2015; 67(11):837-46 [PubMed
] Related Publications
Oxidative stress is postulated as one of the mechanisms underlying the estrogen's carcinogenic effect in thyroid cancer. But the fundamental mechanisms behind this carcinogenic effect remain elusive. Physiologically attainable concentrations of estrogen or estrogen metabolites have been made known to cause reactive oxygen species (ROS). It is envisioned that estrogen-induced ROS mediated signaling is a key congruent mechanism that drives the modulation of uncoupled proteins in papillary thyroid carcinoma cells. The present study investigates that estrogens may increase mitochondrial ROS production by repressing uncoupling proteins, which offers a new perspective on the understanding of why thyroid cancer occurs three times more often in females than in males, and the occurrence decreases after menopause.
Progression from colorectal adenoma to carcinoma is strongly associated with an accumulation of genomic alterations, including gain of chromosome 13. This gain affects the whole q arm and is present in 40%-60% of all colorectal cancers (CRCs). Several genes located at this amplicon are known to be overexpressed in carcinomas due to copy number dosage. A subset of these genes, including the mir-17~92 cluster, are functionally involved in CRC development. The present study set out to explore whether apart from mir-17~92, other miRNAs located at the 13q amplicon show a copy number dependent dosage effect that may contribute to 13q-driven colorectal adenoma-to-carcinoma progression. Integration of publically available miRNA expression, target mRNA expression and DNA copy number data from 125 CRCs yielded three miRNAs, miR-15a, -17, and -20a, of which high expression levels were significantly correlated with a 13q gain and which influenced target mRNA expression. These results could be confirmed by qRT-PCR in a series of 100 colon adenomas and carcinomas.Functional analysis of both mature miRNAs encoded by mir-15a, i.e. miR-15a-5p and miR-15a-3p, showed that silencing of miR-15a-3p significantly inhibited viability of CRC cells. Integration of miR-15a expression levels with mRNA expression data of predicted target genes identified mitochondrial uncoupling protein 2 (UCP2) and COP9 signalosome subunit 2 (COPS2) as candidates with significantly decreased expression in CRCs with 13q gain. Upon silencing of miR-15a-3p, mRNA expression of both genes increased in CRC cells, supporting miR-15a-3p mediated regulation of UPC2 and COPS2 expression. In conclusion, significant overexpression of miR-15a-3p due to gain of 13q is functionally relevant in CRC, with UCP2 and COPS2 as candidate target genes. Taken together our findings suggest that miR-15a-3p may contribute to adenoma-to-carcinoma progression.
Yuan Y, Yao YF, Hu SN, et al.MiR-133a Is Functionally Involved in Doxorubicin-Resistance in Breast Cancer Cells MCF-7 via Its Regulation of the Expression of Uncoupling Protein 2.
PLoS One. 2015; 10(6):e0129843 [PubMed
] Free Access to Full Article Related Publications
The development of novel targeted therapies holds promise for conquering chemotherapy resistance, which is one of the major hurdles in current breast cancer treatment. Previous studies indicate that mitochondria uncoupling protein 2 (UCP-2) is involved in the development of chemotherapy resistance in colon cancer and lung cancer cells. In the present study we found that lower level of miR133a is accompanied by increased expression of UCP-2 in Doxorubicin-resistant breast cancer cell cline MCF-7/Dox as compared with its parental cell line MCF-7. We postulated that miR133a might play a functional role in the development of Doxorubicin-resistant in breast cancer cells. In this study we showed that: 1) exogenous expression of miR133a in MCF-7/Dox cells can sensitize their reaction to the treatment of Doxorubicin, which is coincided with reduced expression of UCP-2; 2) knockdown of UCP-2 in MCF-7/Dox cells can also sensitize their reaction to the treatment of Doxorubicin; 3) intratumoral delivering of miR133a can restore Doxorubicin treatment response in Doxorubicin-resistant xenografts in vivo, which is concomitant with the decreased expression of UCP-2. These findings provided direct evidences that the miR133a/UCP-2 axis might play an essential role in the development of Doxorubicin-resistance in breast cancer cells, suggesting that the miR133a/UCP-2 signaling cohort could be served as a novel therapeutic target for the treatment of chemotherapy resistant in breast cancer.
Pons DG, Nadal-Serrano M, Torrens-Mas M, et al.UCP2 inhibition sensitizes breast cancer cells to therapeutic agents by increasing oxidative stress.
Free Radic Biol Med. 2015; 86:67-77 [PubMed
] Related Publications
Modulation of oxidative stress in cancer cells plays an important role in the study of the resistance to anticancer therapies. Uncoupling protein 2 (UCP2) may play a dual role in cancer, acting as a protective mechanism in normal cells, while its overexpression in cancer cells could confer resistance to chemotherapy and a higher survival through downregulation of ROS production. Thus, our aim was to check whether the inhibition of UCP2 expression and function increases oxidative stress and could render breast cancer cells more sensitive to cisplatin (CDDP) or tamoxifen (TAM). For this purpose, we studied clonogenicity, mitochondrial membrane potential (ΔΨm), cell viability, ROS production, apoptosis, and autophagy in MCF-7 and T47D (only the last four determinations) breast cancer cells treated with CDDP or TAM, in combination or without a UCP2 knockdown (siRNA or genipin). Furthermore, survival curves were performed in order to check the impact of UCP2 expression in breast cancer patients. UCP2 inhibition and cytotoxic treatments produced a decrease in cell viability and clonogenicity, in addition to an increase in ΔΨm, ROS production, apoptosis, and autophagy. It is important to note that CDDP decreased UCP2 protein levels, so that the greatest effects produced by the UCP2 inhibition in combination with a cytotoxic treatment, with regard to treatment alone, were observed in TAM+UCP2siRNA-treated cells. Moreover, this UCP2 inhibition caused autophagic cell death, since apoptosis parameters barely increased after UCP2 knockdown. Finally, survival curves revealed that higher UCP2 expression corresponded with a poorer prognosis. In conclusion, UCP2 could be a therapeutic target in breast cancer, especially in those patients treated with tamoxifen.
Mitochondrial uncoupling protein 2 (UCP2) is suggested to have a role in the development of nonalcoholic steatohepatitis (NASH). However, the mechanism remains unclear. Autophagy is an important mediator of many pathological responses. This study aims to investigate the relationship between UCP2 and hepatoma cells autophagy in palmitic acid- (PA-) induced lipotoxicity. H4IIE cells were treated with palmitic acid (PA), and cell autophagy and apoptosis were examined. UCP2 expression, in association with LC3-II and caspase-3, which are indicators of cell autophagy and apoptosis, respectively,was measured. Results demonstrated that UCP2 was associated with autophagy during PA-induced hepatic carcinoma cells injury. Tests on reactive oxygen species (ROS) showed that UCP2 overexpression strongly decreases PA-induced ROS production and apoptosis. Conversely, UCP2 inhibition by genipin or UCP2 mRNA silencing enhances PA-induced ROS production and apoptosis. Autophagy partially participates in this progress. Moreover, UCP2 was associated with ATP synthesis during PA-induced autophagy. In conclusion, increasing UCP2 expression in hepatoma cells may contribute to cell autophagy and antiapoptotic as result of fatty acid injury. Our results may bring new insights for potential NASH therapies.
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
] Related Publications
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
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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
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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.
Liu Y, Jiang H, He LY, et al.Abnormal expression of uncoupling protein-2 correlates with CYP11A1 expression in polycystic ovary syndrome.
Reprod Fertil Dev. 2011; 23(4):520-6 [PubMed
] Related Publications
Polycystic ovary syndrome (PCOS) may result from hypersensitivity to insulin, which is negatively regulated by uncoupling protein (UCP)-2. Because cholesterol side-chain cleavage enzyme (CYP11A1) is closely linked to PCOS, the expression of UCP-2 and CYP11A1 in ovarian tissues from PCOS patients was examined in the present study. Twelve PCOS patients with hyperandrogenaemia who underwent laparoscopic ovarian wedge resection and 12 age-matched control patients who underwent contralateral ovarian biopsy were enrolled in the study. UCP-2 expression in early stage (primordial, primary and secondary) and late stage (sinus and mature) follicles was examined using immunohistochemistry, whereas UCP-2 and CYP11A1 mRNA and protein levels in ovarian tissue were determined using quantitative reverse transcription-polymerase chain reaction and western blot analyses, respectively. UCP-2 expression increased significantly with follicular development in both control and PCOS tissue, with expression in early stage follicles from PCOS patients significantly greater than that in controls. In addition, both UCP-2 and CYP11A1mRNA and protein levels, mean fasting blood glucose concentrations and fasting serum insulin levels were significantly higher in PCOS patients compared with the control group. Finally, a significant correlation between UCP-2 and CYP11A1 expression was found in PCOS but not control patients. In conclusion, in PCOS patients, there was a correlation between UCP-2 and CYP11A1 expression, which was significantly higher than in the control group. These changes in UCP-2 and CYP11A1 expression may mediate follicle development in 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.
Kondo T, Kishi M, Fushimi T, Kaga TAcetic acid upregulates the expression of genes for fatty acid oxidation enzymes in liver to suppress body fat accumulation.
J Agric Food Chem. 2009; 57(13):5982-6 [PubMed
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We investigated the effect of acetic acid (AcOH) on the prevention of obesity in high-fat-fed mice. The mice were intragastrically administrated with water or 0.3 or 1.5% AcOH for 6 weeks. AcOH administration inhibited the accumulation of body fat and hepatic lipids without changing food consumption or skeletal muscle weight. Significant increases were observed in the expressions of genes for peroxisome-proliferator-activated receptor alpha (PPARalpha) and for fatty-acid-oxidation- and thermogenesis-related proteins: acetyl-CoA oxidase (ACO), carnitine palmitoyl transferase-1 (CPT-1), and uncoupling protein-2 (UCP-2), in the liver of the AcOH-treatment groups. PPARalpha, ACO, CPT-1, and UCP-2 gene expressions were increased in vitro by acetate addition to HepG2 cells. However, the effects were not observed in cells depleted of alpha2 5'-AMP-activated protein kinase (AMPK) by siRNA. In conclusion, AcOH suppresses accumulation of body fat and liver lipids by upregulation of genes for PPARalpha and fatty-acid-oxidation-related proteins by alpha2 AMPK mediation in the liver.
Affourtit C, Brand MDMeasuring mitochondrial bioenergetics in INS-1E insulinoma cells.
Methods Enzymol. 2009; 457:405-24 [PubMed
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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
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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
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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
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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
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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.