Ubiquitin‐specific protease 2‐69 in macrophages potentially modulates metainflammation

Kitamura, Hiroshi; Kimura, Shunsuke; Shimamoto, Yoshinori; Okabe, Jun; Ito, Masako; Miyamoto, Tomomi; Naoe, Yoshinori; Kikuguchi, Chisato; Meek, Bob; Toda, Chitoku; Okamoto, Susumu; Kanehira, Katsushi; Hase, Koji; Watarai, Hiroshi; Ishizuka, Mayumi; El‐Osta, Assam; Ohara, Osamu; Miyoshi, Isao

doi:10.1096/fj.13-233528

Cited by 33 publications

(47 citation statements)

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“…The role of the microbiota and its influence on inflammation has been identified in a number of disease states including obesity, insulin resistance, cardiovascular disease, inflammatory bowel disease, asthma and carcinogenesis. Recent studies have focused on obesity and the concept of "metainflammation", which refers to the concept of chronic systemic inflammation and metabolic dysfunction [25]. Cani et al described that mice with high-fat diets had elevated levels of intestinal Firmicutes and Proteobacteria [26].…”

Section: Systemic Inflammationmentioning

confidence: 99%

The Microbiota and Cancer Cachexia

Herremans

Riner

Cameron

et al. 2019

IJMS

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Cancer cachexia is a multifactorial syndrome defined by weight loss, muscle wasting, and systemic inflammation. It affects the majority of patients with advanced cancer and is associated with poor treatment response, early mortality and decreased quality of life. The microbiota has been implicated in cancer cachexia through pathways of systemic inflammation, gut barrier dysfunction and muscle wasting. The imbalance of the microbiota, known as dysbiosis, has been shown to influence cancer cachexia. Bacteria that play beneficial and detrimental roles in the disease pathogenesis have been identified. The phenotype of cancer cachexia is associated with decreased levels of Lactobacillales and increased levels of Enterobacteriaceae and Parabacteroides. Currently, there are no treatment options that demonstrate increased survival or the quality of life in patients suffering from cancer cachexia. Through the manipulation of beneficial bacteria in the gut microbiota, different treatment options have been explored. Prebiotics and probiotics have been shown to improve outcomes in animal models of cachexia. Expounding on this mechanism, fecal microbiota transplant (FMT) holds promise for a future treatment of cancer cachexia. Further research is necessary to address this detrimental disease process and improve the lives of patients suffering from cancer cachexia.

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Section: Systemic Inflammationmentioning

confidence: 99%

The Microbiota and Cancer Cachexia

Herremans

Riner

Cameron

et al. 2019

IJMS

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“…USP2, a member of the USP family, is widely expressed in organs, with relatively higher expression levels reported in the testis and skeletal muscle (Gousseva and Baker, 2003;Kitamura et al, 2013). It has diverse functions in a wide variety of cells, such as pro-and antiapoptotic effects in cancerous cells (Gewies and Grimm, 2003;Priolo et al, 2006), regulatory roles in cytokine production in macrophages (Zhang et al, 2014;Sun et al, 2016;Kitamura et al, 2017), and modulation of glucose and lipid metabolism (Molusky et al, 2012;Kitamura et al, 2013;Nelson et al, 2016;Saito et al, 2017). In a previous study, dominant negative forms of USP2 were found to interrupt the differentiation of L6 myoblasts into myofibers indicating the involvement of USP2 in myocyte differentiation (Park et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of ubiquitin‐specific protease 2 causes accumulation of reactive oxygen species, mitochondria dysfunction, and intracellular ATP decrement in C2C12 myoblasts

et al. 2019

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Ubiquitin‐specific protease 2 (USP2) is considered to participate in the differentiation of myoblasts to myotubes, however, its functions in myoblasts under growth conditions remain elusive. In this study, we analyzed the physiological roles of USP2 in myoblasts using Usp2 knockout (KO) C2C12 cells as well as a USP2 specific inhibitor. In addition to the disruption of differentiation, clustered regularly interspaced short palindromic repeats/Cas9‐generated Usp2 KO cells exhibited inhibition of proliferation compared to parental C2C12 cells. Usp2 KO cells reduced the accumulation of intracellular adenosine triphosphate (ATP) content and oxygen consumption. Moreover, Usp2 KO cells had fragmented mitochondria, suggesting that mitochondrial respiration was inactive. The deficiency of Usp2 did not affect the enzymatic activities of respiratory chain complexes I, III, IV, and V. However, mitochondrial membrane permeability—evaluated using calcein AM‐cobalt staining—was increased in Usp2 KO cells. The membrane potential of Usp2 KO cells was clearly decreased. Usp2 KO cells accumulated reactive oxygen species (ROS) in the mitochondria. The USP2‐selective inhibitor ML364 also increased the levels of mitochondrial ROS, and modulated the membrane potential and morphology of the mitochondria. These effects were followed by a decrement in the intracellular content of ATP. Based on these findings, we speculate that USP2 may be involved in maintaining the integrity of the mitochondrial membrane. This process ensures the supply of ATP in myoblasts, presumably leading to proliferation and differentiation.

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“…cell lines 17 84 GEO GSE21034 prostate (cancer) tissues 310 36 GEO GSE21163 pancreas (1 benign and 6 cancer) cell lines 22 85,86 GEO GSE21337 acute myeloid leukemia tissues 64 87 GEO GSE21840 MCF7 (breast cancer) cell lines 6 87,89 GEO GSE23361 lung (cancer) tissues 12 90 GEO GSE23514 HeLa S3 (cervical cancer) cell lines 12 91 GEO GSE23768 breast, lung, ovarian and prostate cancer tissues 153 92 GEO GSE24778 K562 (chronic myelogenous leukemia) cell lines 10 93 GEO GSE29682 breast, central nervous system, colon, leukemia, melanoma, lung, ovary, prostate, kidney (cancer) cell lines 178 94,95 GEO GSE29778 HEK293 (embryonic kidney) cell lines 12 96 GEO GSE30472 brain (cancer; glioma) tissues 55 97 GEO GSE30521 prostate (benign and cancer) tissues 23 98 GEO GSE30727 stomach (cancer) tissues 60 99 GEO GSE32875 LNCaP (prostate cancer) cell lines 8 100 GEO GSE37138 lung (cancer) tissues 117 101 GEO GSE40871 acute myeloid leukemia primary cells 67 102 GEO GSE43107 brain (cancer; glioma) tissues 95 103 (provided in a separate file).…”

Section: Geo Gse19891mentioning

confidence: 99%

The long non-coding RNAGHSROSreprograms prostate cancer cell lines toward a more aggressive phenotype

Thomas

Jeffery

Gahete

et al. 2019

Preprint

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42It is now appreciated that long non-coding RNAs (lncRNAs) are important players in the 43 orchestration of cancer progression. In this study we characterized GHSROS, a human 44 lncRNA gene on the opposite DNA strand (antisense) to the ghrelin receptor gene, in prostate 45 cancer. The lncRNA was upregulated by prostate tumors from different clinical datasets. 46Consistently, transcriptome data revealed that GHSROS alters the expression of cancer-47 associated genes. Functional analyses in vitro showed that GHSROS mediates tumor growth, 48 migration, and survival and resistance to the cytotoxic drug docetaxel. Increased cellular 49 proliferation of GHSROS-overexpressing PC3, DU145, and LNCaP prostate cancer cell lines 50 in vitro was recapitulated in a subcutaneous xenograft model. Conversely, in vitro antisense 51 oligonucleotide inhibition of the lncRNA reciprocally regulated cell growth and migration, 52 and gene expression. Notably, GHSROS modulates the expression of PPP2R2C, the loss of 53 which may drive androgen receptor pathway-independent prostate tumor progression in a 54 subset of prostate cancers. Collectively, our findings suggest that GHSROS can reprogram 55 prostate cancer cells toward a more aggressive phenotype and that this lncRNA may 56 represent a potential therapeutic target. 57 58 Keywords: long non-coding RNA, lncRNA, prostate cancer 59 60 5 reprograms prostate cancer cells toward a more aggressive phenotype, possibly by repressing 86 the expression of the tumor suppressor PPP2R2C to allow androgen-independent growth. 87 88 RESULTS 89GHSROS is expressed in prostate cancer 90Microarrays and RNA-sequencing are commonly used to assess the expression of genes. 91LncRNAs are often expressed at orders of magnitude lower than protein-coding transcripts, 92 however, making them difficult to detect 5, 11,12,13,14,15 . Interrogation of exon arrays harboring 93 four different strand-specific probes against GHSROS demonstrated that the lncRNA is 94 actively transcribed, although expressed at very low levels in cancer cell lines and tissues 95 ( Supplementary Fig. S1), consistent with previous observations from Northern blotting and 96 RT-PCR experiments 3 . The low expression across the GHSROS and GHSR loci in RNA-seq 97 datasets is illustrated in Supplementary Fig. S2. Collectively, these data demonstrate that it is 98 not currently possible to detect GHSROS in public genome-wide gene expression datasets. 99 100We next evaluated GHSROS expression in a qRT-PCR tissue array of 18 cancers. This 101 analysis revealed particularly high GHSROS expression in lung tumors, as previously 102 reported 3 , and elevated expression in prostate tumors ( Fig. 1b). Analysis of additional 103 prostate tissue-derived cDNA arrays revealed that GHSROS could be detected in 104 approximately 41.7% of all normal prostate tissues (n=24), 55.7% of tumors (n=88), and 105 58.1% of other prostatic diseases (e.g. prostatitis; n=31) ( Supplementary Table S1). GHSROS 106 was highly expressed by a subset of prostate tumors (~11.4%; ...

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Ubiquitin‐specific protease 2‐69 in macrophages potentially modulates metainflammation

Cited by 33 publications

References 50 publications

The Microbiota and Cancer Cachexia

The Microbiota and Cancer Cachexia

Inhibition of ubiquitin‐specific protease 2 causes accumulation of reactive oxygen species, mitochondria dysfunction, and intracellular ATP decrement in C2C12 myoblasts

The long non-coding RNAGHSROSreprograms prostate cancer cell lines toward a more aggressive phenotype

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