Prohibitin Expression Deregulation in Gastric Cancer Is Associated with the 3′ Untranslated Region 1630 C&gt;T Polymorphism and Copy Number Variation

Leal, Mariana Ferreira; Cirilo, Priscila Daniele Ramos; Mazzotti, Tatiane Katsue Furuya; Calcagno, Danielle Queiroz; Wisnieski, Fernanda; Demachki, Sâmia; Martinez, Margarita Cortes; Assumpção, Paulo Pimentel de; Chammas, Roger; Burbano, Rommel Rodrı́guez; Smith, Marı́lia de Arruda Cardoso

doi:10.1371/journal.pone.0098583

Cited by 15 publications

(18 citation statements)

References 40 publications

(53 reference statements)

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“…The rs9518 (T/C) is located in 3'UTR region of NFATC1 gene. Generally, the SNPs in 3'UTR region may correlate with up-regulation and down-regulation of gene expression 17 . The NFATC1rs9518(T/C) polymorphisms might involve in abnormal gene expression and function during development of ONFH, and the detailed mechanisms remain to be further explored.…”

Section: Discussionmentioning

confidence: 99%

Association of Genes Variants in RANKL/RANK/OPG Signaling Pathway with the Development of Osteonecrosis of the Femoral Head in Chinese Population

Song

Yang

et al. 2017

Int. J. Med. Sci.

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The RANKL/RANK/OPG pathway plays an important role in regulating bone remodeling and bone turnover. However, the association of the genes variants with the risk of ONFH has rarely been reported. Here, we analyzed the correlation of the 10 SNPs polymorphisms of RANKL, RANK, OPG, TRAF6, and NFATC1 genes with the risk and development of ONFH in 200 ONFH patients and 177 health controls of Chinese population with using Mass ARRAY® platform. The results showed that the recessive model of NFATC1rs9518 was significantly associated with increased ONFH risk (OR:8.223, P=0.048); the proportion of stage Ⅳ patients in the rs9518TC genotype carriers was statistically higher than that of stage Ⅲ patients (P=0.03); in the T-C haplotype carriers of Naftac1, the proportion of bilateral hips lesions was also significantly enhanced than that of unilateral hip lesions(P=0.05). In addition, the proportion of idiopathic ONFH in the TT genotype carriers of OPGrs2073617 was significantly higher than that of steroid or alcohol-induced ONFH, respectively, while in the TC genotype carriers of the SNP, the proportion of idiopathic ONFH remarkably decreased compared with that of Alcohol-induced ONFH, P=0.021. Our results were first found that NFATC1rs9518 closely associated with the risk and the development of ONFH, while OPGrs2073617 statistically correlated with the etiological classification of ONFH.

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Section: Discussionmentioning

confidence: 99%

Association of Genes Variants in RANKL/RANK/OPG Signaling Pathway with the Development of Osteonecrosis of the Femoral Head in Chinese Population

Song

Yang

et al. 2017

Int. J. Med. Sci.

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“…Since the PHB1 transcript has an extremely long and highly conserved 3’UTR, the case for regulation at the post-transcriptional level is persuasive. Furthermore, the presence of Single Nucleotide Polymorphisms (SNPs) in the PHB1–3’UTR (SNP rs6917) region has been associated with an increased risk of breast cancer and melanoma, whereas the rare allele of this SNP was associated with reduced PHB1 mRNA levels in gastric cancer [ 34 – 36 ]. These SNPs could modulate the binding site of regulatory elements such as microRNAs and regulate transcript decay [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-195 acts as an anti-proliferative miRNA in human melanoma cells by targeting Prohibitin 1

et al. 2017

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BackgroundMelanoma is the most lethal type of skin cancer. Since chemoresistance is a significant barrier, identification of regulators affecting chemosensitivity is necessary in order to create new forms of intervention. Prohibitin 1 (PHB1) can act as anti-apoptotic or tumor suppressor molecule, depending on its subcellular localization. Our recent data shown that accumulation of PHB1 protects melanoma cells from chemotherapy-induced cell death. Lacking of post-transcriptional regulation of PHB1 could explain this accumulation. Interestingly, most of melanoma patients have down-regulation of microRNA-195. Here, we investigate the role of miR-195, its impact on PHB1 expression, and on chemosensitivity in melanoma cells.MethodsTCGA-RNAseq data obtained from 341 melanoma patient samples as well as a panel of melanoma cell lines were used in an expression correlation analysis between PHB1 and predicted miRNAs. miR-195 impact on PHB1 mRNA and protein levels and relevance of this regulation were investigated in UACC-62 and SK-MEL-5 melanoma lines by RT-qPCR and western blot, luciferase reporter and genetic rescue experiments. Cell proliferation, cell-cycle analysis and caspase 3/7 assay were performed to investigate the potential action of miR-195 as chemosensitizer in melanoma cells treated with cisplatin and temozolomide.ResultsAnalysis of the TCGA-RNAseq revealed a significant negative correlation (Pearson) between miR-195 and PHB1 expression. Moreover, RT-qPCR data showed that miR-195 is down-regulated while PHB1 is up-regulated in a collection of melanoma cells. We demonstrated that miR-195 regulates PHB1 directly by RT-qPCR and western blot in melanoma cells and luciferase assays. To establish PHB1 as a relevant target of miR-195, we conducted rescue experiments in which we showed that PHB1 transgenic expression could antagonize the suppressive effect miR-195 on the proliferation of melanoma cells. Finally, transfection experiments combined with drug treatments performed in the UACC-62 and SK-MEL-5 melanoma cells corroborated miR-195 as potential anti-proliferative agent, with potential impact in sensitization of melanoma cell death.ConclusionsThis study support the role of miR-195 as anti-proliferative miRNA via targeting of PHB1 in melanoma cells.Electronic supplementary materialThe online version of this article (10.1186/s12885-017-3721-7) contains supplementary material, which is available to authorized users.

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“…30 However, inconsistency exists in the literature on the association between PHB T allele and increased risk of breast, ovarian, and gastric cancers. [31][32][33] Continuous interest in the anti-proliferative property of PHB led to the discovery of p53 and Rb, two well-known tumor suppressors, 34,35 as PHB interacting partners. The interaction of PHB with p53 was found to increase the transcriptional activity of p53, whereas co-transfection of an antisense PHB construct reduced p53-mediated transcriptional activation, in breast cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Prohibitin – At the crossroads of obesity-linked diabetes and cancer

Mishra

Nyomba

2017

Exp Biol Med (Maywood)

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Impact statementProhibitin (PHB) is ubiquitously expressed and plays a role in adipocyte-immune cell cross-talk. Both male and female transgenic mice expressing wild-type PHB in adipose tissue and in macrophages are obese, but only males develop diabetes and liver cancer. When the mice express PHB mutated on tyrosine-114 in adipocytes and macrophages, both males and females are still obese, but none develops liver cancer; instead, males develop lymph node tumors. Adipocyte specific functions of PHB are mediated through its mitochondrial function, whereas its immune functions are mediated in a phosphorylation-dependent manner. Thus, PHB appears to be an important molecule linking obesity, diabetes, and cancer. In addition, this link appears to be affected by sex steroids. Therefore, targeting PHB may lead to a better understanding of the pathogenesis of obesity, diabetes and cancer. AbstractThe promoter of a gene that is selectively expressed in just a few cell types provides unique opportunities to study: (1) the pleiotropic function of a protein in two different cell types including the cell compartment specific function, and (2) the crosstalk between two cell/ tissue types at the systemic level. This is not possible with a ubiquitous or a highly specific gene promoter. The adipocyte protein-2 (aP2) is one such gene. It is primarily expressed in adipocytes, but also selectively in monocytic macrophages and dendritic cells, among various immune cell types. Thus, the adipocyte protein-2 gene promoter provides an opportunity to simultaneously manipulate adipose and immune functions in a transgenic animal. Prohibitin (PHB) is a pleiotropic protein that has roles in both adipocytes and immune cells. Adipocyte specific functions of prohibitin are mediated through its mitochondrial function, whereas its immune functions are mediated in a phosphorylation-dependent manner. We capitalized on this attribute of prohibitin to explore the crosstalk between adipose and immune functions, and to discern mitochondrial and plasma membrane-associated cell signaling functions of prohibitin, by expressing wild type prohibitin (Mito-Ob) and a phospho-mutant form of prohibitin (m-Mito-Ob) from the protein-2 gene promoter, individually. Both transgenic mice develop obesity in a sex-neutral manner, but develop obesity-related metabolic dysregulation in a male sex-specific manner. Subsequently, the male Mito-Ob mice spontaneously developed type 2 diabetes and liver cancer, whereas the male m-Mito-Ob mice developed lymph node tumors or autoimmune diabetes in a context-dependent manner. This review provides a point of view on the role of prohibitin in mediating sex differences in adipose and immune functions at the systemic level. We discuss the unique attributes of prohibitin and provide a new paradigm in adipose-immune crosstalk mediated through a pleiotropic protein.

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Prohibitin Expression Deregulation in Gastric Cancer Is Associated with the 3′ Untranslated Region 1630 C>T Polymorphism and Copy Number Variation

Cited by 15 publications

References 40 publications

Association of Genes Variants in RANKL/RANK/OPG Signaling Pathway with the Development of Osteonecrosis of the Femoral Head in Chinese Population

Association of Genes Variants in RANKL/RANK/OPG Signaling Pathway with the Development of Osteonecrosis of the Femoral Head in Chinese Population

MicroRNA-195 acts as an anti-proliferative miRNA in human melanoma cells by targeting Prohibitin 1

Prohibitin – At the crossroads of obesity-linked diabetes and cancer

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