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Fotouh BES, El-Meguid MA, Salum GM, El Naggar GN, El-Sayed AF, Dawood RM. Clinical impact of PTEN rs701848 as a predictive marker for breast cancer. Clin Biochem 2025; 136:110872. [PMID: 39793692 DOI: 10.1016/j.clinbiochem.2025.110872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Revised: 11/25/2024] [Accepted: 12/20/2024] [Indexed: 01/13/2025]
Abstract
BACKGROUND The incidence of Breast cancer (BC) is currently augmented and it has become the most common malignant cancer in females. Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene as a result of blocking the phosphorylation of PIP3 in PI3K pathway. METHODS The computational bioinformatics tools were performed to determine the link between PTEN rs701848T/C genetic variants and breast cancer progression. 50 healthy matched controls and 100 Egyptian women with breast cancer were enrolled in the study. The PTEN rs701848T/C polymorphism was assessed using qRT-PCR. Then the proteomic level of PTEN was measured by ELISA technique. RESULTS Breast cancer patients had considerably higher (TC) genotype frequency than controls, p = 0.03. Moreover, TC carriers had a higher chance of developing tumors with advanced stage, big tumor size, and metastasis at further sites. Regarding proteomic level of PTEN, a remarkable decline was correlated significantly with disease progression. Moreover, the ROC curve analysis showed that the PTEN protein showed comparable diagnostic accuracy in distinguishing between different BC stages. CONCLUSION The current research provides insight into the impact of PTEN as a predictive marker for BC development and progression at genomic and proteomic levels.
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Affiliation(s)
- Basma El-Sayed Fotouh
- Department of Microbial Biotechnology, Biotechnology Research Institute, National Research Centre, Dokki, P.O. 12622, Giza, Egypt
| | - Mai Abd El-Meguid
- Department of Microbial Biotechnology, Biotechnology Research Institute, National Research Centre, Dokki, P.O. 12622, Giza, Egypt
| | - Ghada Maher Salum
- Department of Microbial Biotechnology, Biotechnology Research Institute, National Research Centre, Dokki, P.O. 12622, Giza, Egypt
| | - Ghada Nabil El Naggar
- Department of Clinical Pathology, National Cancer Institute, Cairo University, Egypt
| | - Ahmed F El-Sayed
- Microbial Genetics Department, Biotechnology Research Institute, National Research Centre, Giza, Egypt; Egypt Center for Research and Regenerative Medicine (ECRRM), Cairo, Egypt
| | - Reham Mohammed Dawood
- Department of Microbial Biotechnology, Biotechnology Research Institute, National Research Centre, Dokki, P.O. 12622, Giza, Egypt.
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Zare A, Khosropanah S, Daryabor G, Doroudchi M. mTOR gene variant rs2295080 might be a risk factor for atherosclerosis in Iranian women with type 2 diabetes mellitus. BMC Endocr Disord 2024; 24:162. [PMID: 39198757 PMCID: PMC11361055 DOI: 10.1186/s12902-024-01703-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 08/23/2024] [Indexed: 09/01/2024] Open
Abstract
BACKGROUND Type 2 diabetes mellitus, one of the most prevalent metabolic disorders worldwide, is closely linked with an enhanced risk of atherosclerosis. However, the molecular mechanism of this linkage is not still clear. Genetic variations in the mTOR gene may increase the susceptibility of individuals to these diseases. METHODS One hundred nine diabetic patients and 375 healthy subjects participated in this study. mTOR Single Nucleotide Polymorphism (SNP) rs2295080 was determined using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP). RESULTS Comparison of genotypic, allelic, and genotypic combination frequencies between cases and controls revealed no significant result. Nevertheless, the frequency of rs2295080 GT + TT genotype was significantly more in diabetic women with atherosclerosis compared with those without atherosclerosis (p = 0.047). Besides, the rs2295080 G allele was more frequently detected in diabetic women without atherosclerosis compared to those with atherosclerosis (p = 0.046). CONCLUSION The rs2295080 GT + TT genotype predisposes Iranian diabetic women to atherosclerosis, while the rs2295080 G allele protects them against atherosclerosis. However, additional experiments using larger sample sizes are needed to verify this result.
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Affiliation(s)
- Afsaneh Zare
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Shahdad Khosropanah
- Cardiovascular Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Cardiology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Gholamreza Daryabor
- Autoimmune Diseases Research Center, School of Medicine, Shiraz University of Medical Sciences, PO Box: 71345-1583, Shiraz, Iran.
| | - Mehrnoosh Doroudchi
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
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Rezaei M, Ghasemi M, Saravani M, Ghahghayi F, Shahraki-Ghadim H, Salimi S. The possible effects of the MTOR polymorphisms on preeclampsia susceptibility, severity, and onset: a case-control study and in silico analysis. Mol Biol Rep 2024; 51:335. [PMID: 38393518 DOI: 10.1007/s11033-023-09190-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Accepted: 12/21/2023] [Indexed: 02/25/2024]
Abstract
BACKGROUND Preeclampsia (PE) is a gestational complication with developed hypertension and proteinuria. Evidence showed the role of mTOR in various cellular processes. Therefore, this study aimed to evaluate the effects of MTOR polymorphisms on susceptibility, severity, and onset of Preeclampsia (PE). METHODS AND RESULTS A total of 250 PE pregnant women and 258 age-matched control subjects were recruited in this study. To genotype MTOR polymorphisms, the PCR-RFLP method was used. The SpliceAid 2 and PROMO tools were used for in silico analysis. The maternal MTOR rs17036508T/C polymorphism was associated with PE risk in various genetic models. There was no relationship between rs2536T/C and rs2295080T/G polymorphisms and PE. The TTC and TGC haplotypes of rs2536/ rs2295080/ rs17036508 polymorphisms were significantly higher in PE women. Subgroup analysis revealed the association between the MTOR rs2295080 variant and an increased risk of Early-onset PE (EOPE). However, the MTOR rs17036508 was associated with a higher risk of EOPE and Late- Onset PE. In addition, the MTOR rs2295080 could increase the risk of severe PE. The results of the in silico analysis showed that rs17036508 disrupted several binding motifs in the mutant sequence. The PROMO database revealed that the T to C substitution leads to the loss of the TFII-I binding site in the mutant allele. CONCLUSION The MTOR rs17036508T/C polymorphism was associated with PE risk. There was an association between the MTOR rs2295080 variant and an increased risk of EOPE. The MTOR rs17036508T/C and rs2295080T/C variants could disrupt several binding motifs and TFII-I binding respectively.
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Affiliation(s)
- Mahnaz Rezaei
- Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran
- Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Marzieh Ghasemi
- Department of Obstetrics and Gynecology, Pregnancy Health Research Center, Zahedan University of Medical Sciences, Zahedan, Iran
- Pregnancy Health Research Center, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Mohsen Saravani
- Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran
- Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Fatemeh Ghahghayi
- Department of Obstetrics and Gynecology, Pregnancy Health Research Center, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Hossein Shahraki-Ghadim
- Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Saeedeh Salimi
- Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran.
- Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Vargova D, Kolková Z, Dargaj J, Bris L, Luptak J, Dankova Z, Franova S, Svihra J, Slávik P, Sutovska M. Analysis of HIF-1α expression and genetic polymorphisms in human clear cell renal cell carcinoma. Pathol Oncol Res 2024; 29:1611444. [PMID: 38273861 PMCID: PMC10808674 DOI: 10.3389/pore.2023.1611444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Accepted: 12/05/2023] [Indexed: 01/27/2024]
Abstract
Introduction: Clear cell renal cell carcinoma (ccRCC) is mostly diagnosed incidentally and has relatively high recurrence rates. Alterations in VHL/HIF and mTOR pathways are commonly present in ccRCC. The present study attempted to identify potential diagnostic markers at the biochemical and molecular level. Methods: In total, 54 subjects (36 patients with ccRCC and 18 cancer-free controls) were enrolled. ELISA was used to measure the levels of HIF-1α in the tumor and healthy kidney tissue. The association between five selected SNPs (rs779805, rs11549465, rs2057482, rs2295080 and rs701848) located in genes of pathologically relevant pathways (VHL/HIF and mTOR) and the risk of ccRCC in the Slovak cohort was studied using real-time PCR. Results: Significant differences in HIF-1α tissue levels were observed between the tumor and healthy kidney tissue (p < 0.001). In the majority (69%) of cases, the levels of HIF-1α were higher in the kidney than in the tumor. Furthermore, the concentration of HIF-1α in the tumor showed a significant positive correlation with CCL3 and IL-1β (p (R2) 0.007 (0.47); p (R2) 0.011 (0.38). No relationship between intratumoral levels of HIF-1α and clinical tumor characteristics was observed. Rs11549465, rs2057482 in the HIF1A gene did not correlate with the expression of HIF-1α either in the tumor or in the normal kidney. None of the selected SNPs has influenced the susceptibility to ccRCC. Conclusion: More research is neccesary to elucidate the role of HIF-1α in the pathogenesis of ccRCC and the association between selected SNPs and susceptibility to this cancer.
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Affiliation(s)
- Daniela Vargova
- Department of Pharmacology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
| | - Zuzana Kolková
- Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
| | - Jan Dargaj
- Department of Urology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, and University Hospital Martin, Martin, Slovakia
| | - Lukas Bris
- Department of Urology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, and University Hospital Martin, Martin, Slovakia
| | - Jan Luptak
- Department of Urology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, and University Hospital Martin, Martin, Slovakia
| | - Zuzana Dankova
- Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
| | - Sona Franova
- Department of Pharmacology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
| | - Jan Svihra
- Department of Urology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, and University Hospital Martin, Martin, Slovakia
| | - Pavol Slávik
- Department of Pathological Anatomy, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, and University Hospital Martin, Martin, Slovakia
| | - Martina Sutovska
- Department of Pharmacology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
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Luu D, Shah T, Sakharkar P, Min DI. Genetic variations in a Sestrin2/Sestrin3/mTOR Axis and development of new-onset diabetes after kidney transplantation. Transpl Immunol 2023; 81:101947. [PMID: 37918578 DOI: 10.1016/j.trim.2023.101947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 10/24/2023] [Accepted: 10/30/2023] [Indexed: 11/04/2023]
Abstract
BACKGROUND Genetic variations in Sestrin2/Sestrin3/ mTOR axis may cause obesity-associated metabolic syndrome, including lipid accumulation and insulin resistance thereby increasing individual's risk of diabetes. In this study, we explored the association between single nucleotide polymorphisms (SNPs) of these genes and new onset diabetes after transplantation in Hispanic renal transplant recipients (RTRs). METHODS Nine potential functional polymorphisms in Sestrin2, Sestrin3 and mTOR genes were genotyped using the Taqman qPCR method in this study. We compared 160 Hispanic RTRs with no evidence of pre-existing diabetes, who developed new onset diabetes after transplantation (NODAT) with 152 controls with no history of diabetes. The logistic proportional hazard model was used to examine risks for NODAT. Nongenetic and genetic characteristics were included in the multivariate risk model. RESULTS Significant associations were observed between NODAT and mTOR TT (rs2295080 OR = 1.79, 95% CI =1.14-2.82, p = 0.01), Sestrin2 AA (rs580800, OR = 0.42, 95% CI =0.27-0.67, p = 0.002), and Sestrin3 AA (rs684856, OR = 0.45, 95% CI = 0.27-0.75, p = 0.001). Sestrin2 AA (rs580800), Sestrin3 AA (rs684856) and mTOR TT (rs2295080) remained significantly associated with NODAT after adjusting for acute rejection and sirolimus use. No interactions observed between the mTOR rs2295080 and Sestrin3 rs684856 and risk of NODAT (mTOR rs2295080 and Sestrin3 rs684856, p = 0.123 and mTOR rs2295080 and Sestrin2 rs580800, p = 0.167). Of the nongenetic factors, use of sirolimus and older age were associated with an increased risk for NODAT. CONCLUSION Polymorphisms in the Sestrin2/Sestrin3/ mTOR gene may confer certain protection/predisposition for NODAT.
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Affiliation(s)
- Don Luu
- Saint Vincent Medical Center, Los Angeles, CA, United States of America; Transplant Research Institute, Los Angeles, CA, United States of America; Western University of Health Sciences, Pomona, CA, United States of America.
| | - Tariq Shah
- Saint Vincent Medical Center, Los Angeles, CA, United States of America; Transplant Research Institute, Los Angeles, CA, United States of America
| | - Prashant Sakharkar
- Roosevelt University College of Pharmacy, Schaumburg, IL, United States of America
| | - David I Min
- Saint Vincent Medical Center, Los Angeles, CA, United States of America; Western University of Health Sciences, Pomona, CA, United States of America
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Shafique R, Mahjabeen I, Bibi K, Kalsoom F, Rizwan M, Ashraf NS, Mehmood A, Ul Haq MF, Abbasi SF, Saeed N, Kayani MA. miRNA-767 and its binding site polymorphism in the mTOR gene act as potential biomarkers for female reproductive cancers. Future Oncol 2023; 19:1929-1943. [PMID: 37781867 DOI: 10.2217/fon-2022-1055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/03/2023] Open
Abstract
Aims: The present study aimed to understand the relationship between the mTOR gene SNP (rs2536) and reproductive cancer risk. The expression level of miRNA-767 was also assessed. Methods: 700 tumor samples (300 breast, 200 ovarian and 200 cervical cancers), along with adjacent uninvolved control tissue, were used. rs2536 was screened using Tetra-ARMS PCR and expression level of miRNA-767 was assessed using quantitative PCR. Results: The frequency of the homozygous mutant genotype of rs2536 was observed significantly higher in breast (p < 0.04), ovarian (p < 0.005) and cervical (p < 0.003) cancers. Significant downregulation of miRNA-767 was observed in tumors compared with controls. Conclusion: The present study demonstrates that increased mutant frequency of rs2536 and deregulation of miRNA-767 are associated with increased reproductive cancer risk.
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Affiliation(s)
- Rabia Shafique
- Cancer Genetics & Epigenetics Research Group, Department of Biosciences, COMSATS University, Park Road Islamabad, Pakistan
| | - Ishrat Mahjabeen
- Cancer Genetics & Epigenetics Research Group, Department of Biosciences, COMSATS University, Park Road Islamabad, Pakistan
| | - Kashaf Bibi
- Cancer Genetics & Epigenetics Research Group, Department of Biosciences, COMSATS University, Park Road Islamabad, Pakistan
| | - Farah Kalsoom
- Department of Pathology, Sir Ganga Ram Hospital, Lahore, Pakistan
| | - Muhammad Rizwan
- Cancer Genetics & Epigenetics Research Group, Department of Biosciences, COMSATS University, Park Road Islamabad, Pakistan
| | - Nida Sarosh Ashraf
- Cancer Genetics & Epigenetics Research Group, Department of Biosciences, COMSATS University, Park Road Islamabad, Pakistan
| | - Azhar Mehmood
- Cancer Genetics & Epigenetics Research Group, Department of Biosciences, COMSATS University, Park Road Islamabad, Pakistan
| | - Maria Fazal Ul Haq
- Cancer Genetics & Epigenetics Research Group, Department of Biosciences, COMSATS University, Park Road Islamabad, Pakistan
| | - Sumaira Fida Abbasi
- Cancer Genetics & Epigenetics Research Group, Department of Biosciences, COMSATS University, Park Road Islamabad, Pakistan
| | - Nadia Saeed
- Cancer Genetics & Epigenetics Research Group, Department of Biosciences, COMSATS University, Park Road Islamabad, Pakistan
| | - Mahmood Akhtar Kayani
- Cancer Genetics & Epigenetics Research Group, Department of Biosciences, COMSATS University, Park Road Islamabad, Pakistan
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Ilozumba MN, Yaghjyan L, Datta S, Zhao J, Hong CC, Lunetta KL, Zirpoli G, Bandera EV, Palmer JR, Yao S, Ambrosone CB, Cheng TYD. mTOR pathway candidate genes and obesity interaction on breast cancer risk in black women from the Women's Circle of Health Study. Cancer Causes Control 2023; 34:431-447. [PMID: 36790512 PMCID: PMC10695180 DOI: 10.1007/s10552-022-01657-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 11/11/2022] [Indexed: 02/16/2023]
Abstract
BACKGROUND Obesity is known to stimulate the mammalian target of rapamycin (mTOR) signaling pathway and both obesity and the mTOR signaling pathway are implicated in breast carcinogenesis. We investigated potential gene-environment interactions between mTOR pathway genes and obesity in relation to breast cancer risk among Black women. METHODS The study included 1,655 Black women (821 incident breast cancer cases and 834 controls) from the Women's Circle of Health Study (WCHS). Obesity measures including body mass index (BMI); central obesity i.e., waist circumference (WC) and waist/hip ratio (WHR); and body fat distribution (fat mass, fat mass index and percent body fat) were obtained by trained research staff. We examined the associations of 43 candidate single-nucleotide polymorphisms (SNPs) in 20 mTOR pathway genes with breast cancer risk using multivariable logistic regression. We next examined interactions between these SNPs and measures of obesity using Wald test with 2-way interaction term. RESULTS The variant allele of BRAF (rs114729114 C > T) was associated with an increase in overall breast cancer risk [odds ratio (OR) = 1.81, 95% confidence interval (CI) 1.10-2.99, for each copy of the T allele] and the risk of estrogen receptor (ER)-defined subtypes (ER+ tumors: OR = 1.83, 95% CI 1.04,3.29, for each copy of the T allele; ER- tumors OR = 2.14, 95% CI 1.03,4.45, for each copy of the T allele). Genetic variants in AKT, AKT1, PGF, PRKAG2, RAPTOR, TSC2 showed suggestive associations with overall breast cancer risk and the risk of, ER+ and ER- tumors (range of p-values = 0.040-0.097). We also found interactions of several of the SNPs with BMI, WHR, WC, fat mass, fat mass index and percent body fat in relation to breast cancer risk. These associations and interactions, however, became nonsignificant after correction for multiple testing (FDR-adjusted p-value > 0.05). CONCLUSION We found associations between mTOR genetic variants and breast cancer risk as well as gene and body fatness interactions in relation to breast cancer risk. However, these associations and interactions became nonsignificant after correction for multiple testing. Future studies with larger sample sizes are required to confirm and validate these findings.
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Affiliation(s)
- Mmadili N Ilozumba
- Department of Epidemiology, University of Florida, Gainesville, FL, USA.
- Department of Population Health Sciences, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA.
| | - Lusine Yaghjyan
- Department of Epidemiology, University of Florida, Gainesville, FL, USA
| | - Susmita Datta
- Department of Biostatistics, University of Florida, Gainesville, FL, USA
| | - Jinying Zhao
- Department of Epidemiology, University of Florida, Gainesville, FL, USA
| | - Chi-Chen Hong
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Kathryn L Lunetta
- Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
| | - Gary Zirpoli
- Slone Epidemiology Center, Boston University, Boston, MA, USA
| | - Elisa V Bandera
- Cancer Epidemiology and Health Outcomes, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
| | - Julie R Palmer
- Slone Epidemiology Center, Boston University, Boston, MA, USA
| | - Song Yao
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Christine B Ambrosone
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Ting-Yuan David Cheng
- Department of Epidemiology, University of Florida, Gainesville, FL, USA.
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
- Division of Cancer Prevention and Control, Department of Internal Medicine, The Ohio State University, Suite 525, 1590 North High Street, Columbus, OH, 43201, USA.
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Lan J, Zhu Y, Rao J, Liu L, Gong A, Feng F, Chen B, Huang J, Zhang Y, Chu L, Zhong H, Li L, Yan J, Li W, Xue C. MTOR gene polymorphism may be associated with microscopic polyangiitis susceptibility in a Guangxi population of China. Gene X 2023; 854:147101. [PMID: 36496178 DOI: 10.1016/j.gene.2022.147101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 11/18/2022] [Accepted: 12/02/2022] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVE Microscopic polyangiitis (MPA) onset is affected by genetic predisposition. Autophagy plays a certain role in antineutrophil cytoplasmic antibody-associated vasculitis developing. A key factor in autophagy regulating, the genetic polymorphism of MTOR gene is essential. The objective was to explore the associations between MTOR gene polymorphism and MPA susceptibility in a Guangxi population of China. METHODS A sum of 208 MPA cases and 209 healthy volunteers from Guangxi in this case-control study, four important single nucleotide polymorphism (SNP) loci of MTOR gene including rs3806317, rs1064261, rs1883965 and rs2295080 were examined. Multiplex polymerase chain reaction combined with high-throughput sequencing was performed. Subgroup analysis was evaluated by gender and ethnicity. Linkage disequilibrium and haplotype analysis were tested. Multi-SNPs interaction among mTOR signaling pathway was assessed. RESULTS For rs2295080, homozygous mutant GG genotype was associated with a decreased susceptibility of MPA in recessive model (OR = 0.38, 95%CI: 0.14-1.00, p = 0.040), particularly in the subgroup of female (OR = 0.16, 95%CI: 0.03-0.74, p = 0.006) and Han population (OR = 0.32, 95%CI: 0.10-1.00, p = 0.034). Individual carrying G allele was linked with decreasing MPA susceptibility in Han population of Guangxi (OR = 0.65, 95%CI: 0.44-0.97, p = 0.036). In haplotype analysis, the haplotype AAT was correlated with increasing susceptibility of MPA (OR = 1.347, 95%CI: 1.004-1.807, p = 0.046). Moreover, in the multi-SNPs interaction analysis, the six-locus model was identified as the best interaction model (p < 0.05). CONCLUSION These findings suggest that rs2295080 polymorphism of MTOR gene may be associated with MPA susceptibility in a Guangxi population of China and G allele might be an important protective factor.
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Affiliation(s)
- Jingjing Lan
- Department of Nephrology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, P.R. China
| | - Yan Zhu
- Department of Nephrology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, P.R. China; The First Affiliated Hospital, Department of Nephrology, Hengyang Medical School, University of South China, Hengyang, Hunan, P.R. China
| | - Jinlan Rao
- Department of Nephrology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, P.R. China
| | - Liu Liu
- Department of Nephrology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, P.R. China
| | - Aimei Gong
- Department of Nephrology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, P.R. China; Department of Nephrology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, Guangxi, P.R. China
| | - Fei Feng
- Department of Nephrology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, P.R. China
| | - Bingfang Chen
- Department of Nephrology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, P.R. China
| | - Junxia Huang
- Department of Nephrology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, P.R. China
| | - Yurong Zhang
- Department of Nephrology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, P.R. China
| | - Liepeng Chu
- Department of Nephrology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, P.R. China
| | - Huan Zhong
- Department of Nephrology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, P.R. China
| | - Lizhen Li
- Department of Nephrology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, P.R. China; Department of Nephrology, Hunan Research Institute of Geriatrics, The Peoples Hospital of Hunan Province, Changsha, Hunan, P.R. China
| | - Jinlian Yan
- Department of Nephrology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, P.R. China
| | - Wei Li
- Department of Nephrology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, P.R. China.
| | - Chao Xue
- Department of Nephrology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, P.R. China.
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Gilyazova IR, Ivanova EA, Bermisheva MA, Loginova MV, Asadullina DD, Ishemgulov RR, Mustafin AT, Pavlov VN, Khusnutdinova EK. The Role of Polymorphic Variants of Gene Components of the PTEN/PI3K/AKT Signaling Pathway in the Development of Prostate Cancer. RUSS J GENET+ 2022. [DOI: 10.1134/s1022795422070055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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10
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Associations of Genetic Polymorphisms of mTOR rs2295080 T/G and rs1883965 G/A with Susceptibility of Urinary System Cancers. DISEASE MARKERS 2022; 2022:1720851. [PMID: 35082928 PMCID: PMC8786550 DOI: 10.1155/2022/1720851] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Accepted: 12/18/2021] [Indexed: 11/18/2022]
Abstract
Background. Genetic polymorphisms in mammalian target of rapamycin (mTOR) signaling axis can influence the susceptibility of cancer. The relationship between mTOR gene variants rs2295080 T/G and rs1883965 G/A and the risk of cancer remains inconsistent. The present study is aimed at comprehensively investigating the association between mTOR polymorphisms and susceptibility to cancer. Methods. We conducted a comprehensive assessment using odds ratios (ORs), corresponding 95% confidence intervals (CIs), and in silico tools to evaluate the effect of mTOR variations. Immunohistochemical staining (IHS) and GSEA analysis were used to investigate the expression of mTOR in urinary system cancer. Results. The pooled analysis involved 22 case-control studies including 14,747 cancer patients and 16,399 controls. The rs2295080 T/G polymorphism was associated with the risk of cancer (G-allele versus T-allele,
,
–0.98,
; GT versus TT,
,
–0.96,
; GG+GT versus TT,
,
–0.96,
), especially for cancers of the urinary system, breast, and blood. Variation rs1883965 G/A was associated with cancer susceptibility, especially for digestive cancer. IHS analysis showed that mTOR was upregulated in prostate and bladder cancer. GSEA revealed that the insulin signaling pathway, lysine degradation pathway, and mTOR signaling pathway were enriched in the high mTOR expression group. Conclusions. The mTOR rs2295080 T/G polymorphism may be associated with susceptibility of urinary cancer. The expression of mTOR is positively correlated with tumor malignancy in prostate cancer.
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11
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Simons CCJM, Schouten LJ, Godschalk RWL, van Schooten FJ, Stoll M, Van Steen K, van den Brandt PA, Weijenberg MP. Polymorphisms in the mTOR-PI3K-Akt pathway, energy balance-related exposures and colorectal cancer risk in the Netherlands Cohort Study. BioData Min 2022; 15:2. [PMID: 35012583 PMCID: PMC8751328 DOI: 10.1186/s13040-021-00286-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 12/22/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The mTOR-PI3K-Akt pathway influences cell metabolism and (malignant) cell growth. We generated sex-specific polygenic risk scores capturing natural variation in 7 out of 10 top-ranked genes in this pathway. We studied the scores directly and in interaction with energy balance-related factors (body mass index (BMI), trouser/skirt size, height, physical activity, and early life energy restriction) in relation to colorectal cancer (CRC) risk in the Netherlands Cohort Study (NLCS) (n=120,852). The NLCS has a case-cohort design and 20.3 years of follow-up. Participants completed a baseline questionnaire on diet and cancer in 1986 when 55-69 years old. ~75% of the cohort returned toenail clippings used for DNA isolation and genotyping (n subcohort=3,793, n cases=3,464). To generate the scores, the dataset was split in two and risk alleles were defined and weighted based on sex-specific associations with CRC risk in the other dataset half, because there were no SNPs in the top-ranked genes associated with CRC risk in previous genome-wide association studies at a significance level p<1*10-5. RESULTS Cox regression analyses showed positive associations between the sex-specific polygenic risk scores and colon but not rectal cancer risk in men and women, with hazard ratios for continuously modeled scores close to 1.10. There was no modifying effect observed of the scores on associations between the energy balance-related factors and CRC risk. However, BMI (in men), non-occupational physical activity (in women), and height (in men and women) were associated with the risk of CRC, in particular (proximal and distal) colon cancer, in the direction as expected in the lower tertiles of the sex-specific polygenic risk scores. CONCLUSIONS Current data suggest that the mTOR-PI3K-Akt pathway may be involved in colon cancer development. This study thereby sheds more light on colon cancer etiology through use of genetic variation in the mTOR-PI3K-Akt pathway.
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Affiliation(s)
- Colinda C J M Simons
- Department of Epidemiology, GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands.
| | - Leo J Schouten
- Department of Epidemiology, GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands
| | - Roger W L Godschalk
- Department of Pharmacology and Toxicology, NUTRIM - School for Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
| | - Frederik-Jan van Schooten
- Department of Pharmacology and Toxicology, NUTRIM - School for Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
| | - Monika Stoll
- Institute of Human Genetics, Genetic Epidemiology, University of Münster, Münster, Germany.,Department of Biochemistry, Maastricht Centre for Systems Biology (MaCSBio), School for Cardiovascular Diseases, CARIM-, Maastricht University, Maastricht, the Netherlands
| | | | - Piet A van den Brandt
- Department of Epidemiology, GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands
| | - Matty P Weijenberg
- Department of Epidemiology, GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands
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12
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Lu X, Liu M, Liao Y, Huang C, Chai L, Jin Y, Xiong Q, Chen B. Meta-analysis of the association between mTORC1-related genes polymorphisms and cancer risk. Pathol Res Pract 2021; 229:153696. [PMID: 34839094 DOI: 10.1016/j.prp.2021.153696] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 11/10/2021] [Accepted: 11/16/2021] [Indexed: 10/19/2022]
Abstract
BACKGROUND mTOR, mLST8 and RAPTOR are the core components of mTORC1, which has been found to be closely related to tumorigenesis. Currently, multiple single nucleotide polymorphisms (SNPs) in mTOR gene (rs2295080, rs17036508 and rs1034528), mLST8 gene (rs3160 and rs26865) and RPTOR gene (rs1062935, rs3751932, rs3751834, rs12602885) have been extensively studied for their associations with cancer risk. However, the results remained inconclusive and conflicting. Therefore, we here performed a meta-analysis of all available studies to investigate the association between these SNPs and cancer risk. METHODS Up to April 2021, 25 related publications were retrieved and included in this meta-analysis. The odds ratios (ORs) and 95% confidence intervals (CIs) calculated by fixed or random effects models were applied to assess the strength of association. Trial Sequential Analysis (TSA) was conducted to weaken the random error and enhance the reliability of evidence. RESULTS After Bonferroni correction, it was revealed that rs3160, rs26865, rs1062935, rs3751932, rs3751834 and rs10602885 were not associated with cancer risk. However, rs17036508 and rs1034528 showed significant association with total cancer risk. A significant association was also found between rs2295080 and total cancer risk, and stratified analysis by cancer type suggested that rs2295080 was specifically associated with acute lymphoblastic leukemia risk, prostate cancer risk, and breast cancer risk. CONCLUSIONS The present meta-analysis suggested that the rs2295080, rs17036508 and rs1034528 polymorphisms in mTOR gene may be the susceptive factors for cancer development, while the target genetic polymorphisms in mLST8 gene or RPTOR gene may not be associated with cancer risk. However, these findings remain to be confirmed or further reinforced in large and well-designed studies in different ethnic populations.
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Affiliation(s)
- Xiaoling Lu
- Department of Biological Science and Technology, School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan, China
| | - Meitong Liu
- Department of Biological Science and Technology, School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan, China
| | - Yuxiao Liao
- Department of Biological Science and Technology, School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan, China
| | - Chao Huang
- Department of Biological Science and Technology, School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan, China
| | - Longlong Chai
- Department of Biological Science and Technology, School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan, China; Department of Laboratory, Maternal and Child Health Hospital of Hubei Province, Wuhan, China
| | - Yuchen Jin
- Department of Biological Science and Technology, School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan, China
| | - Qiantao Xiong
- Department of Laboratory, Maternal and Child Health Hospital of Hubei Province, Wuhan, China.
| | - Bifeng Chen
- Department of Biological Science and Technology, School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan, China.
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13
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Thrombospondin-2 and LDH Are Putative Predictive Biomarkers for Treatment with Everolimus in Second-Line Metastatic Clear Cell Renal Cell Carcinoma (MARC-2 Study). Cancers (Basel) 2021; 13:cancers13112594. [PMID: 34070677 PMCID: PMC8199288 DOI: 10.3390/cancers13112594] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 05/20/2021] [Accepted: 05/20/2021] [Indexed: 01/10/2023] Open
Abstract
Simple Summary Treatment of metastatic renal cell carcinoma (mRCC) remains a challenge due to the lack of biomarkers indicating the optimal drug for each patient. This study analyzed blood samples of patients with predominant clear cell mRCC who were treated with the mTOR inhibitor everolimus after failure of one prior tumor therapy. In an exploratory approach, predictive blood biomarkers were searched. We found lower levels of the protein thrombospondin-2 (TSP-2) at the start of the therapy and higher lactate dehydrogenase (LDH) levels in serum two weeks after therapy initiation to be associated with therapy response. Of note, these blood biomarkers had a higher predictive value than baseline patient parameters or risk classifications. Polymorphisms in the mTOR gene appeared to be associated with therapy response, but were not significant. To conclude, it seems feasible to identify patients showing longtime responses to everolimus and possible to increase tumor therapy response rates based on biomarkers for individual therapy selection. Abstract There is an unmet need for predictive biomarkers in metastatic renal cell carcinoma (mRCC) therapy. The phase IV MARC-2 trial searched for predictive blood biomarkers in patients with predominant clear cell mRCC who benefit from second-line treatment with everolimus. In an exploratory approach, potential biomarkers were assessed employing proteomics, ELISA, and polymorphism analyses. Lower levels of angiogenesis-related protein thrombospondin-2 (TSP-2) at baseline (≤665 parts per billion, ppb) identified therapy responders with longer median progression-free survival (PFS; ≤665 ppb at baseline: 6.9 months vs. 1.8, p = 0.005). Responders had higher lactate dehydrogenase (LDH) levels in serum two weeks after therapy initiation (>27.14 nmol/L), associated with a longer median PFS (3.8 months vs. 2.2, p = 0.013) and improved overall survival (OS; 31.0 months vs. 14.0 months, p < 0.001). Baseline TSP-2 levels had a stronger relation to PFS (HR 0.36, p = 0.008) than baseline patient parameters, including IMDC score. Increased serum LDH levels two weeks after therapy initiation were the best predictor for OS (HR 0.21, p < 0.001). mTOR polymorphisms appeared to be associated with therapy response but were not significant. Hence, we identified TSP-2 and LDH as promising predictive biomarkers for therapy response on everolimus after failure of one VEGF-targeted therapy in patients with clear cell mRCC.
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14
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Maruei‐Milan R, Saravani M, Heidari Z, Asadi‐Tarani M, Salimi S. Effects of the
MTOR
and
AKT1
genes polymorphisms on papillary thyroid cancer development. IUBMB Life 2020; 72:2601-2610. [DOI: 10.1002/iub.2388] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 09/01/2020] [Accepted: 09/13/2020] [Indexed: 12/17/2022]
Affiliation(s)
- Rostam Maruei‐Milan
- Department of Clinical Biochemistry, School of Medicine Zahedan University of Medical Sciences Zahedan Iran
| | - Mohsen Saravani
- Department of Clinical Biochemistry, School of Medicine Zahedan University of Medical Sciences Zahedan Iran
- Cellular and Molecular Research Center, Resistant Tuberculosis Institute Zahedan University of Medical Sciences Zahedan Iran
| | - Zahra Heidari
- Department of Internal Medicine Zahedan University of Medical Sciences Zahedan Iran
| | - Mina Asadi‐Tarani
- Department of Clinical Biochemistry, School of Medicine Zahedan University of Medical Sciences Zahedan Iran
| | - Saeedeh Salimi
- Department of Clinical Biochemistry, School of Medicine Zahedan University of Medical Sciences Zahedan Iran
- Cellular and Molecular Research Center, Resistant Tuberculosis Institute Zahedan University of Medical Sciences Zahedan Iran
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15
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Wang M, Ma SJ, Wu XY, Zhang X, Abesig J, Xiao ZH, Huang X, Yan HP, Wang J, Chen MS, Tan HZ. Impact of mTOR gene polymorphisms and gene-tea interaction on susceptibility to tuberculosis. World J Clin Cases 2020; 8:4320-4330. [PMID: 33083391 PMCID: PMC7559685 DOI: 10.12998/wjcc.v8.i19.4320] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 07/30/2020] [Accepted: 08/29/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND mTOR gene is a key component of the PI3K/Akt/mTOR signaling pathway, and its dysregulation is associated with various diseases. Several studies have demonstrated that tea drinking is a protective factor against tuberculosis (TB). This study was designed to explore five single nucleotide polymorphisms (SNPs) of mTOR in the Han population of China to determine how their interactions with tea drinking affect susceptibility to TB.
AIM To investigate if the polymorphisms of mTOR gene and the gene-tea interaction are associated with susceptibility to TB.
METHODS In this case-control study, 503 patients with TB and 494 healthy controls were enrolled by a stratified sampling method. The cases were newly registered TB patients from the county-level centers for disease control and prevention, and the healthy controls were permanent residents from Xin’ansi Community, Changsha city. Demographic data and environmental exposure information including tea drinking were obtained from the study participants. We genotyped five potentially functional SNP sites (rs2295080, rs2024627, rs1057079, rs12137958, and rs7525957) of mTOR gene and assessed their associations with the risk of TB using logistic regression analysis, and marginal structural linear odds models were used to estimate the gene-environment interactions.
RESULTS The frequencies of four SNPs (rs2295080, rs2024627, rs1057079, and rs7525957) were found to be associated with susceptibility to TB (P < 0.05). Genotypes GT (OR 1.334), GG (OR 2.224), and GT + GG (OR 1.403) at rs2295080; genotypes CT (OR 1.562) and CT + TT (OR 1.578) at rs2024627, genotypes CT (OR 1.597), CC (OR 2.858), and CT + CC (OR 1.682) at rs1057079; and genotypes CT (OR 1.559) and CT + CC (OR 1.568) at rs7525957 of mTOR gene were significantly more prevalent in TB patients than in healthy controls. The relative excess risk of interaction between the four SNPs (rs2295080, rs2024627, rs1057079, and rs7525957) of mTOR genes and tea drinking were found to be -1.5187 (95%CI: -1.9826, -1.0547, P < 0.05), -1.8270 (95%CI: -2.3587, -1.2952, P < 0.05), -2.3246 (95%CI: -2.9417, -1.7076, P < 0.05) and -0.4235 (95%CI: -0.7756, -0.0714, P < 0.05), respectively, which suggest negative interactions.
CONCLUSION The polymorphisms of mTOR (rs2295080, rs2024627, rs1057079, and rs7525957) are associated with susceptibility to TB, and there is a negative interaction between each of the four SNPs and tea drinking.
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Affiliation(s)
- Mian Wang
- Hunan Provincial Key Laboratory of Clinical Epidemiology, Xiangya School of Public Health, Central South University, Changsha 410078, Hunan Province, China
| | - Shu-Juan Ma
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha 410078, Hunan Province, China
| | - Xin-Yin Wu
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha 410078, Hunan Province, China
| | - Xian Zhang
- Department of Occupational and Environmental Hygiene, Xiangya School of Public Health, Central South University, Changsha 410078, Hunan Province, China
| | - Julius Abesig
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha 410078, Hunan Province, China
| | - Zheng-Hui Xiao
- Hunan Provincial Key Laboratory of Pediatric Emergency, Hunan Children’s Hospital, Changsha 410007, Hunan Province, China
| | - Xin Huang
- Department of Epidemiology and Health Statistics, Hunan Normal University, Changsha 410008, Hunan Province, China
| | - Hai-Peng Yan
- Hunan Provincial Key Laboratory of Pediatric Emergency, Hunan Children’s Hospital, Changsha 410007, Hunan Province, China
| | - Jing Wang
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha 410078, Hunan Province, China
| | - Meng-Shi Chen
- Hunan Provincial Key Laboratory of Clinical Epidemiology, Xiangya School of Public Health, Central South University, Changsha 410078, Hunan Province, China
| | - Hong-Zhuan Tan
- Hunan Provincial Key Laboratory of Clinical Epidemiology, Xiangya School of Public Health, Central South University, Changsha 410078, Hunan Province, China
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16
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Qi GH, Wang CH, Zhang HG, Yu JG, Ding F, Song ZC, Xia QH. Comprehensive analysis of the effect of rs2295080 and rs2536 polymorphisms within the mTOR gene on cancer risk. Biosci Rep 2020; 40:BSR20191825. [PMID: 32597485 PMCID: PMC7350887 DOI: 10.1042/bsr20191825] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 06/03/2020] [Accepted: 06/08/2020] [Indexed: 12/31/2022] Open
Abstract
There is still no conclusion on the potential effect of the rs2295080 and rs2536 polymorphisms of mTOR (mammalian target of rapamycin) gene on different cancers. Herein, we performed a comprehensive assessment using pooled analysis, FPRP (false-positive report probability), TSA (trial sequential analysis), and eQTL (expression quantitative trait loci) analysis. Eighteen high-quality articles from China were enrolled. The pooled analysis of rs2295080 with 9502 cases and 10,965 controls showed a decreased risk of urinary system tumors and specific prostate cancers [TG vs. TT, TG+GG vs. TT and G vs. T; P<0.05, OR (odds ratio) <1]. FPRP and TSA data further confirmed these results. There was an increased risk of leukemia [G vs. T, GG vs. TT, and GG vs. TT+TG genotypes; P<0.05, OR>1]. The eQTL data showed a potential correlation between the rs2295080 and mTOR expression in whole blood samples. Nevertheless, FPRP and TSA data suggested that more evidence is required to confirm the potential role of rs2295080 in leukemia risk. The pooled analysis of rs2536 (6653 cases and 7025 controls) showed a significant association in the subgroup of "population-based" control source via the allele, heterozygote, dominant, and carrier comparisons (P<0.05, OR>1). In conclusion, the TG genotype of mTOR rs2295080 may be linked to reduced susceptibility to urinary system tumors or specific prostate cancers in Chinese patients. The currently data do not strongly support a role of rs2295080 in leukemia susceptibility. Large sample sizes are needed to confirm the potential role of rs2536 in more types of cancer.
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Affiliation(s)
- Guang-Hui Qi
- Department of Urology, The First Hospital of Zibo City, Zibo, Shandong 255000, China
| | - Chun-Hui Wang
- Second Department of Gastroenterology, The First Hospital of Zibo City, Zibo, Shandong 255000, China
| | - Hong-Ge Zhang
- Third Department of Surgery, Teng zhou Hospital of Traditional Chinese Medicine, Teng zhou, Shandong 277500, China
| | - Jian-Guo Yu
- Department of Urology, The First Hospital of Zibo City, Zibo, Shandong 255000, China
| | - Fei Ding
- Second Department of Oncology, The First Hospital of Zibo City, Zibo, Shandong 255000, China
| | - Zhi-Chao Song
- Department of Anorectal Surgery, The First Hospital of Zibo City, Zibo, Shandong 255000, China
| | - Qing-Hua Xia
- Department of Urology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China
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17
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Xiao Q, Yu H, Zhu X. The associations of hub gene polymorphisms in PI3K/AKT/mTOR pathway and Schistosomiasis Japonica infection and hepatic fibrosis. INFECTION GENETICS AND EVOLUTION 2020; 85:104423. [PMID: 32554084 DOI: 10.1016/j.meegid.2020.104423] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 05/26/2020] [Accepted: 06/11/2020] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Increasing evidence shows that the PI3K/AKT/mTOR pathway can be activated by a variety of stimulus in immune cells. Schistosomiasis Japonica is a serious threat to human health in some lakes of China. METHODS We analyzed the potential associations between the hub gene (PTEN, mTOR, AKT1 and AKT2) polymorphisms of PI3K/AKT/mTOR pathway and S. japonica risk, including infection risk, as well as immunological hepatic fibrosis risk. An immune database named Database of Immune Cell Expression, Expression quantitative trait loci and Epigenomics (DICE) was used to analyze the expression profiles of the hub genes in 15 types of immune cells. RESULTS Of them, two SNPs rs2295080 (mTOR) and rs7254617 (AKT2) were found associated with the risk of infection and fibrosis. We also performed a multivariant Cox regression analysis and found that HBV infection may increase hepatic fibrosis in chronic schistosomiasis patients, instead of genetic polymorphisms on PI3K/AKT/mTOR pathway or any other factors. We also found the expressions of mTOR (RICTOR) and AKT2 in T cells were higher than those in monocyte cells. And, the expressions of PTEN, mTOR (RICTOR) and AKT1 reduced both in activated CD4 T cells and activated CD8 T cells. CONCLUSIONS We concluded that rs2295080 may be an important marker in the diagnosis of susceptibility to schistosomiasis infection. But HBV infection not rs2295080 could promote immunological liver damage with fibrosis in patients with chronic schistosomiasis infection.
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Affiliation(s)
- Qin Xiao
- The Marine Medical Research Institute of Guangdong Zhanjiang (GDZJMMRI), Southern Science and Engineering Guangdong Laboratory Zhanjiang, Guangdong Medical University, Zhanjiang, China; Department of Blood Transfusion, Peking University Shenzhen Hospital, Shenzhen, China
| | - Haibing Yu
- Department of Epidemiology and Medical Statistics, School of Public Health, Guangdong Medical University, Dongguan, China
| | - Xiao Zhu
- The Marine Medical Research Institute of Guangdong Zhanjiang (GDZJMMRI), Southern Science and Engineering Guangdong Laboratory Zhanjiang, Guangdong Medical University, Zhanjiang, China.
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18
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Tumkur Sitaram R, Landström M, Roos G, Ljungberg B. Significance of PI3K signalling pathway in clear cell renal cell carcinoma in relation to VHL and HIF status. J Clin Pathol 2020; 74:216-222. [PMID: 32467322 DOI: 10.1136/jclinpath-2020-206693] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 05/10/2020] [Indexed: 12/30/2022]
Abstract
Renal cell carcinoma (RCC) includes diverse tumour types characterised by various genetic abnormalities. The genetic changes, like mutations, deletions and epigenetic alterations, play a crucial role in the modification of signalling networks, tumour pathogenesis and prognosis. The most prevalent RCC type, clear cell RCC (ccRCC), is asymptomatic in the early stages and has a poorer prognosis compared with the papillary and the chromophobe types RCCs. Generally, ccRCC is refractory to chemotherapy and radiation therapy. Loss of von Hippel-Lindau (VHL) gene and upregulation of hypoxia-inducible factors (HIF), the signature of most sporadic ccRCC, promote multiple growth factors. Hence, VHL/HIF and a variety of pathways, including phosphatase and TEnsin homolog on chromosome 10/phosphatidylinositol-3-kinase (PI3K)/AKT, are closely connected and contribute to the ontogeny of ccRCC. In the recent decade, multiple targeting agents have been developed based on blocking major signalling pathways directly or indirectly involved in ccRCC tumour progression, metastasis, angiogenesis and survival. However, most of these drugs have limitations; either metastatic ccRCC develops resistance to these agents, or despite blocking receptors, tumour cells use alternate signalling pathways. This review compiles the state of knowledge about the PI3K/AKT signalling pathway confined to ccRCC and its cross-talks with VHL/HIF pathway.
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Affiliation(s)
- Raviprakash Tumkur Sitaram
- Department of Medical Biosciences, Pathology, Translational Research Center (TRC), Umeå Universitet, Umeå, Väasterbotten, Sweden
| | - Maréne Landström
- Department of Medical Biosciences, Pathology, Translational Research Center (TRC), Umeå Universitet, Umeå, Väasterbotten, Sweden
| | - Göran Roos
- Department of Medical Biosciences, Pathology, Translational Research Center (TRC), Umeå Universitet, Umeå, Väasterbotten, Sweden
| | - Börje Ljungberg
- Department of Surgical and Preoperative Sciences, Urology and Andrology, Umeå Universitet, Umea, Västerbotten, Sweden
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19
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Cao Q, Li P, Cao P, Qian J, Du M, Li L, Wang M, Qin C, Shao P, Zhang Z, Lu Q, Wang Z. Genetic Variant in Long Non-Coding RNA H19 Modulates Its Expression and Predicts Renal Cell Carcinoma Susceptibility and Mortality. Front Oncol 2020; 10:785. [PMID: 32509581 PMCID: PMC7251175 DOI: 10.3389/fonc.2020.00785] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Accepted: 04/22/2020] [Indexed: 01/07/2023] Open
Abstract
The long non-coding RNA (lncRNA) H19 has been demonstrated to play a crucial role in carcinogenesis, including renal cell carcinoma (RCC). However, the impact of genetic variations in H19 gene on RCC has not been investigated before. In the present study, we sought to evaluate whether genetic polymorphisms in H19 are related to the susceptibility and mortality of RCC. We genotyped four widely studied polymorphisms in H19 and assessed their relationship with susceptibility and prognosis of RCC in a case-control study compromising 1,027 cases and 1,094 controls. The functionality of the important polymorphism was further investigated by real-time polymerase chain reaction and luciferase reporter assay. We found that H19 rs2839698 was significantly associated with risk and prognosis of RCC. Compared with the H19 rs2839698 CC genotype, the variant genotypes (CT/TT) were significantly associated with increased risk of RCC (P = 0.023, OR = 1.21; 95% CI = 1.03–1.45). Besides, patients with variant genotypes (CT/TT) were more likely to develop large tumor (P = 0.003, OR = 1.47; 95% CI = 1.16–1.85) and advanced disease (P = 0.010, OR = 1.59; 95% CI = 1.12–2.26); and had a significantly unfavorable overall survival than those with the rs2839698 CC genotype (CT/TT vs. CC: Log-rank P = 0.026, HR = 2.25, 95%CI = 1.07–4.75). Furthermore, the CT/TT genotypes were associated with significantly increased expression of H19 in renal tissue. The luciferase reporter assays revealed the potential effect of rs2839698 variant on the binding of microRNAs to H19. Our results suggest that the H19 rs2839698 variant may be a genetic predictor of susceptibility and mortality of RCC. The risk effects and the functional impact of the variant on H19 still need further validation.
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Affiliation(s)
- Qiang Cao
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Pengchao Li
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Pu Cao
- Department of Urology, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jian Qian
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Mulong Du
- Department of Molecular & Genetic Toxicology, Nanjing Medical University, Nanjing, China
| | - Li Li
- Department of Ultrasound, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, China
| | - Meilin Wang
- Department of Molecular & Genetic Toxicology, Nanjing Medical University, Nanjing, China
| | - Chao Qin
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Pengfei Shao
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zhengdong Zhang
- Department of Molecular & Genetic Toxicology, Nanjing Medical University, Nanjing, China
| | - Qiang Lu
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zengjun Wang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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20
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Saravani M, Shahraki-Ghadimi H, Maruei-Milan R, Mehrabani M, Mirzamohammadi S, Nematollahi MH. Effects of the mTOR and AKT genes polymorphisms on systemic lupus erythematosus risk. Mol Biol Rep 2020; 47:3551-3556. [PMID: 32319007 DOI: 10.1007/s11033-020-05446-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 04/09/2020] [Indexed: 01/10/2023]
Abstract
The systemic lupus erythematosus (SLE) is an autoimmune disease, leading to inflammatory response and systemic consequences. The mammalian target of rapamycin (mTOR) is a therapeutic target for autoimmune diseases like SLE. The aim of this study was to evaluate the effects of the mTOR rs2295080 and rs2536 polymorphisms and AKT1 rs2494732 gene polymorphism on SLE development. 2 ml of peripheral blood was collected from 165 SLE patients and 170 controls in EDTA-containing tubes. The salting-out and PCR-RFLP methods were used for DNA extraction and genotype analysis, respectively. Based on the regression analysis, the frequency of TT genotype of mTOR rs2295080 polymorphism was significantly higher in the case group than that of the control group, with a 2.6-fold increased risk of SLE. There was also a significant difference between the two groups in terms of allelic distribution. No statistically significant association was found between The AKT1 rs2494732 and mTOR rs2536 polymorphisms and SLE development. Our results showed that the TT genotype and T allele of mTOR rs2295080 polymorphism were risk factors for developing SLE. However, there was no significant association between mTOR rs2536 and AKT1 rs2494732 polymorphisms and the SLE risk.
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Affiliation(s)
- Mohsen Saravani
- Cellular and Molecular Research Center, Zahedan University of Medical Sciences, Zahedan, Iran.,Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Hossein Shahraki-Ghadimi
- Cellular and Molecular Research Center, Zahedan University of Medical Sciences, Zahedan, Iran.,Bioinformatics and Computational Omics Lab (BioCOOL), Department of Biophysics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Rostam Maruei-Milan
- Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Mehrnaz Mehrabani
- School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Solmaz Mirzamohammadi
- Physiology Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran
| | - Mohammad Hadi Nematollahi
- Student Research Committee, Kerman University of Medical Sciences, Kerman, Iran. .,Department of Clinical Biochemistry, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran.
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Changes in PCSK9 and LDL cholesterol concentrations by everolimus treatment and their effects on polymorphisms in PCSK9 and mTORC1. Pharmacol Rep 2020; 72:622-630. [DOI: 10.1007/s43440-020-00090-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 02/17/2020] [Accepted: 02/20/2020] [Indexed: 12/30/2022]
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Bonnet S, Falkowski S, Deppenweiler M, Monchaud C, Arnion H, Picard N, Woillard JB. Effect of genetic polymorphisms in CYP3A4, CYP3A5, and m-TOR on everolimus blood exposure and clinical outcomes in cancer patients. THE PHARMACOGENOMICS JOURNAL 2020; 20:647-654. [PMID: 32015456 DOI: 10.1038/s41397-020-0152-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Revised: 01/21/2020] [Accepted: 01/23/2020] [Indexed: 12/18/2022]
Abstract
Genetic variations in CYP3A4, CYP3A5, and m-TOR could contribute to interpatient variability regarding m-TOR inhibitors pharmacokinetics or cellular effects. The purpose of this study was to evaluate the influence of selected candidate variations in these genes on everolimus pharmacokinetics, efficacy, and toxicity in cancer patients. Thirty-four patients receiving everolimus for breast (n = 22) or renal (n = 10) cancers, or neuroendocrine tumors of pancreatic origin (n = 2) were included in the study. Six variants in genes related to everolimus pharmacokinetics (CYP3A4*22 and CYP3A5*3) or pharmacodynamics (m-TOR rs2295079, rs2295080, rs2024627 and rs1057079) were genotyped. Associations with trough concentrations (C0), dose reductions, or treatment interruptions due to toxicity and progression-free survival were investigated using generalized estimating equations and Cox models. CYP3A5 nonexpressers had significantly higher C0 as compared with expressers (βGG vs AG = + 6.32 ± 2.22 ng/mL, p = 0.004). m-TOR rs2024627 was significantly associated with an increased risk of cancer progression studied alone or as part of an haplotype (T vs C: HR = 2.60, 95% CI [1.16-5.80], p = 0.020; CTCG vs other haplotypes HR = 2.29, 95% CI [1.06-4.95], p = 0.035, respectively). This study showed that CYP3A5 expression impacts everolimus pharmacokinetics in cancer patients and identified a genetic variation in m-TOR associated with the risk of cancer progression.
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Affiliation(s)
- Stéphanie Bonnet
- University of Limoges, IPPRITT, F-87000, Limoges, France.,INSERM, IPPRITT, UMR1248, F-87000, Limoges, France
| | | | | | - Caroline Monchaud
- University of Limoges, IPPRITT, F-87000, Limoges, France.,INSERM, IPPRITT, UMR1248, F-87000, Limoges, France.,Department of Pharmacology and Toxicology, CHU Limoges, F-87000, Limoges, France
| | - Hélène Arnion
- University of Limoges, IPPRITT, F-87000, Limoges, France.,INSERM, IPPRITT, UMR1248, F-87000, Limoges, France
| | - Nicolas Picard
- University of Limoges, IPPRITT, F-87000, Limoges, France.,INSERM, IPPRITT, UMR1248, F-87000, Limoges, France.,Department of Pharmacology and Toxicology, CHU Limoges, F-87000, Limoges, France
| | - Jean-Baptiste Woillard
- University of Limoges, IPPRITT, F-87000, Limoges, France. .,INSERM, IPPRITT, UMR1248, F-87000, Limoges, France. .,Department of Pharmacology and Toxicology, CHU Limoges, F-87000, Limoges, France.
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23
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Zhang S, Shi W, Ramsay ES, Bliskovsky V, Eiden AM, Connors D, Steinsaltz M, DuBois W, Mock BA. The transcription factor MZF1 differentially regulates murine Mtor promoter variants linked to tumor susceptibility. J Biol Chem 2019; 294:16756-16764. [PMID: 31548308 DOI: 10.1074/jbc.ra119.009779] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Revised: 09/18/2019] [Indexed: 01/15/2023] Open
Abstract
Mechanistic target of rapamycin (MTOR) is a highly conserved serine/threonine kinase that critically regulates cell growth, proliferation, differentiation, and survival. Previously, we have implicated Mtor as a plasmacytoma-resistance locus, Pctr2, in mice. Here, we report that administration of the tumor-inducing agent pristane decreases Mtor gene expression to a greater extent in mesenteric lymph nodes of BALB/cAnPt mice than of DBA/2N mice. We identified six allelic variants in the Mtor promoter region in BALB/cAnPt and DBA/2N mice. To determine the effects of these variants on Mtor transcription, we constructed a series of luciferase reporters containing these promoter variants and transfected them into mouse plasmacytoma cells. We could attribute the differences in Mtor promoter activity between the two mouse strains to a C → T change at the -6 position relative to the transcriptional start site Tssr 40273; a T at this position in the BALB promoter creates a consensus binding site for the transcription factor MZF1 (myeloid zinc finger 1). Results from electrophoretic mobility shift assays and DNA pulldown assays with ChIP-PCR confirmed that MZF1 binds to the cis-element TGGGGA located in the -6/-1 Mtor promoter region. Of note, MZF1 significantly and differentially down-regulated Mtor promoter activity, with MZF1 overexpression reducing Mtor expression more strongly in BALB mice than in DBA mice. Moreover, MZF1 overexpression reduced Mtor expression in both fibroblasts and mouse plasmacytoma cells, and Mzf1 knockdown increased Mtor expression in BALB3T3 and NIH3T3 fibroblast cells. Our results provide evidence that MZF1 down-regulates Mtor expression in pristane-induced plasmacytomas in mice.
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Affiliation(s)
- Shuling Zhang
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland 20892
| | - Wei Shi
- Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, Maryland 20892
| | - Edward S Ramsay
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland 20892
| | - Valery Bliskovsky
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland 20892
| | - Adrian Max Eiden
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland 20892
| | - Daniel Connors
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland 20892
| | - Matthew Steinsaltz
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland 20892
| | - Wendy DuBois
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland 20892
| | - Beverly A Mock
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland 20892
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24
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Wen J, Chen L, Tian H, Li J, Zhang M, Cao Q, Zhang W, Chen S, Shi L. Effect of MALAT1 Polymorphisms on Papillary Thyroid Cancer in a Chinese Population. J Cancer 2019; 10:5714-5721. [PMID: 31788131 PMCID: PMC6879318 DOI: 10.7150/jca.28887] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Accepted: 01/05/2019] [Indexed: 12/13/2022] Open
Abstract
Background: Long noncoding RNA MALAT1 has been previously reported in the carcinogenesis of several tumors, and its potential functional polymorphisms have also been investigated in various diseases. However, the relationship between these polymorphisms and the susceptibility of thyroid cancer has still been largely unknown. In the present study, we aimed to explore the association between MALAT1 polymorphisms and thyroid cancer (TC) susceptibility, as well as potential biological function in TC. Methods: We conducted a case-control study with 1134 papillary thyroid cancer (PTC) patients and 1228 controls to evaluate the potential correlation between MALAT1 genetic variations (single nucleotide polymorphism, SNP) and the risk of PTC. More detailed molecular mechanisms were explored by luciferase assay, cell counting kit-8 (CCK-8), and flow cytometry. Results: MALAT1 SNP rs619586 was identified as a significantly protective factor of PTC susceptibility (P = 0.017, OR= 0.76, 95%CI = 0.60-0.95). Further functional experiments of rs619586 indicated that G allele of rs619586 could significantly decrease MALAT1expression, reduce PTC proliferation, and directly increase PTC apoptosis. Conclusions: Our findings suggested that MALAT1 SNP rs619586 could serve as a potential indicator for PTC susceptibility and pathogenesis.
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Affiliation(s)
- Jing Wen
- Department of Ultrasonics, the Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China.,Department of Pathophysiology, the Institute of Basic Medicine, Guizhou Medical University, Guiyang 550004, China
| | - Liang Chen
- Department of General Surgery, Wujiang NO.1 People's Hospital, Suzhou 215200, China
| | - Hua Tian
- Department of acute infectious disease Prevention, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing 210009, China
| | - Ji Li
- Department of Pathophysiology, the Institute of Basic Medicine, Guizhou Medical University, Guiyang 550004, China.,Central Laboratory, the Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China
| | - Miao Zhang
- Department of Endocrinology, the Hospital Affiliated to Guizhou Medical University, Guiyang 550004, China
| | - Qing Cao
- College of Medicine, Henan University of Science and Technology, Luoyang 471023, China
| | - Wei Zhang
- Department of Thyroid Surgery, the Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China
| | - Shi Chen
- Department of Public Health Sciences, University of North Carolina Charlotte, Charlotte, NC 28223, USA
| | - Lixin Shi
- Department of Pathophysiology, the Institute of Basic Medicine, Guizhou Medical University, Guiyang 550004, China.,Department of Endocrinology, the Hospital Affiliated to Guizhou Medical University, Guiyang 550004, China
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25
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Chen Q, Deng X, Hu X, Guan S, He M, Wang Y, Wei B, Zhang J, Zhao H, Yao W, Jin F, Liu Y, Chen J, Olapade OI, Wu H, Wei M. Breast Cancer Risk-Associated SNPs in the mTOR Promoter Form De Novo KLF5- and ZEB1-Binding Sites that Influence the Cellular Response to Paclitaxel. Mol Cancer Res 2019; 17:2244-2256. [PMID: 31467112 DOI: 10.1158/1541-7786.mcr-18-1072] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 01/03/2019] [Accepted: 08/26/2019] [Indexed: 12/24/2022]
Abstract
ZEB1 (a positive enhancer) and KLF5 (a negative silencer) affect transcription factors and play inherently conserved roles in tumorigenesis and multidrug resistance. In humans, the rs2295080T-allele at the mTOR promoter locus has been associated with human cancer risk; however, the 63 bp spacing of another SNP rs2295079 has not been identified. Here, we discovered, for the first time, that rs2295079 (-78C/G) and rs2295080 (-141G/T) formed linkage haplotypes, with Ht1 (-78C/-141G) and Ht2 (-78G/-141T) being dominant, which were associated with distinct susceptibility to breast cancer, response to paclitaxel, and clinical outcomes in breast cancer. At the cellular level, compared with Ht1, Ht2 exhibits a much stronger effect on promoting mTOR expression, leading to enhanced tumor cell growth and strengthened resistance to PTX treatment. Mechanistically, the -141T allele of Ht2 creates a novel ZEB1-binding site; meanwhile, the -78C allele of Ht1 exists as an emerging KLF5-binding site, which synergistically induces promote/inhibit mTOR expression, cell proliferation, and excretion of cytotoxic drugs through the ZEB1/KLF5-mTOR-CCND1/ABCB1 cascade, thereby affecting the response to paclitaxel treatment in vivo and in vitro. Our results suggest the existence of a ZEB1/KLF5-mTOR-CCND1/ABCB1 axis in human cells that could be involved in paclitaxel response pathways and functionally regulate interindividualized breast cancer susceptibility and prognosis. IMPLICATIONS: This study highlights the function of haplotypes of mTOR -78C/-141G and -78G/-141T, in affecting breast cancer susceptibility and paclitaxel response regulated by ZEB1/KLF5-mTOR-CCND1/ABCB1 axis.
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Affiliation(s)
- Qiuchen Chen
- Department of Pharmacology, School of Pharmacy, Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, China
| | - Xiaolan Deng
- Department of Pharmacology, School of Pharmacy, Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, China.,Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, California
| | - Xiaoyun Hu
- Department of Pharmacology, School of Pharmacy, Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, China
| | - Shu Guan
- Department of Breast Surgery, First Hospital of China Medical University, Shenyang, China
| | - Miao He
- Department of Pharmacology, School of Pharmacy, Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, China
| | - Yilin Wang
- Department of Pharmacology, School of Pharmacy, Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, China
| | - Binbin Wei
- Department of Pharmacology, School of Pharmacy, Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, China
| | - Jing Zhang
- Department of Pharmacology, School of Pharmacy, Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, China
| | - Haishan Zhao
- Department of Pharmacology, School of Pharmacy, Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, China
| | - Weifan Yao
- Department of Pharmacology, School of Pharmacy, Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, China
| | - Feng Jin
- Department of Breast Surgery, First Hospital of China Medical University, Shenyang, China
| | - Yong Liu
- Department of Clinical Laboratory, Shengjing Hospital of China Medical University, Shenyang, China
| | - Jianjun Chen
- Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, California
| | | | - Huizhe Wu
- Department of Pharmacology, School of Pharmacy, Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, China.
| | - Minjie Wei
- Department of Pharmacology, School of Pharmacy, Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, China.
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26
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Husen P, Straub K, Willuweit K, Hagemann A, Wedemeyer H, Bachmann HS, Herzer K. SNPs Within the MTOR Gene Are Associated With an Increased Risk of Developing De Novo Diabetes Mellitus Following the Administration of Everolimus in Liver Transplant Recipients. Transplant Proc 2019; 51:1962-1971. [PMID: 31303410 DOI: 10.1016/j.transproceed.2019.03.027] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Revised: 02/27/2019] [Accepted: 03/13/2019] [Indexed: 12/15/2022]
Abstract
BACKGROUND The impact of immunosuppressive drugs in patients following liver transplantation (LT) is very individual. Despite the multiple beneficial effects of the mammalian target of rapamycin (mTOR) inhibitor everolimus (EVR) in LT recipients, some patients do not benefit from EVR administration. We investigated whether the presence of common single-nucleotide polymorphisms (SNPs) in the mTOR gene are predictive for adverse events following the introduction of EVR after LT. MATERIALS AND METHODS The feasibility and efficacy of EVR in 127 liver transplant recipients who were converted to EVR-based immunosuppression was documented retrospectively. Blood samples of these patients were analyzed for the occurrence of 4 SNPs in the mTOR promoter region (mTOR3099/rs2295079 C>G, mTOR3162/rs2295080 A>C) and the mTOR 3' untranslated regio (mTOR8167/rs12139042 C>T, mTOR8600/rs2536 A>G); the specific allele variants were also associated with the incidence of adverse events (AEs). RESULTS Of all patients, 21 (16.5%) did not tolerate the medication and had to discontinue. Of those patients who continued, 37% developed signs of reduced tolerance within the first 6 months, resolving after 12 months. When the cohort was divided according to genotype and allele frequency, patients with the mTOR3162/rs2295080 CC variant had a significantly higher risk (odds ratio = 5.89; 95% confidence interval = 1.48-23.40; P = .012) of developing new-onset diabetes mellitus following EVR treatment than AA or AC genotype carriers. CONCLUSION Our results suggest that the SNP mTOR3162/rs2295080 CC genotype is associated with the development of new-onset diabetes mellitus following EVR treatment.
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Affiliation(s)
- Peri Husen
- Department of General, Visceral- and Transplantation Surgery, Faculty of Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Katja Straub
- Department of Gastroenterology and Hepatology, Faculty of Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Katharina Willuweit
- Department of Gastroenterology and Hepatology, Faculty of Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Anna Hagemann
- Institute of Pharmacology and Toxicology, School of Medicine, Faculty of Health, Witten/Herdecke University, Witten, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology and Hepatology, Faculty of Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Hagen S Bachmann
- Institute of Pharmacology and Toxicology, School of Medicine, Faculty of Health, Witten/Herdecke University, Witten, Germany; Institute of Pharmacogenetics, Faculty of Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Kerstin Herzer
- Department of Gastroenterology and Hepatology, Faculty of Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
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Shi J, Luo Y. Effects of RHD gene polymorphisms on distinguishing weak D or DEL from RhD- in blood donation in a Chinese population. Mol Genet Genomic Med 2019; 7:e00681. [PMID: 30950221 PMCID: PMC6565595 DOI: 10.1002/mgg3.681] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Revised: 03/05/2019] [Accepted: 03/07/2019] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND Weak D or DEL red blood cell units may be mistyped as RhD- by current serology assays, which can lead to incompatible transfusion to RhD- recipients and further cause anti-D immunization. Molecular RHD blood group typing is a very effective method for overcoming current technical limits. The purpose of this study was to identify RHD single-nucleotide polymorphisms (SNPs) and compare the genotype prevalence among confirmed RhD- individuals in a Chinese population as well as explore effective biomarkers for current weak D or DEL detection before blood transfusion. METHODS In the present study, 125 weak D (1, 2, 3, and 4.1) or DEL and 185 RhD- blood samples from donors detected by current standard serology were collected. Genotyping system was used to analyze the SNPs of RHD in each sample. RESULTS Seven SNPs (rs592372, rs11485789, rs6669352, rs3118454, rs1053359, rs590787, and rs3927482) were detected in the RHD region. Rs3118454, rs1053359, rs590787, and rs3927482 showed significant differences between the weak D (1, 2, 3 and 4.1) or DEL and RhD- groups. Further combined analysis of the allelic distribution of these four SNPs revealed their higher frequencies in the RhD- group. CONCLUSION The SNPs rs3118454, rs1053359, rs590787, and rs3927482 in RHD showed a significantly higher frequency among an RhD- Chinese population and are potential biomarkers.
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Affiliation(s)
- Jie Shi
- Nanjing Red Cross Blood Center, Nanjing, Jiangsu, P. R. China
| | - Ying Luo
- Nanjing Red Cross Blood Center, Nanjing, Jiangsu, P. R. China.,Division of Nephrology and Rheumatology, Center for Nephrology and Metabolomics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, P. R. China
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Gao X, Yang J, Wang M, Zhang J. TCF21 genetic polymorphisms and breast cancer risk in Chinese women. Oncotarget 2018; 7:55757-55764. [PMID: 27270650 PMCID: PMC5342451 DOI: 10.18632/oncotarget.9825] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2016] [Accepted: 05/20/2016] [Indexed: 12/29/2022] Open
Abstract
Transcription factor 21 (TCF21) functions as a tumor suppressor and is inactivated in several types of cancer. The purpose of this study is to investigate whether TCF21 genetic polymorphisms(rs2327429 T>C, rs2327430 T>C, rs2327433 A>G, rs12190287 C>G, rs7766238 G>A, rs4896011 T>A) are associated with the risk of breast cancer in Chinese women. Logistic regression analyses showed that TCF21 rs12190287 polymorphism was significantly associated with the reduced risk of breast cancer. Stratified analyses based on pathological type indicated that TCF21 rs12190287 polymorphism was only associated with the reduced risk of infiltrative ductal carcinoma. Real-time quantitative PCR analyses revealed that compared with those carrying rs12190287 CC genotype, subjects with GG genotype had higher expression levels of TCF21 mRNA in normal breast tissues. Furthermore, luciferase activity assay showed that the rs12190287 G allele weakened the binding affinity of hsa-miR-224 to TCF21 3′ UTR. These findings suggest that TCF21 rs12190287 polymorphism can regulate TCF21 expression and may serve as a potential marker for genetic susceptibility to breast cancer.
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Affiliation(s)
- Xueren Gao
- Jiangsu Key Laboratory of Molecule Imaging and Functional Imaging, Key Laboratory of Developmental Genes and Human Disease, Ministry of Education, Department of Microbiology and Immunology, Medical School of Southeast University, Nanjing, Jiangsu, China
| | - Jiaojiao Yang
- Jiangsu Key Laboratory of Molecule Imaging and Functional Imaging, Key Laboratory of Developmental Genes and Human Disease, Ministry of Education, Department of Microbiology and Immunology, Medical School of Southeast University, Nanjing, Jiangsu, China
| | - Mingxi Wang
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
| | - Jianqiong Zhang
- Jiangsu Key Laboratory of Molecule Imaging and Functional Imaging, Key Laboratory of Developmental Genes and Human Disease, Ministry of Education, Department of Microbiology and Immunology, Medical School of Southeast University, Nanjing, Jiangsu, China
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Zhang Z, Chen Q, Zhang J, Wang Y, Hu X, Yin S, He M, Guan S, Qin W, Xiao Q, Zhao H, Yao W, Wu H, Wei M. Associations of genetic polymorphisms in pTEN/AKT/mTOR signaling pathway genes with cancer risk: A meta-analysis in Asian population. Sci Rep 2017; 7:17844. [PMID: 29259266 PMCID: PMC5736732 DOI: 10.1038/s41598-017-17250-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Accepted: 11/23/2017] [Indexed: 12/14/2022] Open
Abstract
The pTEN/AKT/mTOR signaling pathways play a critical role in balancing cell proliferation, differentiation, and survival. Recent studies researched the associations of core genes in the pTEN/AKT/mTOR pathway polymorphisms with the cancer susceptibility; however, the results are inconclusive. Therefore, a systematically meta-analysis was performed to evaluate the association between the five SNPs (mTOR rs2295080 and rs2536, AKT1 rs2494750 and rs2494752, pTEN rs701848) and cancer risk by systematic review of the literature in 31 eligible studies. The results showed a significant decreased risk between rs2295080 TG, GG genotype, and GG/TG genotypes and overall cancer [TG vs.TT: OR(95% CI) = 0.82(0.76, 0.89), GG/TG vs. TT: OR(95% CI) = 0.82(0.76, 0.88), and GG vs. TG/TT: OR(95% CI) = 0.67(0.51, 0.88)] and the subgroup of urinary system cancer and digestive system cancer. Moreover, the SNP rs701848 CC, TC genotype showed significantly increased the overall cancer risk both in dominant model [CC/TC vs. TT: OR(95% CI) = 1.25(1.15, 1.36)] and recessive model [CC vs. TC/TT: OR(95% CI) = 1.20(1.09, 1.32)], and digestive system cancer and urinary system cancer. In addition, AG genotype and GG/AG genotype of rs2494752 was associated with increased risk of cancer. Therefore, this meta-analysis provided genetic risk factors for carcinogenesis and the most valid cancer prevalence estimate for Asian population.
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Affiliation(s)
- Zhen Zhang
- Department of Pharmacology, School of Pharmacy, Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, 110122, P. R. China
| | - Qiuchen Chen
- Department of Pharmacology, School of Pharmacy, Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, 110122, P. R. China
| | - Jing Zhang
- Department of Pharmacology, School of Pharmacy, Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, 110122, P. R. China
| | - Yilin Wang
- Department of Pharmacology, School of Pharmacy, Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, 110122, P. R. China
| | - Xiaoyun Hu
- Department of Pharmacology, School of Pharmacy, Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, 110122, P. R. China
| | - Sainan Yin
- Department of Pharmacology, School of Pharmacy, Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, 110122, P. R. China
| | - Miao He
- Department of Pharmacology, School of Pharmacy, Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, 110122, P. R. China
| | - Shu Guan
- Department of Breast Surgery, First Hospital of China Medical University, Shenyang, 110001, P. R. China
| | - Wenyan Qin
- Department of Pharmacology, School of Pharmacy, Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, 110122, P. R. China
| | - Qinghuan Xiao
- Department of Ion Channel Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, P.R. China
| | - Haishan Zhao
- Department of Pharmacology, School of Pharmacy, Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, 110122, P. R. China
| | - Weifan Yao
- Department of Pharmacology, School of Pharmacy, Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, 110122, P. R. China
| | - Huizhe Wu
- Department of Pharmacology, School of Pharmacy, Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, 110122, P. R. China.
| | - Minjie Wei
- Department of Pharmacology, School of Pharmacy, Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, 110122, P. R. China.
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Song DD, Zhang Q, Li JH, Hao RM, Ma Y, Wang PY, Xie SY. Single nucleotide polymorphisms rs701848 and rs2735343 in PTEN increases cancer risks in an Asian population. Oncotarget 2017; 8:96290-96300. [PMID: 29221206 PMCID: PMC5707100 DOI: 10.18632/oncotarget.22019] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2017] [Accepted: 09/22/2017] [Indexed: 01/19/2023] Open
Abstract
We performed this meta-analysis to analyze the cancer risk to individuals carrying the rs701848 and rs2735343 single nucleotide polymorphisms (SNPs) in the phosphatase and tensin homolog (PTEN) gene. We searched the PubMed, EMBASE, Cochrane library and the national knowledge infrastructure of China (CNKI) databases and identified 18 eligible case-control studies with 5458 cases and 6003 controls for rs701848 as well as 5490 cases and 6209 controls for rs2735343. Our analyses demonstrated that cancer risk was associated with rs701848 in the recessive model (CC vs. CT+TT, OR=1.169, 95% CI: 1.061-1.288) and with rs2735343 in the dominant model (GC+CC vs. GG, OR=0.758, 95% CI: 0.590-0.972). Subgroup analysis showed that in Asian subjects, carrying the C allele of rs701848 or GG genotype of rs2735343 was associated with increased cancer risk. Moreover, Asian subjects carrying the TC/CC genotype or C allele of rs701848 were associated with increased risk of esophageal squamous cell cancer. This meta-analysis indicates that the PTEN rs701848 (CC) and rs2735343 (GG) polymorphisms are associated with increased cancer risk in Asian subjects.
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Affiliation(s)
- Dan-Dan Song
- Key Laboratory of Tumor Molecular Biology in Binzhou Medical University, Department of Biochemistry and Molecular Biology, Binzhou Medical University, Yantai, ShanDong 264003, P.R.China
| | - Qian Zhang
- Key Laboratory of Tumor Molecular Biology in Binzhou Medical University, Department of Biochemistry and Molecular Biology, Binzhou Medical University, Yantai, ShanDong 264003, P.R.China
| | - Jing-Hua Li
- Key Laboratory of Tumor Molecular Biology in Binzhou Medical University, Department of Biochemistry and Molecular Biology, Binzhou Medical University, Yantai, ShanDong 264003, P.R.China
- Department of Epidemiology, Binzhou Medical University, Yantai, ShanDong 264003, P.R.China
| | - Rui-Min Hao
- Key Laboratory of Tumor Molecular Biology in Binzhou Medical University, Department of Biochemistry and Molecular Biology, Binzhou Medical University, Yantai, ShanDong 264003, P.R.China
| | - Ying Ma
- Key Laboratory of Tumor Molecular Biology in Binzhou Medical University, Department of Biochemistry and Molecular Biology, Binzhou Medical University, Yantai, ShanDong 264003, P.R.China
| | - Ping-Yu Wang
- Key Laboratory of Tumor Molecular Biology in Binzhou Medical University, Department of Biochemistry and Molecular Biology, Binzhou Medical University, Yantai, ShanDong 264003, P.R.China
- Department of Epidemiology, Binzhou Medical University, Yantai, ShanDong 264003, P.R.China
| | - Shu-Yang Xie
- Key Laboratory of Tumor Molecular Biology in Binzhou Medical University, Department of Biochemistry and Molecular Biology, Binzhou Medical University, Yantai, ShanDong 264003, P.R.China
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Comprehensive Analysis of Cancer-Proteogenome to Identify Biomarkers for the Early Diagnosis and Prognosis of Cancer. Proteomes 2017; 5:proteomes5040028. [PMID: 29068423 PMCID: PMC5748563 DOI: 10.3390/proteomes5040028] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2017] [Revised: 10/13/2017] [Accepted: 10/17/2017] [Indexed: 02/07/2023] Open
Abstract
During the past century, our understanding of cancer diagnosis and treatment has been based on a monogenic approach, and as a consequence our knowledge of the clinical genetic underpinnings of cancer is incomplete. Since the completion of the human genome in 2003, it has steered us into therapeutic target discovery, enabling us to mine the genome using cutting edge proteogenomics tools. A number of novel and promising cancer targets have emerged from the genome project for diagnostics, therapeutics, and prognostic markers, which are being used to monitor response to cancer treatment. The heterogeneous nature of cancer has hindered progress in understanding the underlying mechanisms that lead to abnormal cellular growth. Since, the start of The Cancer Genome Atlas (TCGA), and the International Genome consortium projects, there has been tremendous progress in genome sequencing and immense numbers of cancer genomes have been completed, and this approach has transformed our understanding of the diagnosis and treatment of different types of cancers. By employing Genomics and proteomics technologies, an immense amount of genomic data is being generated on clinical tumors, which has transformed the cancer landscape and has the potential to transform cancer diagnosis and prognosis. A complete molecular view of the cancer landscape is necessary for understanding the underlying mechanisms of cancer initiation to improve diagnosis and prognosis, which ultimately will lead to personalized treatment. Interestingly, cancer proteome analysis has also allowed us to identify biomarkers to monitor drug and radiation resistance in patients undergoing cancer treatment. Further, TCGA-funded studies have allowed for the genomic and transcriptomic characterization of targeted cancers, this analysis aiding the development of targeted therapies for highly lethal malignancy. High-throughput technologies, such as complete proteome, epigenome, protein-protein interaction, and pharmacogenomics data, are indispensable to glean into the cancer genome and proteome and these approaches have generated multidimensional universal studies of genes and proteins (OMICS) data which has the potential to facilitate precision medicine. However, due to slow progress in computational technologies, the translation of big omics data into their clinical aspects have been slow. In this review, attempts have been made to describe the role of high-throughput genomic and proteomic technologies in identifying a panel of biomarkers which could be used for the early diagnosis and prognosis of cancer.
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Gene polymorphisms in the PI3K/AKT/mTOR signaling pathway contribute to prostate cancer susceptibility in Chinese men. Oncotarget 2017; 8:61305-61317. [PMID: 28977864 PMCID: PMC5617424 DOI: 10.18632/oncotarget.18064] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2017] [Accepted: 04/15/2017] [Indexed: 12/28/2022] Open
Abstract
In this hospital-based case-control study of 413 prostate cancer (PCa) cases and 807 cancer-free controls, we investigated the role of functional single nucleotide polymorphisms (SNPs) of pivotal genes in the PI3K/AKT/mTOR pathway. We genotyped 17 SNPs in mTOR, Raptor, AKT1, AKT2, PTEN, and K-ras and found that 4 were associated with PCa susceptibility. Among the variants, the homozygote variant CC genotype of mTOR rs17036508 C>T were associated with higher PCa risk than the wild TT genotypes (adjusted OR = 3.73 (95% CI = 1.75-7.94), P = 0.001). The GT genotype of mTOR rs2295080 G>T was more protective than the TT genotypes (adjusted OR=0.54 (95% CI=0.32-0.91), P=0.020). The distributions of Raptor rs1468033 A>G genotypes differed between cases and controls, especially in subgroups defined by age, BMI, smoking status, and ethnicity. The CT/CC genotypes of AKT2 rs7250897 C>T were associated with an increased risk of PCa, particularly in subgroups of age >71 and BMI >24 kg/m2. These findings suggest that SNPs in the PI3K/AKT/mTOR pathway may contribute to the risk of PCa in Chinese men.
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Li X, Zhang R, Liu Z, Li S, Xu H. The genetic variants in the PTEN/PI3K/AKT pathway predict susceptibility and CE(A)F chemotherapy response to breast cancer and clinical outcomes. Oncotarget 2017; 8:20252-20265. [PMID: 28423632 PMCID: PMC5386760 DOI: 10.18632/oncotarget.15690] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2016] [Accepted: 01/04/2017] [Indexed: 11/25/2022] Open
Abstract
The PI3K/PTEN/AKT pathway play a critical role in balancing cell growth and death. Epidemiologic studies suggested that mutations of the PI3K/PTEN/AKT pathway genes are associated with cancer risk, yet no data are available for PTEN rs701848, PIK3CA rs2699887, and AKT1 rs2494752 polymorphism and breast cancer(BC) risk. A case-control study was performed in 920 BC patients and 908 healthy controls using the TaqMan assay method. Overall, individuals with PTEN rs701848 TC, CC and TC/CC genotypes showed significant increased BC risk (P=0.043, P=0.002, P=0.008, respectively), and the C allele carriers had a 1.224-fold significantly increased risk of developing BC (P= 0.003). Moreover, a higher frequency of AKT rs2494752 AG genotype was observed among cases (P=0.045). Individuals harboring rs2494752 AG/AA genotype had a vital increased susceptibility to BC in the dominant model (P=0.039). More importantly, AKT1 rs2494752 GG genotype showed significantly rates of response to NCT chemotherapy (P=0.048). Furthermore, AKT1 rs2494752 AG genotype carriers showed significantly shorter DFS time, and GG genotype as the independent prognostic factor (DFS: adjusted HR=1.523, 95% CI=1.012-2.293, P=0.044; OS: adjusted HR=2.321, 95% CI=1.281-4.204, P=0.005). Moreover, MDR analysis consistently revealed that the combination of 3 selected SNPs and 7 known risk factors represented the best model to predicting BC prognosis. The luciferase assay showed that the G allele of rs2494752 significantly increased AKT1 promoter activity. These results suggest that PTEN rs701848 and AKT1 rs2494752 polymorphisms might be a candidate pharmacogenomic factor to assess the susceptibility of BC and response and prognosis prediction for interindividualized CE(A)F chemotherapy in BC patients.
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Affiliation(s)
- Xiang Li
- Department of Breast Cancer, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Insititute, Dadong District, Shenyang City, Liaoning Province, 110042, P.R.China
| | - Ruishan Zhang
- Department of Breast Cancer, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Insititute, Dadong District, Shenyang City, Liaoning Province, 110042, P.R.China
| | - Zhuangkai Liu
- Department of Breast Cancer, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Insititute, Dadong District, Shenyang City, Liaoning Province, 110042, P.R.China
| | - Shuang Li
- Department of Breast Cancer, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Insititute, Dadong District, Shenyang City, Liaoning Province, 110042, P.R.China
| | - Hong Xu
- Department of Breast Cancer, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Insititute, Dadong District, Shenyang City, Liaoning Province, 110042, P.R.China
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Genetic variation in IGF1 predicts renal cell carcinoma susceptibility and prognosis in Chinese population. Sci Rep 2016; 6:39014. [PMID: 27976731 PMCID: PMC5157037 DOI: 10.1038/srep39014] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2016] [Accepted: 11/17/2016] [Indexed: 12/21/2022] Open
Abstract
Insulin-like growth factor 1 (IGF1) and IGF binding protein 3 (IGFBP3) play an important role in the development and progression of renal cell carcinoma (RCC). We evaluated the association of functional polymorphisms in IGF1 and IGFBP3 with susceptibility and prognosis of RCC. We genotyped nine potentially functional polymorphisms in IGF1 and IGFBP3 and assessed their association with risk of RCC in a two-stage case-control study compromising 1027 cases and 1094 controls, and with prognosis in a cohort of 311 patients. We found rs5742714 in the 3'-UTR of IGF1 was significantly associated with risk and prognosis of RCC. In the combined set, the rs5742714 GC/CC genotypes were significantly associated with decreased risk of RCC compared with the GG genotype (OR = 0.82; 95% CI = 0.68-0.98, P = 0.002). Furthermore, patients with the rs5742714 GC/CC genotypes showed improved survival than those with the GG genotype (Log-rank P = 0.025, HR = 0.36, 95% CI = 0.14-0.93). Besides, the rs5742714 GC/CC genotypes were associated with significantly decreased expression of IGF1 mRNA and lower IGF1 serum levels. Moreover, the luciferase reporter assays revealed the potential effect of rs5742714 genotype on the binding of microRNAs to IGF1. Our findings suggest that the IGF1 polymorphism rs5742714 may be a genetic predictor of susceptibility and prognosis of RCC.
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Zining J, Lu X, Caiyun H, Yuan Y. Genetic polymorphisms of mTOR and cancer risk: a systematic review and updated meta-analysis. Oncotarget 2016; 7:57464-57480. [PMID: 27462867 PMCID: PMC5302868 DOI: 10.18632/oncotarget.10805] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Accepted: 06/29/2016] [Indexed: 12/16/2022] Open
Abstract
mTOR regulates several cellular processes that are critical for tumorigenesis. However, previous studies on the association of mTOR polymorphisms with predisposition to different cancer types are somewhat contradictory. Therefore, we performed a systematic review and updated meta-analysis of the available evidence regarding the relationship between mTOR single nucleotide polymorphisms (SNPs) and cancer risk. Up to November 2015, 23 original publications were identified covering 20 mTOR SNPs, of which seven SNPs (rs2536, rs2295080, rs1883965, rs1034528, rs17036508, rs3806317 and rs1064261) were included in the final meta-analysis. We estimated the summary odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for mTOR polymorphisms and cancer risk, and used the model-free approach to investigate the biological effect of each polymorphism. Our meta-analysis found that rs1883965, rs1034528, and rs17036508 were correlated with increased cancer risk in the complete over-dominant model (rs1883965 GA versus GG/AA: fixed-effects OR=1.15, 95% CI 1.02-1.29; rs1034528 GC versus GG/CC: fixed-effects OR=1.30, 95% CI 1.13-1.48; rs17036508 TC versus CC/TT: fixed-effects OR=1.23, 95% CI 1.06-1.43). Stratifying analyses by cancer type, we found that the rs2295080 G allele was associated with a significantly higher risk of acute leukemia in the recessive model (GG versus GT/TT: fixed-effects OR=2.08, 95% CI 1.34-3.22) and a lower risk of genitourinary cancers in the dominant model (TG/GG versus TT: fixed-effects OR=0.77, 95% CI 0.68-0.86). Interestingly, further expression analysis showed that homozygous variant genotype carriers of rs1883965, rs1034528 and rs17036508 had lower mTOR transcript levels, based on HapMap data.
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Affiliation(s)
- Jin Zining
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, Key Laboratory of Cancer Etiology and Prevention of Liaoning Provincial Education Department, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Xu Lu
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, Key Laboratory of Cancer Etiology and Prevention of Liaoning Provincial Education Department, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - He Caiyun
- Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Yuan Yuan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, Key Laboratory of Cancer Etiology and Prevention of Liaoning Provincial Education Department, The First Affiliated Hospital of China Medical University, Shenyang, China
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Granata S, Dalla Gassa A, Carraro A, Brunelli M, Stallone G, Lupo A, Zaza G. Sirolimus and Everolimus Pathway: Reviewing Candidate Genes Influencing Their Intracellular Effects. Int J Mol Sci 2016; 17:ijms17050735. [PMID: 27187382 PMCID: PMC4881557 DOI: 10.3390/ijms17050735] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Revised: 04/21/2016] [Accepted: 05/06/2016] [Indexed: 02/07/2023] Open
Abstract
Sirolimus (SRL) and everolimus (EVR) are mammalian targets of rapamycin inhibitors (mTOR-I) largely employed in renal transplantation and oncology as immunosuppressive/antiproliferative agents. SRL was the first mTOR-I produced by the bacterium Streptomyces hygroscopicus and approved for several medical purposes. EVR, derived from SRL, contains a 2-hydroxy-ethyl chain in the 40th position that makes the drug more hydrophilic than SRL and increases oral bioavailability. Their main mechanism of action is the inhibition of the mTOR complex 1 and the regulation of factors involved in a several crucial cellular functions including: protein synthesis, regulation of angiogenesis, lipid biosynthesis, mitochondrial biogenesis and function, cell cycle, and autophagy. Most of the proteins/enzymes belonging to the aforementioned biological processes are encoded by numerous and tightly regulated genes. However, at the moment, the polygenic influence on SRL/EVR cellular effects is still not completely defined, and its comprehension represents a key challenge for researchers. Therefore, to obtain a complete picture of the cellular network connected to SRL/EVR, we decided to review major evidences available in the literature regarding the genetic influence on mTOR-I biology/pharmacology and to build, for the first time, a useful and specific “SRL/EVR genes-focused pathway”, possibly employable as a starting point for future in-depth research projects.
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Affiliation(s)
- Simona Granata
- Renal Unit, Department of Medicine, University/Hospital of Verona, 37126 Verona, Italy.
| | | | - Amedeo Carraro
- Liver Transplant Unit, Department of General Surgery and Odontoiatrics, University/Hospital of Verona, 37126 Verona, Italy.
| | - Matteo Brunelli
- Department of Pathology and Diagnostics, University of Verona, Azienda Ospedaliera Universitaria Integrata, 37126 Verona, Italy.
| | - Giovanni Stallone
- Nephrology, Dialysis and Transplantation Unit, University of Foggia, 71122 Foggia, Italy.
| | - Antonio Lupo
- Renal Unit, Department of Medicine, University/Hospital of Verona, 37126 Verona, Italy.
| | - Gianluigi Zaza
- Renal Unit, Department of Medicine, University/Hospital of Verona, 37126 Verona, Italy.
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Zhu J, Wang M, He J, Zhu M, Wang JC, Jin L, Wang XF, Yang YJ, Xiang JQ, Wei Q. Polymorphisms in the AKT1 and AKT2 genes and oesophageal squamous cell carcinoma risk in an Eastern Chinese population. J Cell Mol Med 2016; 20:666-677. [PMID: 26828791 PMCID: PMC5126231 DOI: 10.1111/jcmm.12750] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Accepted: 11/02/2015] [Indexed: 02/05/2023] Open
Abstract
Ethnic Han Chinese are at high risk of developing oesophageal squamous cell carcinoma (ESCC). Aberrant activation of the AKT signalling pathway is involved in many cancers, including ESCC. Some single nucleotide polymorphisms (SNPs) in genes involved in this pathway may contribute to ESCC susceptibility. We selected five potentially functional SNPs in AKT1 (rs2494750, rs2494752 and rs10138277) and AKT2 (rs7254617 and rs2304186) genes and investigated their associations with ESCC risk in 1117 ESCC cases and 1096 controls in an Eastern Chinese population. None of individual SNPs exhibited an association with ESCC risk. However, the combined analysis of three AKT1 SNPs suggested that individuals carrying one of AKT1 variant genotypes had a decreased ESCC risk [adjusted odds ratio (OR) = 0.60, 95% CI = 0.42-0.87]. Further stratified analysis found that AKT1 rs2294750 SNP was associated with significantly decreased ESCC risk among women (adjusted OR = 0.63, 95% CI = 0.43-0.94) and non-drinkers (OR = 0.79, 95% CI = 0.64-0.99). Similar protective effects on women (adjusted OR = 0.56, 95% CI = 0.37-0.83) and non-drinker (adjusted OR = 0.75, 95% CI = 0.60-0.94) were also observed for the combined genotypes of AKT1 SNPs. Consistently, logistic regression analysis indicated significant gene-gene interactions among three AKT1 SNPs (P < 0.015). A three-AKT1 SNP haplotype (C-A-C) showed a significant association with a decreased ESCC risk (adjusted OR = 0.70, 95% CI = 0.52-0.94). Multifactor dimensionality reduction analysis confirmed a high-order gene-environment interaction in ESCC risk. Overall, we found that three AKT1 SNPs might confer protection against ESCC risk; nevertheless, these effects may be dependent on other risk factors. Our results provided evidence of important gene-environment interplay in ESCC carcinogenesis.
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Affiliation(s)
- Jinhong Zhu
- Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Molecular Epidemiology Laboratory and Department of Laboratory Medicine, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China
| | - Mengyun Wang
- Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jing He
- Department of Pediatric Surgery, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Meiling Zhu
- Department of Oncology, Xinhua Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai, China
| | - Jiu-Cun Wang
- Ministry of Education Key Laboratory of Contemporary Anthropology, State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
- Fudan-Taizhou Institute of Health Sciences, Taizhou, Jiangsu, China
| | - Li Jin
- Ministry of Education Key Laboratory of Contemporary Anthropology, State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
- Fudan-Taizhou Institute of Health Sciences, Taizhou, Jiangsu, China
| | - Xiao-Feng Wang
- Ministry of Education Key Laboratory of Contemporary Anthropology, State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
- Fudan-Taizhou Institute of Health Sciences, Taizhou, Jiangsu, China
| | - Ya-Jun Yang
- Ministry of Education Key Laboratory of Contemporary Anthropology, State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
- Fudan-Taizhou Institute of Health Sciences, Taizhou, Jiangsu, China
| | - Jia-Qing Xiang
- Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China
| | - Qingyi Wei
- Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China
- Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA
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38
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Pouché L, Stojanova J, Marquet P, Picard N. New challenges and promises in solid organ transplantation pharmacogenetics: the genetic variability of proteins involved in the pharmacodynamics of immunosuppressive drugs. Pharmacogenomics 2016; 17:277-96. [PMID: 26799749 DOI: 10.2217/pgs.15.169] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Interindividual variability in immunosuppressive drug responses might be partly explained by genetic variants in proteins involved in the immune response or associated with IS pharmacodynamics. On a general basis, the pharmacogenetics of drug target proteins is less known and understood than that of proteins involved in drug disposition pathways. The aim of this review is to facilitate research related to the pharmacodynamics of the main immunosuppressive drugs used in solid organ transplantation. We elaborated a quality of evidence grading system based on a literature review and identified 'highly recommended', 'recommended' or 'potential' candidates for further research. It is likely that a number of additional rare variants might further explain drug response phenotypes in transplantation, and particularly the most severe ones. The advent of next-generation sequencing will help to identify those variants.
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Affiliation(s)
- Lucie Pouché
- Inserm, UMR 850, 2 Avenue Martin-Luther King, F-87042 Limoges, France.,CHU Limoges, Department of Pharmacology, Toxicology & Pharmacovigilance, 2 Avenue Martin-Luther King, F-87042 Limoges, France
| | - Jana Stojanova
- Laboratory of Chemical Carcinogenesis & Pharmacogenetics, University of Chile, Santiago, Chile
| | - Pierre Marquet
- Inserm, UMR 850, 2 Avenue Martin-Luther King, F-87042 Limoges, France.,CHU Limoges, Department of Pharmacology, Toxicology & Pharmacovigilance, 2 Avenue Martin-Luther King, F-87042 Limoges, France.,Univ. Limoges, Faculty of Medicine & Pharmacy, 2 rue du Dr Marcland, F-87025 Limoges, France.,FHU SUPORT, 87000 Limoges, France
| | - Nicolas Picard
- Inserm, UMR 850, 2 Avenue Martin-Luther King, F-87042 Limoges, France.,CHU Limoges, Department of Pharmacology, Toxicology & Pharmacovigilance, 2 Avenue Martin-Luther King, F-87042 Limoges, France.,Univ. Limoges, Faculty of Medicine & Pharmacy, 2 rue du Dr Marcland, F-87025 Limoges, France.,FHU SUPORT, 87000 Limoges, France
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Yang Y, Xu W, Liu D, Ding X, Su B, Sun Y, Gao W. PTEN polymorphisms contribute to clinical outcomes of advanced lung adenocarcinoma patients treated with platinum-based chemotherapy. Tumour Biol 2015; 37:7785-96. [PMID: 26695147 DOI: 10.1007/s13277-015-4651-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Accepted: 12/14/2015] [Indexed: 12/22/2022] Open
Abstract
This study aimed to elucidate the impact of PTEN single nucleotide polymorphism (SNP) on clinical outcomes for advanced lung adenocarcinoma (LAC) patients treated with platinum-based chemotherapy. Three functional SNPs (rs11202607 G>A, rs701848 A>G, and rs11202592 G>C) of PTEN gene were genotyped by using DNA from blood samples of 618 advanced LAC patients, and their relationships with clinical outcomes were analyzed. The carriers of homozygous mutant of rs701848 and rs11202592 polymorphisms revealed significantly worse overall survival (OS) than those with heterozygote or wild-type homozygote (18.83 vs. 21.47 vs. 24.37 months, P = 0.034 and 13.40 vs. 19.03 vs. 21.90 months, P = 0.025, respectively). Subgroup analysis revealed that this association was particularly significant in tumor-lymph-node metastasis (TNM) stage III patients. The objective response rates (ORR) and disease control rates (DCR) of patients with genotype AA, AG, and GG in PTEN rs701848 polymorphism were statistically different (24.1 vs 16.6 vs 12.2 %, P = 0.017 and 82.7 vs 76.0 vs 70.2 %, P = 0.029, respectively). Haplotype analysis revealed a protective effect of the haplotype G-A-A (in the order of rs11202592, rs701848, and rs11202607) on chemotherapy efficacy and survival. Taken together, PTEN polymorphisms may contribute to survival and chemotherapy efficacy of advanced LAC patients treated with platinum-based agents.
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Affiliation(s)
- Yang Yang
- Department of Thoracic Surgery, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao-tong University, No. 241, Huaihaixi Road, Shanghai, 200030, China
| | - Wen Xu
- Central Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, No. 507, Zhengmin Road, Shanghai, 200433, China
| | - Di Liu
- Central Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, No. 507, Zhengmin Road, Shanghai, 200433, China
| | - Xi Ding
- Central Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, No. 507, Zhengmin Road, Shanghai, 200433, China
| | - Bo Su
- Central Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, No. 507, Zhengmin Road, Shanghai, 200433, China
| | - Yifeng Sun
- Department of Thoracic Surgery, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao-tong University, No. 241, Huaihaixi Road, Shanghai, 200030, China.
| | - Wen Gao
- Department of Thoracic Surgery, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao-tong University, No. 241, Huaihaixi Road, Shanghai, 200030, China.
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Wang MY, Li QX, He J, Qiu LX, Wang YN, Li J, Sun MH, Wang XF, Yang YJ, Wang JC, Jin L, Wei QY. Genetic variations in the mTOR gene contribute toward gastric adenocarcinoma susceptibility in an Eastern Chinese population. Pharmacogenet Genomics 2015; 25:521-530. [PMID: 26287940 DOI: 10.1097/fpc.0000000000000163] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIM Genetic variants in the mammalian target of rapamycin (mTOR) gene have become an interesting topic for the study of genetic susceptibility to cancer, but their associations with the risk of gastric cancer have not been fully investigated. MATERIALS AND METHODS In a hospital-based case-control study of 1002 gastric cancer patients and 1003 cancer-free controls, we genotyped four potentially functional single nucleotide polymorphisms (SNPs) (rs1034528G>C, rs17036508T>C, rs3806317A>G, and rs2295080T>G) of mTOR and assessed their associations with the risk of gastric cancer using univariate and multivariate logistic regression analyses. We also used the multifactorial dimension reduction analysis to explore possible interactions and the false-positive report probabilities to assess significant findings. RESULTS We found that rs1034528 CG/CC and rs3806317 GA/GG variant genotypes were associated with an increased risk of gastric cancer under a dominant model (adjusted odds ratio=1.27 and 1.22, respectively). In the combined analysis of all four SNPs under investigation, patients with 3-4 risk genotypes of mTOR had a significantly increased risk of gastric cancer (adjusted odds ratio=1.46, 95% confidence interval=1.19-1.79) compared with those with 0-2 risk genotypes. Stratified analysis indicated that this risk was more pronounced in subgroups of men, never-smokers, never-drinkers, and clinical stages III+IV. The multifactorial dimension reduction analysis suggested some evidence of interactions between the combined genotypes and other risk factors for gastric cancer. CONCLUSION These findings suggest that potentially functional SNPs of mTOR may individually or collectively contribute to the risk of gastric cancer. Larger studies with diverse ethnic populations are warranted to validate our findings.
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Affiliation(s)
- Meng-Yun Wang
- aCancer Institute, Collaborative Innovation Center for Cancer Medicine bDepartment of Medical Oncology cDepartment of Abdominal Surgery dDepartment of Pathology, Fudan University Shanghai Cancer Center eDepartment of Oncology, Shanghai Medical College fMinistry of Education Key Laboratory of Contemporary Anthropology, State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai gState Key Laboratory of Oncology in South China, Department of Experimental Research, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangdong hFudan-Taizhou Institute of Health Sciences, Taizhou, Jiangsu, China iDuke Cancer Institute, Duke University Medical Center, Durham, North Carolina, USA
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Lin L, Zhang Z, Zhang W, Wang L, Wang J. Roles of genetic variants in the PI3K/PTEN pathways in susceptibility to colorectal carcinoma and clinical outcomes treated with FOLFOX regimen. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2015; 8:13314-13322. [PMID: 26722535 PMCID: PMC4680480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Accepted: 09/25/2015] [Indexed: 06/05/2023]
Abstract
UNLABELLED The genetic or abnormal activation of PI3K/PTEN signaling pathway play an important role with regard to disease progression in variety of human malignancies. Experimental and epidemiologic studies indicated that the genetic polymorphisms in the PTEN, PI3K genes are associated with cancer risk, yet little evidence exists for those 2 genes and colorectal cancer (CRC) risk. To address this, we evaluated whether PTEN rs701848, PIK3CA rs2699887 variants are associated with CRC susceptibility, clinicopathological parameters and clinical outcomes in CRC patients treated with FOLFOX (Oxaliplatin, Leucovorin, 5-Fluorouracil) regimen. A case-control study was performed in 780 CRC patients and 764 healthy controls using the TaqMan assay method. A significant increased risk of CRC was observed in patients carrying PTEN rs701848 TC or CC genotype (adjusted OR=1.306, 95% CI=1.030-1.655, P=0.027; adjusted OR=1.543, 95% CI=1.148-2.075, P=0.004, respectively), TC/CC genotype (adjusted OR=1.367, 95% CI=1.090-1.714, P=0.043) in the dominant model, and C allele (adjusted OR=1.229, 95% CI=1.067-1.416, P=0.004). However, no association was detected between rs2699887 in the PIK3CA gene and CRC risk. A significant association was found between pathological grade (Dukes A and B vs. Dukes C and D) and PIK3CA rs2699887 genotypes. Furthermore, Kaplan-Meier analysis revealed that PTEN rs701848 genotypes were significantly associated with the overall survival (OS) of CRC patients treated with FOLFOX regimen (n=780). Individuals carrying PTEN rs701848 TC or TC/CC genotypes showed significantly longer median survival time (MST) than TT genotype and significant hazard ratio (TC: adjusted HR=0.523, 95% CI=0.325-0.840, P=0.007; TC/CC adjusted HR=0.545, 95% CI=0.351-0.845, P=0.007). Therefore, rs701848 polymorphism in the PTEN gene is associated with susceptibility to CRC, and C allele of rs701848 showed significant independent better prognosis of CRC patients treated with FOLFOX regimen. These results indicate that rs701848 in the PTEN gene might be a candidate pharmacogenomic factor to assess the susceptibility and prognosis in CRC patients.
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Affiliation(s)
- Lin Lin
- Department of Medical Oncology, Cancer Hospital (Institute), Chinese Academy of Medical Science, Peking Union Medical CollegeBeijing 100021, China
| | - Zhaoxu Zhang
- Department of Abdominal Surgery, Cancer Hospital (Institute), Chinese Academy of Medical Science, Peking Union Medical CollegeBeijing 100021, China
| | - Wen Zhang
- Department of Medical Oncology, Cancer Hospital (Institute), Chinese Academy of Medical Science, Peking Union Medical CollegeBeijing 100021, China
| | - Lin Wang
- Department of Medical Oncology, Cancer Hospital (Institute), Chinese Academy of Medical Science, Peking Union Medical CollegeBeijing 100021, China
| | - Jinwan Wang
- Department of Medical Oncology, Cancer Hospital (Institute), Chinese Academy of Medical Science, Peking Union Medical CollegeBeijing 100021, China
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Piao Y, Li Y, Xu Q, Liu JW, Xing CZ, Xie XD, Yuan Y. Association of MTOR and AKT Gene Polymorphisms with Susceptibility and Survival of Gastric Cancer. PLoS One 2015; 10:e0136447. [PMID: 26317520 PMCID: PMC4552869 DOI: 10.1371/journal.pone.0136447] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2015] [Accepted: 08/03/2015] [Indexed: 12/16/2022] Open
Abstract
Background The phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB, AKT)/mammalian target of rapamycin (mTOR) signaling pathway plays a critical role in angiogenesis and cell growth, proliferation, metabolism, migration, differentiation, and apoptosis. Genetic diversity in key factors of this pathway may influence protein function and signal transduction, contributing to disease initiation and progression. Studies suggest that MTOR rs1064261 and AKT rs1130233 polymorphisms are associated with risk and/or prognosis of multiple cancer types. However, this relationship with gastric cancer (GC) remains unclear. The aim of this study was to investigate the role of MTOR and AKT polymorphisms in the risk and prognosis of GC. Methods The Sequenom MassARRAY platform was used to genotype 1842 individuals for MTOR rs1064261 T→C and AKT rs1130233 G→A polymorphisms. ELISA was used to detect Helicobacter pylori antibodies in serum. Immunohistochemical analysis was used to detect total and phosphorylated MTOR and AKT proteins. Results The MTOR rs1064261 (TC+CC) genotype and the AKT rs1130233 (GA+AA) genotype were associated with increased risk of GC in men (P = 0.049, P = 0.030). In H. pylori-negative individuals, the AKT rs1130233 GA and (GA+AA) genotypes were related to increased risk of atrophic gastritis (AG; P = 0.012, P = 0.024). Notably, the AKT rs1130233 (GA+AA) genotype demonstrated significant interactions with H. pylori in disease progression from healthy controls (CON) to AG (P = 0.013) and from AG to GC (P = 0.049). Additionally, for individuals with the AKT rs1130233 variant, those in the H. pylori-positive group had higher levels of phosphorylated AKT (p-AKT) expression. The AKT rs1130233 genotype was found to be associated with clinicopathological parameters including lymph node metastasis and alcohol drinking (P<0.05). Conclusion MTOR rs1064261and AKT rs1130233 polymorphisms were associated with increased GC risk in males and increased AG risk in H. pylori-negative individuals. A significant interaction existed between the AKT rs1130233 genotype and H. pylori infection in CON→AG→GC disease progression. The AKT rs1130233 genotype influenced p-AKT protein expression in H. pylori-infected individuals.
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Affiliation(s)
- Ying Piao
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang, People’s Republic of China
- Oncology Department, General Hospital of Shenyang Military Region, Shenyang, Liaoning, People’s Republic of China
| | - Ying Li
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang, People’s Republic of China
| | - Qian Xu
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang, People’s Republic of China
| | - Jing-wei Liu
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang, People’s Republic of China
| | - Cheng-zhong Xing
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang, People’s Republic of China
| | - Xiao-dong Xie
- Oncology Department, General Hospital of Shenyang Military Region, Shenyang, Liaoning, People’s Republic of China
| | - Yuan Yuan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang, People’s Republic of China
- * E-mail:
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Zhu J, Wang M, Zhu M, He J, Wang JC, Jin L, Wang XF, Xiang JQ, Wei Q. Associations of PI3KR1 and mTOR polymorphisms with esophageal squamous cell carcinoma risk and gene-environment interactions in Eastern Chinese populations. Sci Rep 2015; 5:8250. [PMID: 25654238 PMCID: PMC4318264 DOI: 10.1038/srep08250] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Accepted: 01/12/2015] [Indexed: 02/07/2023] Open
Abstract
Single nucleotide polymorphisms (SNPs) in the PI3K/PTEN/AKT/mTOR signaling pathway may contribute to carcinogenesis. We genotyped five potentially functional PIK3R1 and mTOR SNPs in 1116 esophageal squamous cell cancer (ESCC) patients and 1117 cancer-free controls to assess their associations with ESCC risk. We observed no association with ESCC risk for any of the selected SNPs. However, the combined analysis of these SNPs revealed that subjects with one-to-three risk genotypes had an increased ESCC risk. Stratified analysis by body mass index (BMI) found that ESCC risk was significantly associated with each of three mTOR SNPs among subjects with BMI < 25.0. Specifically, we found that subjects carrying ≥ 1 risk genotypes had significantly increased ESCC risk, particularly for males, ever-smokers, ever-drinkers, and those with age > 60, or BMI < 25.0. Moreover, three mTOR haplotypes were associated with an increase in ESCC risk. Our meta-analysis of mTOR rs2295080 and cancer risk provided further evidence that mTOR SNPs might modulate cancer susceptibility. In this population, such risk effects might be modified by other risk factors, highlighting the importance of gene-environment interaction in esophageal carcinogenesis. Additional, larger studies are warranted to validate our findings.
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Affiliation(s)
- Jinhong Zhu
- Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Molecular Epidemiology Laboratory and Laboratory Medicine, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China
| | - Mengyun Wang
- Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Meiling Zhu
- Department of Oncology, Xinhua Hospital affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai, China
| | - Jin He
- State Key Laboratory of Oncology in South China, Department of Experimental Research, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
| | - Jiu-Cun Wang
- Ministry of Education Key Laboratory of Contemporary Anthropology, State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
- Fudan-Taizhou Institute of Health Sciences, Taizhou, Jiangsu, China
| | - Li Jin
- Ministry of Education Key Laboratory of Contemporary Anthropology, State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
- Fudan-Taizhou Institute of Health Sciences, Taizhou, Jiangsu, China
| | - Xiao-Feng Wang
- Ministry of Education Key Laboratory of Contemporary Anthropology, State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
- Fudan-Taizhou Institute of Health Sciences, Taizhou, Jiangsu, China
| | - Jia-Qing Xiang
- Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China
| | - Qingyi Wei
- Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China
- Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA
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Xu M, Gao Y, Yu T, Wang J, Cheng L, Cheng L, Cheng D, Zhu B. Functional promoter rs2295080 T>G variant in MTOR gene is associated with risk of colorectal cancer in a Chinese population. Biomed Pharmacother 2015; 70:28-32. [PMID: 25776475 DOI: 10.1016/j.biopha.2014.12.045] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2014] [Accepted: 12/30/2014] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND The mammalian target of rapamycin (mTOR) plays an important role in the development and progression of colorectal cancer (CRC). Recently, a functional polymorphism (rs2295080 T>G) in the promoter of MTOR has been shown to influence its expression and confer susceptibility to cancer. Therefore, in the present study, we sought to investigate the influence of this polymorphism on the risk of CRC. METHODS We genotyped this polymorphism by using the TaqMan method in a case-control study comprising of 737 CRC patients and 777 controls. The logistic regression was used to assess the genetic association with occurrence of CRC. The functionality of the polymorphism was examined by luciferase reporter assay. RESULTS We found the variant genotypes of MTOR rs2295080 (TG/GG) were significantly associated with decreased CRC risk, compared with the wild genotype [TG/GG vs. TT: adjusted odds ratio (OR)=0.76, 95% confidence interval (CI)=0.62-0.94, P=0.011], and the protective effect of this polymorphism was more predominant among the subgroups of elder (OR=0.66, 95% CI=0.49-0.89) and male (OR=0.63, 95% CI=0.48-0.84) subjects. Furthermore, the luciferase reporter assay showed that the rs2295080G allele significantly decreased the luciferase activity in both sw480 and sw620 cell lines (P=0.002 and P<0.001, respectively). CONCLUSIONS Our results suggest that the functional rs2295080 T>G in the promoter of MTOR may influence the susceptibility of CRC in the Chinese population through regulating the transcription activity of MTOR promoter. Large population-based prospective studies are required to validate our findings.
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Affiliation(s)
- Ming Xu
- Department of Pharmaceutics, College of Pharmaceutical Science, Soochow University, Suzhou, China
| | - Yan Gao
- Suzhou Center for Disease Prevention and Control, Suzhou, China
| | - Tingting Yu
- Department of Developmental Genetics, Nanjing Medical University, Nanjing, China
| | - Jirong Wang
- Department of Oncology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Liang Cheng
- Department of Pharmaceutics, College of Pharmaceutical Science, Soochow University, Suzhou, China
| | - Lifang Cheng
- Department of Pharmaceutics, College of Pharmaceutical Science, Soochow University, Suzhou, China
| | - Dawei Cheng
- Department of Pharmaceutics, College of Pharmaceutical Science, Soochow University, Suzhou, China.
| | - Baoli Zhu
- Institute of Occupational Disease Prevention, Jiangsu Provincial Center for Disease Prevention and Control, Nanjing, China.
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Association of mTOR polymorphisms with cancer risk and clinical outcomes: a meta-analysis. PLoS One 2014; 9:e97085. [PMID: 24816861 PMCID: PMC4016248 DOI: 10.1371/journal.pone.0097085] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2014] [Accepted: 04/14/2014] [Indexed: 11/25/2022] Open
Abstract
Genetic polymorphisms in mTOR gene may be associated with cancer risk and clinical outcomes of cancer patients by affecting mTOR gene expression or its activation. However, inconsistent results have been reported. The aim of this study is to systematically evaluate the association between mTOR polymorphisms (rs2295080, rs2536 and rs11121704) and cancer risk as well as clinical outcome by a meta-analysis. We identified 10 eligible studies and extracted data by two investigators. Based on dominant and recessive models, odds ratio (ORs) and 95% confidence intervals (CIs) were calculated by using Stata, version 11 to evaluate the association strength. Our meta-analysis results showed that the wild genotype TT of rs2295080 polymorphism was associated with increased cancer risk under dominant model (OR = 1.24, 95%CI: 1.12–1.36, p<0.0005) in Chinese but not with clinical outcome parameters, while the TT genotype of rs11121704 was associated with poor clinical outcome parameters (OR = 1.53, 95%CI: 1.01–2.32, p = 0.044), such as death, metastasis and resistance to chemotherapy. However, rs2536 may not influence cancer susceptibility. In conclusion, this meta-analysis indicated the common polymorphisms in mTOR gene might be genetic risk factors for the carcinogenesis and clinical outcomes of cancer patients. However, further investigation on large population and different ethnicities are warranted.
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Abstract
Post-translational modifications (PTMs) are known to be essential mechanisms used by eukaryotic cells to diversify their protein functions and dynamically coordinate their signaling networks. Defects in PTMs have been linked to numerous developmental disorders and human diseases, highlighting the importance of PTMs in maintaining normal cellular states. Human pluripotent stem cells (hPSCs), including embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs), are capable of self-renewal and differentiation into a variety of functional somatic cells; these cells hold a great promise for the advancement of biomedical research and clinical therapy. The mechanisms underlying cellular pluripotency in human cells have been extensively explored in the past decade. In addition to the vast amount of knowledge obtained from the genetic and transcriptional research in hPSCs, there is a rapidly growing interest in the stem cell biology field to examine pluripotency at the protein and PTM level. This review addresses recent progress toward understanding the role of PTMs (glycosylation, phosphorylation, acetylation and methylation) in the regulation of cellular pluripotency.
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Li Q, Gu C, Zhu Y, Wang M, Yang Y, Wang J, Jin L, Zhu ML, Shi TY, He J, Zhou X, Ye DW, Wei Q. Polymorphisms in the mTOR gene and risk of sporadic prostate cancer in an Eastern Chinese population. PLoS One 2013; 8:e71968. [PMID: 23940798 PMCID: PMC3734314 DOI: 10.1371/journal.pone.0071968] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2013] [Accepted: 07/10/2013] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The mTOR gene regulates cell growth by controlling mRNA translation, ribosome biogenesis, autophagy, and metabolism. Abnormally increased expression of mTOR was associated with carcinogenesis, and its functional single nucleotide polymorphisms (SNPs) may regulate the expression of mTOR and thus contribute to cancer risk. METHODOLOGY/PRINCIPAL FINDINGS In a hospital-based case-control study of 1004 prostate cancer (PCa) cases and 1051 cancer-free controls, we genotyped six potentially functional SNPs of mTOR (rs2536 T>C, rs1883965 G>A, rs1034528 G>C, rs17036508 T>C, rs3806317 A>G, and rs2295080 T>G) and assessed their associations with risk of PCa by using logistic regression analysis. CONCLUSIONS/SIGNIFICANCES In the single-locus analysis, we found a significantly increased risk of PCa associated with mTOR rs2536 CT/CC and rs1034528 CG/CC genotypes [adjusted OR = 1.42 (1.13-1.78), P = 0.003 and 1.29 (1.07-1.55), P = 0.007), respectively], compared with their common homozygous genotypes, whereas mTOR rs2295080 GT/GG genotypes were associated with a decreased risk of PCa [adjusted OR = 0.76 (0.64-0.92), P = 0.003], compared with wild-type TT genotypes. In the combined analysis of the six SNPs, we found that individuals carrying two or more adverse genotypes had an increased risk of PCa [adjusted OR = 1.24 (1.04-1.47), P = 0.016], compared with individuals carrying less than two adverse genotypes. In the multiple dimension reduction analysis, body mass index (BMI) was the best one-factor model with the highest CVC (100%) and the lowest prediction error (42.7%) among all seven factors. The model including an interaction among BMI, rs17036508, and rs2536 was the best three-factor model with the highest CVC (100%) and the lowest prediction error of 41.9%. These findings suggested that mTOR SNPs may contribute to the risk of PCa in Eastern Chinese men, but the effect was weak and needs further validation by larger population-based studies.
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Affiliation(s)
- Qiaoxin Li
- Cancer Institute, Fudan University Shanghai Cancer Institute, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Chengyuan Gu
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Urology, Fudan University Shanghai Cancer Institute, Shanghai, China
| | - Yao Zhu
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Urology, Fudan University Shanghai Cancer Institute, Shanghai, China
| | - Mengyun Wang
- Cancer Institute, Fudan University Shanghai Cancer Institute, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yajun Yang
- Ministry of Education Key Laboratory of Contemporary Anthropology, State Key Laboratory of Genetic Engineering, School of life Sciences, Fudan University, Shanghai, China
- Fudan-Taizhou Institute of Health Sciences, Taizhou, Jiangsu, China
| | - Jiucun Wang
- Ministry of Education Key Laboratory of Contemporary Anthropology, State Key Laboratory of Genetic Engineering, School of life Sciences, Fudan University, Shanghai, China
- Fudan-Taizhou Institute of Health Sciences, Taizhou, Jiangsu, China
| | - Li Jin
- Ministry of Education Key Laboratory of Contemporary Anthropology, State Key Laboratory of Genetic Engineering, School of life Sciences, Fudan University, Shanghai, China
- Fudan-Taizhou Institute of Health Sciences, Taizhou, Jiangsu, China
| | - Mei-Ling Zhu
- Cancer Institute, Fudan University Shanghai Cancer Institute, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Ting-Yan Shi
- Cancer Institute, Fudan University Shanghai Cancer Institute, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jing He
- Cancer Institute, Fudan University Shanghai Cancer Institute, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xiaoyan Zhou
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Pathology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Ding-wei Ye
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Urology, Fudan University Shanghai Cancer Institute, Shanghai, China
| | - Qingyi Wei
- Cancer Institute, Fudan University Shanghai Cancer Institute, Shanghai, China
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, The United States of America
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Xu M, Tao G, Kang M, Gao Y, Zhu H, Gong W, Wang M, Wu D, Zhang Z, Zhao Q. A polymorphism (rs2295080) in mTOR promoter region and its association with gastric cancer in a Chinese population. PLoS One 2013; 8:e60080. [PMID: 23555892 PMCID: PMC3612103 DOI: 10.1371/journal.pone.0060080] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2012] [Accepted: 02/21/2013] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND As an imperative part of PI3K/Akt/mTOR pathway, mammalian target of rapamycin (mTOR) has been demonstrated to increase in gastric cancer cells and tumors. Our research explored the relationship between single nucleotide polymorphism (SNP) rs2295080 in mTOR promoter region and the risk of gastric cancer (GC). METHODS Seven hundred and fifty-three (753) gastric adenocarcinoma patients and 854 matched healthy subjects were recruited in the cancer association study and 60 tissues were used to test the expression of mTOR. Unconditional logistic regression was selected to evaluate the association between the rs2295080 T>G polymorphism and GC risk. We then examined the functionality of this promoter genetic variant by luciferase assay and EMSA. RESULTS Individuals with G allele had a 23% decreased risk of GC, comparing with those carrying T allele (adjusted OR = 0.77, 95% CI = 0.65-0.92). This protective effect of G allele stood out better in male group. Meanwhile, GC patients carrying TG/GG genotype also displayed a decreased mRNA level of mTOR (P = 0.004). In luciferase assay, T allele tended to enhance the transcriptional activity of mTOR with an approximate 0.5-fold over G allele. Furthermore, EMSA tests explained that different alleles of rs2295080 displayed different affinities to some transcriptional factor. CONCLUSION The mTOR promoter polymorphism rs2295080 was significantly associated with GC risk. This SNP, which effectively influenced the expression of mTOR, may be a new biomarker of early diagnosis of gastric cancer and a suitable indicator of utilizing mTOR inhibitor for treatment of GC.
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Affiliation(s)
- Ming Xu
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing, China
- Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Guoquan Tao
- Department of General Surgery, Huai-An First People’s Hospital Affiliated to Nanjing Medical University, Huai-an, China
| | - Meiyun Kang
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing, China
- Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Yan Gao
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing, China
- Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Haixia Zhu
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing, China
- Core Laboratory of Nantong Tumor Hospital, Nantong, China
| | - Weida Gong
- Department of General Surgery, Yixing Cancer Hospital, Yixing, China
| | - Meilin Wang
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing, China
- Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Dongmei Wu
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing, China
- Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Zhengdong Zhang
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing, China
- Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
- * E-mail: (ZZ); (QZ)
| | - Qinghong Zhao
- Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
- * E-mail: (ZZ); (QZ)
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