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Yang S, Ye Z, Ning J, Wang P, Zhou X, Li W, Cheng F. Cholesterol Metabolism and Urinary System Tumors. Biomedicines 2024; 12:1832. [PMID: 39200296 PMCID: PMC11351655 DOI: 10.3390/biomedicines12081832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 08/06/2024] [Accepted: 08/09/2024] [Indexed: 09/02/2024] Open
Abstract
Cancers of the urinary system account for 13.1% of new cancer cases and 7.9% of cancer-related deaths. Of them, renal cancer, bladder cancer, and prostate cancer are most prevalent and pose a substantial threat to human health and the quality of life. Prostate cancer is the most common malignant tumor in the male urinary system. It is the second most common type of malignant tumor in men, with lung cancer surpassing its incidence and mortality. Bladder cancer has one of the highest incidences and is sex-related, with men reporting a significantly higher incidence than women. Tumor development in the urinary system is associated with factors, such as smoking, obesity, high blood pressure, diet, occupational exposure, and genetics. The treatment strategies primarily involve surgery, radiation therapy, and chemotherapy. Cholesterol metabolism is a crucial physiological process associated with developing and progressing urinary system tumors. High cholesterol levels are closely associated with tumor occurrence, invasion, and metastasis. This warrants thoroughly investigating the role of cholesterol metabolism in urinary system tumors and identifying novel treatment methods for the prevention, early diagnosis, targeted treatment, and drug resistance of urinary system tumors.
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Affiliation(s)
- Songyuan Yang
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan 430060, China; (S.Y.); (Z.Y.); (J.N.); (P.W.); (X.Z.)
| | - Zehua Ye
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan 430060, China; (S.Y.); (Z.Y.); (J.N.); (P.W.); (X.Z.)
| | - Jinzhuo Ning
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan 430060, China; (S.Y.); (Z.Y.); (J.N.); (P.W.); (X.Z.)
| | - Peihan Wang
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan 430060, China; (S.Y.); (Z.Y.); (J.N.); (P.W.); (X.Z.)
| | - Xiangjun Zhou
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan 430060, China; (S.Y.); (Z.Y.); (J.N.); (P.W.); (X.Z.)
| | - Wei Li
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan 430060, China;
| | - Fan Cheng
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan 430060, China; (S.Y.); (Z.Y.); (J.N.); (P.W.); (X.Z.)
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Mwangi GF, Niyonzima N, Atwine R, Tusubira D, Mugyenyi GR, Ssedyabane F. Dyslipidemia: prevalence and association with precancerous and cancerous lesions of the cervix; a pilot study. Lipids Health Dis 2024; 23:3. [PMID: 38184564 PMCID: PMC10770978 DOI: 10.1186/s12944-023-01997-8] [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: 08/03/2023] [Accepted: 12/28/2023] [Indexed: 01/08/2024] Open
Abstract
BACKGROUND In Sub-Saharan Africa, the prevalence of dyslipidemia is on the rise, with studies showing dyslipidemia as a contributing factor to the progression of premalignant lesions to cervical cancer. In Uganda, cervical cancer and dyslipidemia are common health concerns, considering the increasing trends of dyslipidemia in the general population and inadequate information regarding dyslipidemia and cervical lesions. This study aimed to determine the prevalence of dyslipidemia and its association with precancerous and cancerous lesions of the cervix among women attending a cervical cancer clinic at the Uganda Cancer Institute. METHODS This cross-sectional study was conducted from February to April 2022 among women with premalignant and malignant lesions of the cervix. Data on social demographics and health-seeking behaviours were collected using a pretested structured questionnaire after written informed consent had been obtained. Pap smear collection preceded visual inspection with acetic acid; cervical biopsies were collected appropriately from eligible participants; and cervical lesions were classified using the Bethesda system 2014. Serum lipids, total cholesterol (T.C.), high-density lipoprotein (HDLc), low-density lipoprotein (LDLc), and triglycerides (T.G.s) were analysed using the COBAS™ 6000 Clinical Chemistry Analyser. The associations were assessed using the chi-square test, and P ≤ 0.05 was considered statistically significant. RESULTS The overall prevalence of dyslipidemia among women with cervical lesions was 118/159 (74%), and low HDLc was the most prevalent at 64.6% (95% CI 39.0-54.3). High T.C. (P = 0.05), high T.G.s (P = 0.011), and low HDL-c (P = 0.05) showed a significant association with precancerous lesions. High LDL-c (P = 0.019), high T.G.s (P = 0.02), and high T.G.s (P < 0.001) showed a statistically significant association with cancerous lesions. CONCLUSION The prevalence of dyslipidemia was high, with high TC, T.G.s, and low HDL-c significantly associated with precancerous lesions. Also, elevated T.G.s and high LDLc were significantly associated with cancerous lesions. Women may benefit from dyslipidemia screening along with cervical cancer screening. WHAT THIS STUDY ADDS The present study builds upon previous findings suggesting a link between dyslipidemia and cervical lesions by investigating the relationship between these two factors, specifically in women of this geographical location, where we need adequate information on these associations.
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Affiliation(s)
- Gakii Fridah Mwangi
- Department of Medical Laboratory Science, Mbarara University of Science and Technology (MUST), P.O. Box 1410, Mbarara, Uganda.
| | - Nixon Niyonzima
- Uganda Cancer Institute (UCI), P.O. Box 3935, Kampala, Uganda
| | - Raymond Atwine
- Department of Pathology, Mbarara University of Science and Technology (MUST), P.O. Box 1410, Mbarara, Uganda
| | - Deusdedit Tusubira
- Department of Biochemistry, Mbarara University of Science and Technology (MUST), P.O. Box 1410, Mbarara, Uganda
| | - Godfrey R Mugyenyi
- Department of Obstetrics and Gynecology, Mbarara University of Science and Technology (MUST), P.O. Box 1410, Mbarara, Uganda
| | - Frank Ssedyabane
- Department of Medical Laboratory Science, Mbarara University of Science and Technology (MUST), P.O. Box 1410, Mbarara, Uganda
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Kumar R, Chhillar N, Gupta DS, Kaur G, Singhal S, Chauhan T. Cholesterol Homeostasis, Mechanisms of Molecular Pathways, and Cardiac Health: A Current Outlook. Curr Probl Cardiol 2024; 49:102081. [PMID: 37716543 DOI: 10.1016/j.cpcardiol.2023.102081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Accepted: 09/11/2023] [Indexed: 09/18/2023]
Abstract
The metabolism of lipoproteins, which regulate the transit of the lipid to and from tissues, is crucial to maintaining cholesterol homeostasis. Cardiac remodeling is referred to as a set of molecular, cellular, and interstitial changes that, following injury, affect the size, shape, function, mass, and geometry of the heart. Acetyl coenzyme A (acetyl CoA), which can be made from glucose, amino acids, or fatty acids, is the precursor for the synthesis of cholesterol. In this article, the authors explain concepts behind cardiac remodeling, its clinical ramifications, and the pathophysiological roles played by numerous various components, such as cell death, neurohormonal activation, oxidative stress, contractile proteins, energy metabolism, collagen, calcium transport, inflammation, and geometry. The levels of cholesterol are traditionally regulated by 2 biological mechanisms at the transcriptional stage. First, the SREBP transcription factor family regulates the transcription of crucial rate-limiting cholesterogenic and lipogenic proteins, which in turn limits cholesterol production. Immune cells become activated, differentiated, and divided, during an immune response with the objective of eradicating the danger signal. In addition to creating ATP, which is used as energy, this process relies on metabolic reprogramming of both catabolic and anabolic pathways to create metabolites that play a crucial role in regulating the response. Because of changes in signal transduction, malfunction of the sarcoplasmic reticulum and sarcolemma, impairment of calcium handling, increases in cardiac fibrosis, and progressive loss of cardiomyocytes, oxidative stress appears to be the primary mechanism that causes the transition from cardiac hypertrophy to heart failure. De novo cholesterol production, intestinal cholesterol absorption, and biliary cholesterol output are consequently crucial processes in cholesterol homeostasis. In the article's final section, the pharmacological management of cardiac remodeling is explored. The route of treatment is explained in different steps: including, promising, and potential strategies. This chapter offers a brief overview of the history of the study of cholesterol absorption as well as the different potential therapeutic targets.
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Affiliation(s)
| | - Neelam Chhillar
- Deparetment of Biochemistry, School of Medicine, DY Patil University, Navi Mumbai, India
| | - Dhruv Sanjay Gupta
- Department of Pharmacology, SPP School of Pharmacy & Technology Management, SVKM's NMIMS, Mumbai, India
| | - Ginpreet Kaur
- Department of Pharmacology, SPP School of Pharmacy & Technology Management, SVKM's NMIMS, Mumbai, India
| | - Shailey Singhal
- Cluster of Applied Sciences, University of Petroleum and Energy Studies, Dehradun, India
| | - Tanya Chauhan
- Division of Forensic Biology, National Forensic Sciences University, Delhi Campus (LNJN NICFS) Delhi, India
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Chen G, Dai X, Zhang M, Tian Z, Jin X, Mei K, Huang H, Wu Z. Machine learning-based prediction model and visual interpretation for prostate cancer. BMC Urol 2023; 23:164. [PMID: 37838656 PMCID: PMC10576344 DOI: 10.1186/s12894-023-01316-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Accepted: 09/03/2023] [Indexed: 10/16/2023] Open
Abstract
BACKGROUND Most prostate cancers(PCa) rely on serum prostate-specific antigen (PSA) testing for biopsy confirmation, but the accuracy needs to be further improved. We need to continue to develop PCa prediction model with high clinical application value. METHODS Benign prostatic hyperplasia (BPH) and prostate cancer data were obtained from the Chinese National Clinical Medical Science Data Center for retrospective analysis. The model was constructed using the XGBoost algorithm, and patients' age, body mass index (BMI), PSA-related parameters and serum biochemical parameters were used as model variables. Using decision analysis curve (DCA) to evaluate the clinical utility of the models. The shapley additive explanation (SHAP) framework was used to analyze the importance ranking and risk threshold of the variables. RESULTS A total of 1915 patients were included in this study, including 823 (43.0%) were BPH patients and 1092 (57.0%) were PCa patients. The XGBoost model provided better performance (AUC 0.82) compared with f/tPSA (AUC 0.75),tPSA (AUC 0.68) and fPSA (AUC 0.61), respectively. Based on SHAP values, f/tPSA was the most important variable, and the top five most important biochemical parameter variables were inorganic phosphorus (P), potassium (K), creatine kinase MB isoenzyme (CKMB), low-density lipoprotein cholesterol (LDL-C), and creatinine (Cre). PCa risk thresholds for these risk markers were f/tPSA (0.13), P (1.29 mmol/L), K (4.29 mmol/L), CKMB ( 11.6U/L), LDL-C (3.05mmol/L) and Cre (74.5-99.1umol/L). CONCLUSION The present model has advantages of wide-spread availability and high net benefit, especially for underdeveloped countries and regions. Furthermore, these risk thresholds can assist in the diagnosis and screening of prostate cancer in clinical practice.
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Affiliation(s)
- Gang Chen
- School of Public Health and Management, Wenzhou Medical University, Wenzhou, 325035, China
| | - Xuchao Dai
- School of Public Health and Management, Wenzhou Medical University, Wenzhou, 325035, China
| | - Mengqi Zhang
- School of Public Health and Management, Wenzhou Medical University, Wenzhou, 325035, China
| | - Zhujun Tian
- School of Public Health and Management, Wenzhou Medical University, Wenzhou, 325035, China
| | - Xueke Jin
- School of Public Health and Management, Wenzhou Medical University, Wenzhou, 325035, China
| | - Kun Mei
- School of Environmental Science and Engineering, Suzhou University of Science and Technology, Suzhou, 215009, China
| | - Hong Huang
- Center for Health Assessment, Wenzhou Medical University, Wenzhou, 325035, China.
- Zhejiang Provincial Key Laboratory of Watershed Sciences and Health, Wenzhou, 325035, China.
| | - Zhigang Wu
- Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China.
- Reproductive Health Research Center, Health Assessment Center of Wenzhou Medical University, Wenzhou, 325000, China.
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Liu H, Shui IM, Keum N, Shen X, Wu K, Clinton SK, Cao Y, Song M, Zhang X, Platz EA, Giovannucci EL. Plasma total cholesterol concentration and risk of higher-grade prostate cancer: A nested case-control study and a dose-response meta-analysis. Int J Cancer 2023; 153:1337-1346. [PMID: 37306155 PMCID: PMC10527248 DOI: 10.1002/ijc.34621] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 05/18/2023] [Accepted: 05/22/2023] [Indexed: 06/13/2023]
Abstract
Our previous publication found an increased risk of higher-grade (Gleason sum ≥7) prostate cancer for men with high total cholesterol concentration (≥200 mg/dl) in the Health Professionals Follow-up Study (HPFS). With additional 568 prostate cancer cases, we are now able to investigate this association in more detail. For the nested case-control study, we included 1260 men newly diagnosed with prostate cancer between 1993 and 2004, and 1328 controls. For the meta-analyses, 23 articles studied the relationship between total cholesterol level and prostate cancer incidence were included. Logistic regression models and dose-response meta-analysis were performed. An increased risk of higher-grade (Gleason sum ≥4 + 3) prostate cancer for high vs low quartile of total cholesterol level was observed in the HPFS (ORmultivariable = 1.56; 95% CI = 1.01-2.40). This finding was compatible with the association noted in the meta-analysis of highest vs lowest group of total cholesterol level, which suggested a moderately increased risk of higher-grade prostate cancer (Pooled RR =1.21; 95%CI: 1.11-1.32). Moreover, the dose-response meta-analysis indicated that an increased risk of higher-grade prostate cancer occurred primarily at total cholesterol levels ≥200 mg/dl, where the RR was 1.04 (95%CI: 1.01-1.08) per 20 mg/dl increase in total cholesterol level. However, total cholesterol concentration was not associated with the risk of prostate cancer overall either in the HPFS or in the meta-analysis. Our primary finding, as well as the result of the meta-analysis suggested a modest increased risk of higher-grade prostate cancer, at total cholesterol concentrations exceeding 200 mg/dl.
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Affiliation(s)
- Hui Liu
- Central Lab, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310058, China
- Department of Nutrition, Harvard School of Public Health, Boston, MA, 02115, USA
| | | | - NaNa Keum
- Department of Food Science and Biotechnology, Dongguk University, Goyang, 10326, Korea
| | - Xudan Shen
- Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Zhejiang University, Hangzhou, China
| | - Kana Wu
- Department of Nutrition, Harvard School of Public Health, Boston, MA, 02115, USA
| | - Steven K. Clinton
- Division of Public Health Sciences, Division of Medical Oncology, The James Cancer Hospital and The Ohio State University Comprehensive Cancer Center, Columbus, OH, 43210, USA
| | - Yin Cao
- Department of Surgery, Washington University School of Medicine, St Louis, MO, 63110, USA
- Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Mingyang Song
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Xuehong Zhang
- Department of Nutrition, Harvard School of Public Health, Boston, MA, 02115, USA
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, 02115, USA
| | - Elizabeth A. Platz
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, 21205, USA
| | - Edward L. Giovannucci
- Department of Nutrition, Harvard School of Public Health, Boston, MA, 02115, USA
- Department of Epidemiology, Harvard School of Public Health, Boston, MA, 02115, USA
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Cao Z, Yao J, He Y, Lou D, Huang J, Zhang Y, Chen M, Zhou Z, Zhou X. Association Between Statin Exposure and Incidence and Prognosis of Prostate Cancer: A Meta-analysis Based on Observational Studies. Am J Clin Oncol 2023; 46:323-334. [PMID: 37143189 PMCID: PMC10281183 DOI: 10.1097/coc.0000000000001012] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/06/2023]
Abstract
It is widely thought that statins have huge therapeutic potential against prostate cancer (PCA). This study aimed to investigate the effect of statin exposure on PCA incidence and prognosis. PubMed, Web of Science, Embase, and Cochrane databases were searched for observational studies on the association between statin exposure and PCA from inception until July 2022. The primary endpoints were the incidence of PCA and the survival rate. A total of 21 studies were included in this meta-analysis. The pooled estimates showed that exposure to hydrophilic statins was not associated with the incidence of PCA (odds ratio [OR]=0.94, 95% CI=0.88-1.01, P =0.075), while the incidence of PCA was significantly decreased in populations exposed to lipophilic statins compared with the nonexposed group (OR=0.94, 95% CI=0.90-0.98, P =0.001), mainly in Western countries (OR=0.94, 95% CI=0.91-0.98, P =0.006). Subgroup analysis showed that simvastatin (OR=0.83, 95% CI=0.71-0.97, P =0.016) effectively reduced the incidence of PCA. The prognosis of PCA in patients exposed to both hydrophilic (hazard ratio [HR]=0.57, 95% CI=0.49-0.66, P <0.001) and lipophilic (HR=0.65, 95% CI=0.58-0.73, P <0.001) statins were better than in the nonexposed group, and this improvement was more significant in the East than in Western countries. This study demonstrates that statins can reduce the incidence of PCA and improve prognosis, and are affected by population region and statin properties (hydrophilic and lipophilic).
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Affiliation(s)
- Zipei Cao
- Urology Department, Ningbo Urology & Nephrology Hospital
- Urology Department, Ningbo Yinzhou No. 2 Hospital, Ningbo
| | | | | | - Dandi Lou
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou
| | | | | | | | | | - Xiaomei Zhou
- Department of Pharmacy, Hangzhou Women’s Hospital, Hangzhou, Zhejiang, China
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Wang H, Li Y, Huang J, Ma Y, Lyu S, Lang R. Prognostic value of perioperative serum low-density lipoprotein cholesterol level for postoperative prognosis of pancreatic cancer: a retrospective study. Lipids Health Dis 2023; 22:88. [PMID: 37391827 PMCID: PMC10311825 DOI: 10.1186/s12944-023-01851-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Accepted: 06/16/2023] [Indexed: 07/02/2023] Open
Abstract
BACKGROUND As a common malignant tumour, pancreatic cancer (PC) has the worst clinical outcome. Early evaluation of the postoperative prognosis has certain clinical value. Low-density lipoprotein cholesterol (LDL-c), which is mainly composed of cholesteryl esters, phospholipids, and proteins, plays an important role in transporting cholesterol into peripheral tissues. LDL-c has also been reported to be correlated with the occurrence and progression of malignant tumours and can predict postoperative prognosis in various tumours. AIMS To determine correlation between serum LDL-c level and clinical outcome in PC patients after surgery. METHODS Data of PC patients that received surgery at our department from January 2015 to December 2021 were retrospectively analysed. Receiver operating characteristic (ROC) curves between perioperative serum LDL-c at different timepoints and survival rate at postoperative 1-year were drawn, and the optimal cut-off value was calculated. Patients were categorized into low and high LDL-c groups, and their clinical data and outcome were compared. Univariate and multivariate analyses were applied to screen out risk markers for poor prognosis of PC patients after surgery. RESULTS The area under the ROC curve of serum LDL-c at 4 weeks after surgery and prognosis was 0.669 (95% CI: 0.581-0.757), and the optimal cut-off value was 1.515 mmol/L. The median disease-free survival (DFS) rates of low and high LDL-c groups were 9 months and 16 months, respectively, and the 1-, 2- and 3-year DFS rates were 42.6%, 21.1% and 11.7% in low LDL-c group, respectively, and, 60.2%, 35.3% and 26.2% in high LDL-c group, respectively (P = 0.005). The median overall survival (OS) rates of low and high LDL-c groups were 12 months and 22 months, respectively, and the 1-, 2- and 3-year OS rates were 46.8%, 22.6% and 15.8% in low LDL-c group, respectively, and 77.9%, 46.8% and 30.4% in high LDL-c group, respectively (P = 0.004). Multivariate analysis confirmed low postoperative 4-week serum LDL-c as independent risk marker for early tumour recrudesce and poor clinical outcome in PC patients. CONCLUSION High postoperative 4-week serum LDL-c is a prognostic marker for prolonged DFS and OS time in PC patients.
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Affiliation(s)
- Hanxuan Wang
- Hepatobiliary Surgery Department, Beijing Chao-Yang Hospital, Beijing, No. 8 Gongti South Road, Chao-Yang District, 100020, China
| | - Yulin Li
- Hepatobiliary Surgery Department, Beijing Chao-Yang Hospital, Beijing, No. 8 Gongti South Road, Chao-Yang District, 100020, China
| | - Jincan Huang
- Hepatobiliary Surgery Department, Beijing Chao-Yang Hospital, Beijing, No. 8 Gongti South Road, Chao-Yang District, 100020, China
| | - Youwei Ma
- Hepatobiliary Surgery Department, Beijing Chao-Yang Hospital, Beijing, No. 8 Gongti South Road, Chao-Yang District, 100020, China
| | - Shaocheng Lyu
- Hepatobiliary Surgery Department, Beijing Chao-Yang Hospital, Beijing, No. 8 Gongti South Road, Chao-Yang District, 100020, China.
| | - Ren Lang
- Hepatobiliary Surgery Department, Beijing Chao-Yang Hospital, Beijing, No. 8 Gongti South Road, Chao-Yang District, 100020, China.
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Cardoso HJ, Figueira MI, Carvalho TM, Serra CD, Vaz CV, Madureira PA, Socorro S. Androgens and low density lipoprotein-cholesterol interplay in modulating prostate cancer cell fate and metabolism. Pathol Res Pract 2022; 240:154181. [PMID: 36327818 DOI: 10.1016/j.prp.2022.154181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 10/16/2022] [Indexed: 11/15/2022]
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Novel plasma exosome biomarkers for prostate cancer progression in co-morbid metabolic disease. ADVANCES IN CANCER BIOLOGY - METASTASIS 2022; 6:100073. [PMID: 36644690 PMCID: PMC9836031 DOI: 10.1016/j.adcanc.2022.100073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Comorbid Type 2 diabetes (T2D), a metabolic complication of obesity, associates with worse cancer outcomes for prostate, breast, head and neck, colorectal and several other solid tumors. However, the molecular mechanisms remain poorly understood. Emerging evidence shows that exosomes carry miRNAs in blood that encode the metabolic status of originating tissues and deliver their cargo to target tissues to modulate expression of critical genes. Exosomal communication potentially connects abnormal metabolism to cancer progression. Here, we hypothesized that T2D plasma exosomes induce epithelial-mesenchymal transition (EMT) and immune checkpoints in prostate cancer cells. We demonstrate that plasma exosomes from subjects with T2D induce EMT features in prostate cancer cells and upregulate the checkpoint genes CD274 and CD155. We demonstrate that specific exosomal miRNAs that are differentially abundant in plasma of T2D adults compared to nondiabetic controls (miR374a-5p, miR-93-5p and let-7b-3p) are delivered to cancer cells, thereby regulating critical target genes. We build on our previous reports showing BRD4 controls migration and dissemination of castration-resistant prostate cancer, and transcription of key EMT genes, to show that T2D exosomes require BRD4 to drive EMT and immune ligand expression. We validate our findings with gene set enrichment analysis of human prostate tumor tissue in TGCA genomic data. These results suggest novel, non-invasive approaches to evaluate and potentially block progression of prostate and other cancers in patients with comorbid T2D.
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Interleukin-17 Family Cytokines in Metabolic Disorders and Cancer. Genes (Basel) 2022; 13:genes13091643. [PMID: 36140808 PMCID: PMC9498678 DOI: 10.3390/genes13091643] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 09/04/2022] [Accepted: 09/07/2022] [Indexed: 02/07/2023] Open
Abstract
Interleukin-17 (IL-17) family cytokines are potent drivers of inflammatory responses. Although IL-17 was originally identified as a cytokine that induces protective effects against bacterial and fungal infections, IL-17 can also promote chronic inflammation in a number of autoimmune diseases. Research in the last decade has also elucidated critical roles of IL-17 during cancer development and treatment. Intriguingly, IL-17 seems to play a role in the risk of cancers that are associated with metabolic disorders. In this review, we summarize our current knowledge on the biochemical basis of IL-17 signaling, IL-17′s involvement in cancers and metabolic disorders, and postulate how IL-17 family cytokines may serve as a bridge between these two types of diseases.
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Mangu SR, Patel K, Sukhdeo SV, Savitha MR, Sharan K. Maternal high-cholesterol diet negatively programs offspring bone development and downregulates hedgehog signaling in osteoblasts. J Biol Chem 2022; 298:102324. [PMID: 35931113 PMCID: PMC9440389 DOI: 10.1016/j.jbc.2022.102324] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 07/18/2022] [Accepted: 07/19/2022] [Indexed: 11/21/2022] Open
Abstract
Cholesterol is one of the essential intrauterine factors required for fetal growth and development. Maternal high cholesterol levels are known to be detrimental for offspring health. However, its long-term effect on offspring skeletal development remains to be elucidated. We performed our studies in two strains of mice (C57BL6/J and Swiss Albino) and human subjects (65 mother-female newborn dyads) to understand the regulation of offspring skeletal growth by maternal high cholesterol. We found that mice offspring from high-cholesterol-fed dams had low birth weight, smaller body length, and delayed skeletal ossification at the E18.5 embryonic stage. Moreover, we observed that the offspring did not recover from the reduced skeletal mass and exhibited a low bone mass phenotype throughout their life. We attributed this effect to reduced osteoblast cell activity with a concomitant increase in the osteoclast cell population. Our investigation of the molecular mechanism revealed that offspring from high-cholesterol-fed dams had a decrease in the expression of ligands and proteins involved in hedgehog signaling. Further, our cross-sectional study of human subjects showed a significant inverse correlation between maternal blood cholesterol levels and cord blood bone formation markers. Moreover, the bone formation markers were significantly lower in the female newborns of hypercholesterolemic mothers compared with mothers with normal cholesterolemic levels. Together, our results suggest that maternal high cholesterol levels deleteriously program offspring bone mass and bone quality and downregulate the hedgehog signaling pathway in their osteoblasts.
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Affiliation(s)
- Svvs Ravi Mangu
- Department of Molecular Nutrition, CSIR-Central Food Technological Research Institute, Mysuru, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Kalpana Patel
- Department of Molecular Nutrition, CSIR-Central Food Technological Research Institute, Mysuru, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Shinde Vijay Sukhdeo
- Department of Meat and Marine Sciences, CSIR-Central Food Technological Research Institute, Mysuru, India
| | - M R Savitha
- Department of Paediatrics, Mysore Medical College and Research Institute, Mysuru, India
| | - Kunal Sharan
- Department of Molecular Nutrition, CSIR-Central Food Technological Research Institute, Mysuru, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.
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Abdalkareem Jasim S, Kzar HH, Haider Hamad M, Ahmad I, Al-Gazally ME, Ziyadullaev S, Sivaraman R, Abed Jawad M, Thaeer Hammid A, Oudaha KH, Karampoor S, Mirzaei R. The emerging role of 27-hydroxycholesterol in cancer development and progression: An update. Int Immunopharmacol 2022; 110:109074. [PMID: 35978522 DOI: 10.1016/j.intimp.2022.109074] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 07/09/2022] [Accepted: 07/17/2022] [Indexed: 02/07/2023]
Abstract
Oxysterols are cholesterol metabolites generated in the liver and other peripheral tissues as a mechanism of removing excess cholesterol. Oxysterols have a wide range of biological functions, including the regulation of sphingolipid metabolism, platelet aggregation, and apoptosis. However, it has been found that metabolites derived from cholesterol play essential functions in cancer development and immunological suppression. In this regard, research indicates that 27-hydroxycholesterol (27-HC) might act as an estrogen, promoting the growth of estrogen receptor (ER) positive breast cancer cells. The capacity of cholesterol to dynamically modulate signaling molecules inside the membrane and particular metabolites serving as signaling molecules are two possible contributory processes. 27-HC is a significant metabolite produced mainly through the CYP27A1 (Cytochrome P450 27A1) enzyme. 27-HC maintains cholesterol balance biologically by promoting cholesterol efflux via the liver X receptor (LXR) and suppressing de novo cholesterol production through the Insulin-induced Genes (INSIGs). It has been demonstrated that 27-HC is able to function as a selective ER regulator. Moreover, enhanced 27-HC production is in favor of the growth of end-stage malignancies in the brain, thyroid organs, and colon, as shown in breast cancer, probably due to pro-survival and pro-inflammatory signaling induced by unbalanced levels of oxysterols. However, the actual role of 27-HC in cancer promotion and progression remains debatable, and many studies are warranted to be performed to unravel the precise function of these molecules. This review article will summarize the latest evidence on the deleterious or beneficial functions of 27-HC in various types of cancer, such as breast cancer, prostate cancer, colon cancer, gastric cancer, ovarian cancer, endometrial cancer, lung cancer, melanoma, glioblastoma, thyroid cancer, adrenocortical cancer, and hepatocellular carcinoma.
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Affiliation(s)
- Saade Abdalkareem Jasim
- Medical Laboratory Techniques Department, Al-maarif University College, Al-anbar-Ramadi, Iraq
| | - Hamzah H Kzar
- Veterinary medicine college, Al-Qasim green University, Al-Qasim, Iraq
| | - Mohammed Haider Hamad
- Medical Laboratory Techniques Department, Al Mustaqbal University college, Babylon, Iraq
| | - Irfan Ahmad
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | | | - Shukhrat Ziyadullaev
- Professor, Doctor of Medical Sciences, No.1 Department of Internal Diseases, Vice-rector for Scientific Affairs and Innovations, Samarkand State Medical University, Amir Temur Street 18, Samarkand, Uzbekistan
| | - R Sivaraman
- Department of Mathematics, Institution of Dwaraka Doss Goverdhan Doss Vaishnav College, Arumbakkam, Chennai, University of Madras, Chennai, India
| | | | - Ali Thaeer Hammid
- Computer Engineering Techniques Department, Faculty of Information Technology, Imam Ja'afar Al-Sadiq University, Baghdad, Iraq
| | - Khulood H Oudaha
- Pharmaceutical Chemistry Department, College of Pharmacy, Al-Ayen University Thi-Qar, Iraq
| | - Sajad Karampoor
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran.
| | - Rasoul Mirzaei
- Venom and Biotherapeutics Molecules Lab, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.
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13
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Ma Y, Jian Z, Xiang L, Jin X. Higher genetically predicted low-density lipoprotein levels increase the renal cancer risk independent of triglycerides and high-density lipoprotein levels: A Mendelian randomization study. Int J Cancer 2022; 151:518-525. [PMID: 35429337 DOI: 10.1002/ijc.34032] [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: 09/21/2021] [Revised: 03/14/2022] [Accepted: 04/06/2022] [Indexed: 02/05/2023]
Abstract
The causation between lipids and renal cancer remains inconclusive. Our purpose is to explore the causal relationships between the three primary lipid metabolism-related substances, namely triglycerides (TG), low-density lipoprotein (LDL) and high-density lipoprotein (HDL) with the risk of renal cancer using Mendelian randomization (MR) methods. Genetic instruments for lipids were acquired from the UK Biobank. Outcome data were from the FinnGen study (1397 renal cancer cases and 204 070). Single-variable MR (SVMR) and multi-variable MR (MVMR) analyses were conducted with TwoSampleMR package based on R 4.0.3. The random-effect inverse-variance weighted (IVW), MR-Egger, weighted-median method, and weighted mode were the four main computing methods. We found that per 1 SD elevated LDL level was causally associated with renal cancer occurrence based on SVMR (OR, 1.31, 95% CI: 1.05-1.64, P = .016). Similar significant associations were found in other methods. However, the results of SVMR did not support significant associations between TG, and HDL with renal cancer risk in all methods. The association between LDL and renal cancer was still significant in MVMR analysis (OR for IVW method: 1.22 per 1 SD higher trait (SD, 95% CI: 1.11-1.34, P < .001; OR for MR-Egger: 1.22 per 1 SD higher trait, 95% CI: 1.01-1.47, P = .042) when taking TG and HDL into consideration. Our study supported that elevated serum LDL levels is causally associated with an increased risk of renal cancer independent of TG and HDL.
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Affiliation(s)
- Yucheng Ma
- Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Zhongyu Jian
- Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Liyuan Xiang
- Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xi Jin
- Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, Sichuan, China
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14
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Deng CF, Zhu N, Zhao TJ, Li HF, Gu J, Liao DF, Qin L. Involvement of LDL and ox-LDL in Cancer Development and Its Therapeutical Potential. Front Oncol 2022; 12:803473. [PMID: 35251975 PMCID: PMC8889620 DOI: 10.3389/fonc.2022.803473] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 01/12/2022] [Indexed: 01/17/2023] Open
Abstract
Lipid metabolism disorder is related to an increased risk of tumorigenesis and is involved in the rapid growth of cancer cells as well as the formation of metastatic lesions. Epidemiological studies have demonstrated that low-density lipoprotein (LDL) and oxidized low-density lipoprotein (ox-LDL) are closely associated with breast cancer, colorectal cancer, pancreatic cancer, and other malignancies, suggesting that LDL and ox-LDL play important roles during the occurrence and development of cancers. LDL can deliver cholesterol into cancer cells after binding to LDL receptor (LDLR). Activation of PI3K/Akt/mTOR signaling pathway induces transcription of the sterol regulatory element-binding proteins (SREBPs), which subsequently promotes cholesterol uptake and synthesis to meet the demand of cancer cells. Ox-LDL binds to the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and cluster of differentiation 36 (CD36) to induce mutations, resulting in inflammation, cell proliferation, and metastasis of cancer. Classic lipid-lowering drugs, statins, have been shown to reduce LDL levels in certain types of cancer. As LDL and ox-LDL play complicated roles in cancers, the potential therapeutic effect of targeting lipid metabolism in cancer therapy warrants more investigation.
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Affiliation(s)
- Chang-Feng Deng
- Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
| | - Neng Zhu
- Department of Urology, The First Hospital of Hunan University of Chinese Medicine, Changsha, China
| | - Tan-Jun Zhao
- Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
| | - Hong-Fang Li
- Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
| | - Jia Gu
- Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
| | - Duan-Fang Liao
- Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
| | - Li Qin
- Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
- Institutional Key Laboratory of Vascular Biology and Translational Medicine in Hunan Province, Hunan University of Chinese Medicine, Changsha, China
- *Correspondence: Li Qin,
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15
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Patel KK, Kashfi K. Lipoproteins and cancer: The role of HDL-C, LDL-C, and cholesterol-lowering drugs. Biochem Pharmacol 2022; 196:114654. [PMID: 34129857 PMCID: PMC8665945 DOI: 10.1016/j.bcp.2021.114654] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 06/09/2021] [Accepted: 06/10/2021] [Indexed: 02/03/2023]
Abstract
Cholesterol is an amphipathic sterol molecule that is vital for maintaining normal physiological homeostasis. It is a relatively complicated molecule with 27 carbons whose synthesis starts with 2-carbon units. This in itself signifies the importance of this molecule. Cholesterol serves as a precursor for vitamin D, bile acids, and hormones, including estrogens, androgens, progestogens, and corticosteroids. Although essential, high cholesterol levels are associated with cardiovascular and kidney diseases and cancer initiation, progression, and metastasis. Although there are some contrary reports, current literature suggests a positive association between serum cholesterol levels and the risk and extent of cancer development. In this review, we first present a brief overview of cholesterol biosynthesis and its transport, then elucidate the role of cholesterol in the progression of some cancers. Suggested mechanisms for cholesterol-mediated cancer progression are plentiful and include the activation of oncogenic signaling pathways and the induction of oxidative stress, among others. The specific roles of the lipoprotein molecules, high-density lipoprotein (HDL) and low-density lipoprotein (LDL), in this pathogenesis, are also reviewed. Finally, we hone on the potential role of some cholesterol-lowering medications in cancer.
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Affiliation(s)
- Kush K Patel
- Department of Molecular, Cellular, and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY, USA
| | - Khosrow Kashfi
- Department of Molecular, Cellular, and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY, USA; Graduate Program in Biology, City University of New York Graduate Center, NY, USA.
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16
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Raftopulos NL, Washaya TC, Niederprüm A, Egert A, Hakeem-Sanni MF, Varney B, Aishah A, Georgieva ML, Olsson E, Dos Santos DZ, Nassar ZD, Cochran BJ, Nagarajan SR, Kakani MS, Hastings JF, Croucher DR, Rye KA, Butler LM, Grewal T, Hoy AJ. Prostate cancer cell proliferation is influenced by LDL-cholesterol availability and cholesteryl ester turnover. Cancer Metab 2022; 10:1. [PMID: 35033184 PMCID: PMC8760736 DOI: 10.1186/s40170-021-00278-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 11/24/2021] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Prostate cancer growth is driven by androgen receptor signaling, and advanced disease is initially treatable by depleting circulating androgens. However, prostate cancer cells inevitably adapt, resulting in disease relapse with incurable castrate-resistant prostate cancer. Androgen deprivation therapy has many side effects, including hypercholesterolemia, and more aggressive and castrate-resistant prostate cancers typically feature cellular accumulation of cholesterol stored in the form of cholesteryl esters. As cholesterol is a key substrate for de novo steroidogenesis in prostate cells, this study hypothesized that castrate-resistant/advanced prostate cancer cell growth is influenced by the availability of extracellular, low-density lipoprotein (LDL)-derived, cholesterol, which is coupled to intracellular cholesteryl ester homeostasis. METHODS C4-2B and PC3 prostate cancer cells were cultured in media supplemented with fetal calf serum (FCS), charcoal-stripped FCS (CS-FCS), lipoprotein-deficient FCS (LPDS), or charcoal-stripped LPDS (CS-LPDS) and analyzed by a variety of biochemical techniques. Cell viability and proliferation were measured by MTT assay and Incucyte, respectively. RESULTS Reducing lipoprotein availability led to a reduction in cholesteryl ester levels and cell growth in C4-2B and PC3 cells, with concomitant reductions in PI3K/mTOR and p38MAPK signaling. This reduced growth in LPDS-containing media was fully recovered by supplementation of exogenous low-density lipoprotein (LDL), but LDL only partially rescued growth of cells cultured with CS-LPDS. This growth pattern was not associated with changes in androgen receptor signaling but rather increased p38MAPK and MEK1/ERK/MSK1 activation. The ability of LDL supplementation to rescue cell growth required cholesterol esterification as well as cholesteryl ester hydrolysis activity. Further, growth of cells cultured in low androgen levels (CS-FCS) was suppressed when cholesteryl ester hydrolysis was inhibited. CONCLUSIONS Overall, these studies demonstrate that androgen-independent prostate cancer cell growth can be influenced by extracellular lipid levels and LDL-cholesterol availability and that uptake of extracellular cholesterol, through endocytosis of LDL-derived cholesterol and subsequent delivery and storage in the lipid droplet as cholesteryl esters, is required to support prostate cancer cell growth. This provides new insights into the relationship between extracellular cholesterol, intracellular cholesterol metabolism, and prostate cancer cell growth and the potential mechanisms linking hypercholesterolemia and more aggressive prostate cancer.
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Affiliation(s)
- Nikki L Raftopulos
- School of Medical Sciences, Charles Perkins Centre, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Tinashe C Washaya
- School of Medical Sciences, Charles Perkins Centre, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Andreas Niederprüm
- School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.,Faculty of Medicine, Ruprecht Karl University of Heidelberg, Baden-Wuerttemberg, Heidelberg, Germany
| | - Antonia Egert
- School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Mariam F Hakeem-Sanni
- School of Medical Sciences, Charles Perkins Centre, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Bianca Varney
- School of Medical Sciences, Charles Perkins Centre, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Atqiya Aishah
- School of Medical Sciences, Charles Perkins Centre, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Mariya L Georgieva
- School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Ellinor Olsson
- School of Medical Sciences, Charles Perkins Centre, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Diandra Z Dos Santos
- School of Medical Sciences, Charles Perkins Centre, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.,Biotechnology Program/RENORBIO, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Brazil
| | - Zeyad D Nassar
- Adelaide Medical School and Freemasons Centre for Male Health and Wellbeing, University of Adelaide, Adelaide, South Australia, Australia.,South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
| | - Blake J Cochran
- School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
| | - Shilpa R Nagarajan
- School of Medical Sciences, Charles Perkins Centre, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Meghna S Kakani
- School of Medical Sciences, Charles Perkins Centre, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Jordan F Hastings
- The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales, Australia
| | - David R Croucher
- The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.,St Vincent's Hospital Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
| | - Kerry-Anne Rye
- School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
| | - Lisa M Butler
- Adelaide Medical School and Freemasons Centre for Male Health and Wellbeing, University of Adelaide, Adelaide, South Australia, Australia.,South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
| | - Thomas Grewal
- School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Andrew J Hoy
- School of Medical Sciences, Charles Perkins Centre, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.
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17
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Karahan I, Arslan F, Yalçin S. The prediction of lung cancer prognosis with blood lipid levels and ratios at the time of diagnosis. BIOMEDICAL AND BIOTECHNOLOGY RESEARCH JOURNAL (BBRJ) 2022. [DOI: 10.4103/bbrj.bbrj_311_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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18
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Yang L, Sun J, Li M, Long Y, Zhang D, Guo H, Huang R, Yan J. Oxidized low-density lipoprotein links hypercholesterolemia and bladder cancer aggressiveness by promoting cancer stemness. Cancer Res 2021; 81:5720-5732. [PMID: 34479964 DOI: 10.1158/0008-5472.can-21-0646] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 07/20/2021] [Accepted: 09/02/2021] [Indexed: 01/17/2023]
Abstract
Hypercholesterolemia is a prevalent metabolic disorder that has been implicated in the development of steroid-targeted cancers. However, the link between hypercholesterolemia and urinary bladder cancer (UBC), a non-steroid-targeted cancer, remains unresolved. Here we show that diet- and Ldlr deficiency-induced hypercholesterolemia enhances both UBC stemness and progression. Inhibition of intestinal cholesterol absorption by Ezetimibe reversed diet-induced hypercholesterolemia and cancer stemness. As a key component in hypercholesterolemic sera, oxidized low-density lipoprotein (ox-LDL), but not native low-density lipoprotein-cholesterol or metabolite 27-hydroxycholesterol, increased cancer stemness through its receptor CD36. Depletion of CD36, ectopic expression of an ox-LDL binding-disabled mutant form of CD36(K164A), and the neutralization of ox-LDL and CD36 via neutralizing antibodies all reversed ox-LDL-induced cancer stemness. Mechanistically, ox-LDL enhanced the interaction of CD36 and JAK2, inducing phosphorylation of JAK2 and subsequently activating STAT3 signaling, which was not mediated by JAK1 or Src in UBC cells. Finally, ox-LDL levels in serum predicted poor prognosis, and the ox-LDLhigh signature predicted worse survival in UBC patients. These findings indicate that ox-LDL links hypercholesterolemia with UBC progression by enhancing cancer stemness. Lowering serum ox-LDL or targeting the CD36/JAK2/STAT3 axis might serve as a potential therapeutic strategy for UBCs with hypercholesterolemia. Moreover, elevated ox-LDL may serve as a biomarker for UBC.
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Affiliation(s)
- Lin Yang
- Department of Urology, Drum Tower Hospital, Medical School of Nanjing University, Institute of Urology, Nanjing University
| | - Jingya Sun
- Pharmacology, Shanghai Institute of Materia Medica
| | - Meiqian Li
- MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University
| | - Yiming Long
- Molecular Imaging Research Center, Shanghai Institute of Materia Medica
| | - Dianzheng Zhang
- Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine
| | - Hongqian Guo
- Department of Urology, Drum Tower Hospital, Medical School of Nanjing University, Institute of Urology, Nanjing University
| | - Ruimin Huang
- Molecular Imaging Research Center, Shanghai Institute of Materia Medica
| | - Jun Yan
- Department of Laboratory Animal Science, Fudan University
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19
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Wang Q, Wang J, Wang J, Zhang H. Molecular mechanism of liver X receptors in cancer therapeutics. Life Sci 2021; 273:119287. [PMID: 33667512 DOI: 10.1016/j.lfs.2021.119287] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 02/16/2021] [Accepted: 02/23/2021] [Indexed: 02/08/2023]
Abstract
Liver X receptors (LXRs) are receptors that belong to the nuclear receptor superfamily (NRs). It was originally called the "orphan receptor" when it was firstly discovered. Then it was found to be activated by oxysterol and it was officially named LXRs. LXRs are activated by ligands and bind to the retinol X receptor to form a heterodimer and regulate metabolism. Numerous studies have shown that LXRs are involved in regulating immune function and maintaining immune tolerance. Activating LXRs can also inhibit the tumorigenesis and promote apoptosis of tumor cells, which make LXRs as potential targets in cancer treatment. This review will discuss the recent progress of LXRs from the structure and function of LXRs, the signaling pathway of LXRs, the molecular mechanism of LXRs activation in cancers, and the potential targets of LXRs in cancer therapy.
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Affiliation(s)
- Qiang Wang
- Institute of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Jing Wang
- Institute of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Jiayou Wang
- Institute of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Heng Zhang
- Department of General Surgery, Nanjing Lishui District People's Hospital, Zhongda Hospital Lishui Branch, Southeast University, Nanjing, China.
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20
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Guo H, Jia X, Liu H. Based on biomedical index data: Risk prediction model for prostate cancer. Medicine (Baltimore) 2021; 100:e25602. [PMID: 33907111 PMCID: PMC8084031 DOI: 10.1097/md.0000000000025602] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 02/12/2021] [Accepted: 04/02/2021] [Indexed: 11/30/2022] Open
Abstract
ABSTRACT To explore the influencing factors of prostate cancer occurrence, set up risk prediction model, require reference for the preliminary diagnosis of clinical doctors, this model searched database through the data of prostate cancer patients and prostate hyperplasia patients National Clinical Medical Science Data Center.With the help of Stata SE 12.0 and SPSS 25.0 software, the biases between groups were balanced by propensity score matching. Based on the matched data, the relevant factors were further screened by stepwise logistic regression analysis, the key variable and artificial neural network model are established. The prediction accuracy of the model is evaluated by combining the probability of test set with the area under receiver operating characteristic curve (ROC).After 1:2 PSM, 339 pairs were matched successfully. There are 159 cases in testing groups and 407 cases in training groups. And the regression model was P = 1 / (1 + e (0.122 ∗ age + 0.083 ∗ Apo lipoprotein C3 + 0.371 ∗ total prostate specific antigen (tPSA) -0.227 ∗ Apo lipoprotein C2-6.093 ∗ free calcium (iCa) + 0.428 ∗ Apo lipoprotein E-1.246 ∗ triglyceride-1.919 ∗ HDL cholesterol + 0.083 ∗ creatine kinase isoenzyme [CKMB])). The logistic regression model performed very well (ROC, 0.963; 95% confidence interval, 0.951 to 0.978) and artificial neural network model (ROC, 0.983; 95% confidence interval, 0.964 to 0.997). High degree of Apo lipoprotein E (Apo E) (Odds Ratio, [OR], 1.535) in blood test is a risk factor and high triglyceride (TG) (OR, 0.288) is a protective factor.It takes the biochemical examination of the case as variables to establish a risk prediction model, which can initially reflect the risk of prostate cancer and bring some references for diagnosis and treatment.
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Affiliation(s)
- Hanxu Guo
- School of Clinical Medicine, Bengbu Medical College
| | - Xianjie Jia
- Department of Epidemiology and Health Statistics, School of Public Health, Bengbu Medical College
| | - Hao Liu
- Department of Pharmacy, Bengbu Medical College, Anhui Biochemical Drug Engineering Technology Research Center, Bengbu, China
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21
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Cardoso HJ, Carvalho TMA, Fonseca LRS, Figueira MI, Vaz CV, Socorro S. Revisiting prostate cancer metabolism: From metabolites to disease and therapy. Med Res Rev 2020; 41:1499-1538. [PMID: 33274768 DOI: 10.1002/med.21766] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 10/24/2020] [Accepted: 11/22/2020] [Indexed: 12/24/2022]
Abstract
Prostate cancer (PCa), one of the most commonly diagnosed cancers worldwide, still presents important unmet clinical needs concerning treatment. In the last years, the metabolic reprogramming and the specificities of tumor cells emerged as an exciting field for cancer therapy. The unique features of PCa cells metabolism, and the activation of specific metabolic pathways, propelled the use of metabolic inhibitors for treatment. The present work revises the knowledge of PCa metabolism and the metabolic alterations that underlie the development and progression of the disease. A focus is given to the role of bioenergetic sources, namely, glucose, lipids, and glutamine sustaining PCa cell survival and growth. Moreover, it is described as the action of oncogenes/tumor suppressors and sex steroid hormones in the metabolic reprogramming of PCa. Finally, the status of PCa treatment based on the inhibition of metabolic pathways is presented. Globally, this review updates the landscape of PCa metabolism, highlighting the critical metabolic alterations that could have a clinical and therapeutic interest.
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Affiliation(s)
- Henrique J Cardoso
- CICS-UBI-Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal
| | - Tiago M A Carvalho
- CICS-UBI-Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal
| | - Lara R S Fonseca
- CICS-UBI-Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal
| | - Marília I Figueira
- CICS-UBI-Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal
| | - Cátia V Vaz
- CICS-UBI-Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal
| | - Sílvia Socorro
- CICS-UBI-Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal
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22
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Asghari A, Umetani M. Obesity and Cancer: 27-Hydroxycholesterol, the Missing Link. Int J Mol Sci 2020; 21:E4822. [PMID: 32650428 PMCID: PMC7404106 DOI: 10.3390/ijms21144822] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Revised: 07/02/2020] [Accepted: 07/06/2020] [Indexed: 02/07/2023] Open
Abstract
Obesity is currently affecting more than 40% of the Americans, and if it progresses with this rate, soon one out of two Americans will be obese. Obesity is an important risk factor for several disorders including cardiovascular disease, the first cause of death in the United States. Cancer follows as the second deadliest disease, and a link between obesity and cancer has been suggested. However, it is very hard to establish an exact connection between obesity and cancers due to the multifactorial nature of obesity. Hypercholesterolemia is a comorbidity of obesity and also linked to several cancers. Recently a cholesterol metabolite 27-hydroxycholesterol (27HC) was found to be an endogenous selective estrogen receptor modulator (SERM), which opened new doors toward several interesting studies on the role of this molecule in biological disorders. It is speculated that 27HC might be the missing link in the obesity and cancer chain. Here, we explored the effects of 27-hydroxycholesterol on obesity and cancers with a focus on the SERM capacity of 27HC.
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Affiliation(s)
- Arvand Asghari
- Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77204-5056, USA;
| | - Michihisa Umetani
- Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77204-5056, USA;
- HEALTH Research Institute, University of Houston, Houston, TX 77204-5056, USA
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Hryniewicz-Jankowska A, Augoff K, Sikorski AF. The role of cholesterol and cholesterol-driven membrane raft domains in prostate cancer. Exp Biol Med (Maywood) 2020; 244:1053-1061. [PMID: 31573840 DOI: 10.1177/1535370219870771] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Membrane rafts are heterogeneous and dynamic domains that are characterized by tight packing of lipids. They are enriched in cholesterol, sphingolipids, and certain types of proteins. Among these are various cell signaling proteins, which indicate that rafts play an important role in cell signal transduction pathways, including some involved in cancer development, progression, and invasiveness. Due to their increased cholesterol content, raft domains exhibit lower fluidity than the surrounding membrane. The cell membranes of some solid tumors, such as breast and prostate cancer, contain higher levels of cholesterol, which means larger raft domain can form in those membranes. This may stimulate signaling pathways to promote tumor growth and progression. This review focuses on the known raft-dependent regulatory mechanisms that promote prostate cancer progression.Impact statementProstate cancer remains the most common malignancy and second most frequent cause of cancer-related death in men. Cholesterol levels are usually higher in prostate cancer cells. This affects the cell membrane composition, with cholesterol and sphingolipid-containing raft membrane domains becoming a greater component. In addition to polar lipids, these domains recruit and regulate certain types of protein, including various cell signaling proteins that are critical to cancer cell survival and invasiveness. This suggests that membrane rafts have a regulatory role in tumor progression, making them a potential target in prostate cancer treatment.
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Affiliation(s)
| | - Katarzyna Augoff
- Department of Surgical Education, Wrocław Medical University, Wroclaw 50-369, Poland
| | - Aleksander F Sikorski
- Department of Cytobiochemistry, Faculty of Biotechnology, University of Wroclaw, Wroclaw 50-383, Poland
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24
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Cheboub A, Regouat N, Djidjik R, Slimani A, Hadj-Bekkouche F. Short-term aromatase inhibition induces prostatic alterations in adult wistar rat: A biochemical, histopathological and immunohistochemical study. Acta Histochem 2019; 121:151441. [PMID: 31522738 DOI: 10.1016/j.acthis.2019.151441] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 08/08/2019] [Accepted: 09/04/2019] [Indexed: 12/22/2022]
Abstract
PURPOSE This study aimed to evaluate the effects of estrogen reduction on amyloid deposition, some lipid metabolism and oxidative stress markers, PSA-like production and p63 expression in the prostate of the adult rat. METHODS Aromatase inhibitor: Formestane (4-OHA), was administrated to male rats, at a dose of 0.1 mg/kg b.w./day, for 10 days. The control group (CONT) received the same volume of placebo injection (NaCl 0.9%). RESULTS 4-OHA treatment induced a significant accumulation of intraprostatic cholesterol (138.90 ± 17.64 vs 85.12 ± 2.87, p = 0.01); against an insignificant diminution of malondialdehyde (412.6 ± 54.35 vs 842.70 ± 336.50, p > 0.05) and glutathione (2.40 ± 0.23 vs 3.65 ± 0.88, p > 0.05). This was associated with a significant decrease of nitric oxide (31.76 ± 7.07 vs 179.40 ± 58.35, p = 0.024). Additionally, 4-OHA significantly increased the intraprostatic production of PSA-like (11.12 ± 2.78 vs 3.91 ± 0.43, p = 0.043). The prostatic histology revealed an amyloid deposition, in all prostatic lobes and a smooth muscle layer growth (p < 0.05); especially significant in the dorsal and lateral lobes. Theses lobes manifested a basal cells proliferation, with a 3-fold increase of p63 expression (p < 0.001). The ventral lobe presented epithelial atrophy (37.80 ± 16.20 vs 167.60 ± 5.16, p < 0.05); with occasional and significant proliferative foci (247.00 ± 9.573 vs 167.60 ± 5.16 p < 0.05). DISCUSSION AND CONCLUSION Aromatase inhibition, in the adult male rat, alters the prostatic function by reducing nitric oxide availability and inducing amyloid deposition along with limiting the differentiation of basal cells, through a lobe-specific p63-overexpression.
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Affiliation(s)
- Amina Cheboub
- Faculty of Biology Sciences, University of Sciences and Technology Houari Boumediene, Algeria.
| | - Nadia Regouat
- Faculty of Biology Sciences, University of Sciences and Technology Houari Boumediene, Algeria
| | - Reda Djidjik
- Immunology Service of Isaad Hassani-Beni Messous Hospital, Algiers, Algeria
| | - Assia Slimani
- Pathological Anatomy Service of Isaad Hassani-Beni Messous Hospital, Algiers, Algeria
| | - Fatima Hadj-Bekkouche
- Faculty of Biology Sciences, University of Sciences and Technology Houari Boumediene, Algeria
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25
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Liang Z, Chen Y, Wang L, Li D, Yang X, Ma G, Wang Y, Li Y, Zhao H, Liang Y, Niu H. CYP27A1 inhibits bladder cancer cells proliferation by regulating cholesterol homeostasis. Cell Cycle 2018; 18:34-45. [PMID: 30563407 DOI: 10.1080/15384101.2018.1558868] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
Abstract
CYP27A1, an enzyme involved in regulating cellular cholesterol homeostasis, converts cholesterol into 27-hydroxycholesterol (27-HC). The relationship between CYP27A1 and cell proliferation was studied to determine the role of CYP27A1 in bladder cancer. The expression of CYP27A1 in three bladder cancer cell lines (T24, UM-UC-3 and 5637) were assessed by qRT-PCR and Western blotting, and cells with stable CYP27A1 expression were generated by lentiviral infection. Cell proliferation was detected by MTT assays, colony formation assays and a tumor xenograft model in vitro and in vivo, and the intracellular 27-HC and cholesterol secretion levels were detected by enzyme-linked immunosorbent assays (ELISA). The results revealed that CYP27A1 expression was downregulated in androgen receptor (AR)-positive T24/UM-UC-3 cells compared with AR-negative 5637 cell. After CYP27A1 expression was restored, cell proliferation was inhibited in vitro and in vivo because much more intracellular 27-HC was produced in the CYP27A1-overexpressing cells than in the control cells. Both T24 and UM-UC-3 cells treated with 27-HC showed similar results. In addition, CYP27A1/27HC could reduce the cellular cholesterol level in both T24 and UM-UC-3 cells by upregulating ATP-binding cassette transporters G1 and A1 (ABCG1 and ABCA1) through Liver X receptors (LXRs) pathway and downregulating low-density lipoprotein receptor (LDLR) expression. These findings all suggest that CYP27A1 is a critical cholesterol sensor in bladder cancer cells that may contribute significantly to bladder cancer proliferation.
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Affiliation(s)
- Zhijuan Liang
- a Key Laboratory, Department of Urology and Andrology , Affiliated Hospital of Qingdao University , Qingdao , China
| | - Yuanbin Chen
- a Key Laboratory, Department of Urology and Andrology , Affiliated Hospital of Qingdao University , Qingdao , China
| | - Liping Wang
- a Key Laboratory, Department of Urology and Andrology , Affiliated Hospital of Qingdao University , Qingdao , China
| | - Dan Li
- a Key Laboratory, Department of Urology and Andrology , Affiliated Hospital of Qingdao University , Qingdao , China
| | - Xuecheng Yang
- b Department of Urology , Affiliated Hospital of Qingdao University , Qingdao , China
| | - Guofeng Ma
- b Department of Urology , Affiliated Hospital of Qingdao University , Qingdao , China
| | - Yonghua Wang
- b Department of Urology , Affiliated Hospital of Qingdao University , Qingdao , China
| | - Yongxin Li
- c Department of Vascular Surgery , Affiliated Hospital of Qingdao University , Qingdao , China
| | - Han Zhao
- d Department of Pathology , Affiliated Hospital of Qingdao University , Qingdao , China
| | - Ye Liang
- a Key Laboratory, Department of Urology and Andrology , Affiliated Hospital of Qingdao University , Qingdao , China
| | - Haitao Niu
- a Key Laboratory, Department of Urology and Andrology , Affiliated Hospital of Qingdao University , Qingdao , China.,b Department of Urology , Affiliated Hospital of Qingdao University , Qingdao , China
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26
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Hao B, Yu M, Sang C, Bi B, Chen J. Dyslipidemia and non-small cell lung cancer risk in Chinese population: a case-control study. Lipids Health Dis 2018; 17:278. [PMID: 30522496 PMCID: PMC6284307 DOI: 10.1186/s12944-018-0925-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Accepted: 11/22/2018] [Indexed: 12/16/2022] Open
Abstract
Background Numerous studies reported that dyslipidemia was associated with cancer risk. However, few studies investigated the associations between dyslipidemia and non-small cell lung cancer (NSCLC). Methods Four hundred twenty-four histologically confirmed NSCLC cases and 414 controls, matched for age and sex, were enrolled to examine the relationship between dyslipidemia and NSCLC. Demographic and clinical data were obtained from patients’ medical records and telephone interviews. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression. Results Abnormal triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) levels showed statistically significant coexistence with NSCLC compared with controls. Higher levels of TG were associated with a higher risk of NSCLC (OR = 1.541, 95% CI, (1.072–2.215)). The odds ratios (ORs) for NSCLC for normal and high levels of HDL-C versus those with a low level of HDL-C were 0.337(95% CI, (0.242–0.468)) and 0.288(95% CI, (0.185–0.448)), respectively. After adjustment for age, sex, smoking status, hypertension, body mass index, diabetes and lipid profiles, the adjusted OR for normal and high levels of HDL-C were 0.320(95% CI, (0.218–0.470)) and 0.233(95% CI, (0.134–0.407)), respectively. However, after adjustment, high levels of TG increased the risk of NSCLC but not significantly (OR = 1.052, 95% CI (0.671–1.649)). Conclusions This study provided evidence that dyslipidemia increased the risk of NSCLC in Chinese population.
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Affiliation(s)
- Bo Hao
- Department of Cardiothoracic Surgery, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, 441021, China
| | - Miaomei Yu
- Comprehensive Laboratory, the Third Affiliated Hospital of Soochow University, Changzhou, 213003, China
| | - Chen Sang
- Department of Cardiothoracic Surgery, the Third Affiliated Hospital of Soochow University, Changzhou, 213003, China
| | - Baochen Bi
- Department of Cardiothoracic Surgery, the Third Affiliated Hospital of Soochow University, Changzhou, 213003, China
| | - Jiajun Chen
- Department of Cardiothoracic Surgery, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, 441021, China.
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27
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Zadra G, Loda M. Metabolic Vulnerabilities of Prostate Cancer: Diagnostic and Therapeutic Opportunities. Cold Spring Harb Perspect Med 2018; 8:cshperspect.a030569. [PMID: 29229664 DOI: 10.1101/cshperspect.a030569] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Cancer cells hijack metabolic pathways to support bioenergetics and biosynthetic requirements for their uncontrolled growth. Thus, cancer can be considered as a metabolic disease. In this review, we discuss the main metabolic features of prostate cancer with a particular focus on the link between oncogene-directed cancer metabolic regulation, metabolism rewiring, and epigenetic regulation. The potential of using metabolic profiling as a means to predict disease behavior and to identify novel therapeutic targets and new diagnostic markers will be addressed as well as the current challenges in metabolomics analyses. Finally, diagnostic and prognostic metabolic imaging approaches, including positron emission tomography, mass spectrometry, nuclear magnetic resonance, and their translational applications, will be discussed. Here, we emphasize how targeting metabolic vulnerabilities in prostate cancer may pave the way for novel personalized diagnostic and therapeutic interventions.
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Affiliation(s)
- Giorgia Zadra
- Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215.,Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215
| | - Massimo Loda
- Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215.,Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215.,The Broad Institute, Cambridge, Massachusetts 02142
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28
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Pirro M, Ricciuti B, Rader DJ, Catapano AL, Sahebkar A, Banach M. High density lipoprotein cholesterol and cancer: Marker or causative? Prog Lipid Res 2018; 71:54-69. [DOI: 10.1016/j.plipres.2018.06.001] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2018] [Revised: 05/15/2018] [Accepted: 06/02/2018] [Indexed: 12/11/2022]
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29
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BMI and serum lipid parameters predict increasing risk and aggressive prostate cancer in Chinese people. Oncotarget 2017; 8:66051-66060. [PMID: 29029491 PMCID: PMC5630391 DOI: 10.18632/oncotarget.19790] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Accepted: 06/29/2017] [Indexed: 01/01/2023] Open
Abstract
OBJECTIVES To determine if obesity and serum lipid parameters are associated with increased risk and more aggressive prostate cancer in Chinese population. MATERIALS AND METHODS We conducted a retrospective cohort analysis including 3102 patients. Kruskal-Wallis test for continuous variables and the chi-squared tests for categorical variables were used for univariate comparison of the differences in patient characteristics across BMI categories between different groups. Odds ratios (OR) and 95% confidence intervals (CI) were estimated for the association between prostate cancer and the various patient characteristics. Multivariable Cox proportional hazards regression was performed to assess the risk of prostate cancer recurrence. RESULTS 974 consecutive men were diagnosed as prostate cancer and 700 patients subsequently received radical prostatectomy immediately, and 1031 patients were pathologically diagnosed as biopsy negative. The level of low-density-lipoprotein cholesterol (LDL-c) and total cholesterol was significantly higher and the high-density-lipoprotein cholesterol (HDL-c) level is much lower in prostate cancer patients. Patients with low level of HDL-c, who subsequently received radical prostatectomy, had increased risk of high risk disease. In addition, patients with normal weight were less likely to develop a biochemical recurrence. Combined analysis revealed that obese patients had significantly higher rates of PSA recurrence over time than nonobese patients. CONCLUSIONS In our study, lipid parameters are supposed to be associated with prostate cancer risk and aggressiveness. Obese men are at increased risk of PSA recurrence after radical prostatectomy.
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30
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He S, Nelson ER. 27-Hydroxycholesterol, an endogenous selective estrogen receptor modulator. Maturitas 2017; 104:29-35. [PMID: 28923174 DOI: 10.1016/j.maturitas.2017.07.014] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2017] [Revised: 07/26/2017] [Accepted: 07/28/2017] [Indexed: 12/11/2022]
Abstract
Estrogen receptors (ERs) mediate the actions of the steroidal estrogens, and are important for the regulation of several physiological and pathophysiological processes, including reproduction, bone physiology, cardiovascular physiology and breast cancer. The unique pharmacology of the ERs allows for certain ligands, such as tamoxifen, to elicit tissue- and context-specific responses, ligands now referred to as selective estrogen receptor modulators (SERMs). Recently, the cholesterol metabolite 27-hydroxychoelsterol (27HC) has been defined as an endogenous SERM, with activities in atherosclerosis, osteoporosis, breast and prostate cancers, and neural degenerative diseases. Since 27HC concentrations closely mirror those of cholesterol, it is possible that 27HC mediates many of the biological effects of cholesterol. This paper provides an overview of ER pharmacology and summarizes the work to date implicating 27HC in various diseases. Wherever possible, we highlight clinical data in support of a role for 27HC in the diseases discussed.
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Affiliation(s)
- Sisi He
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Erik R Nelson
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA; University of Illinois Cancer Center, Chicago, IL, USA; Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
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31
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Ducheix S, Montagner A, Polizzi A, Lasserre F, Régnier M, Marmugi A, Benhamed F, Bertrand-Michel J, Mselli-Lakhal L, Loiseau N, Martin PG, Lobaccaro JM, Ferrier L, Postic C, Guillou H. Dietary oleic acid regulates hepatic lipogenesis through a liver X receptor-dependent signaling. PLoS One 2017; 12:e0181393. [PMID: 28732092 PMCID: PMC5521785 DOI: 10.1371/journal.pone.0181393] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Accepted: 06/22/2017] [Indexed: 12/13/2022] Open
Abstract
Olive oil consumption is beneficial for health as it is associated with a decreased prevalence of cancer and cardiovascular diseases. Oleic acid is, by far, the most abundant component of olive oil. Since it can be made through de novo synthesis in animals, it is not an essential fatty acid. While it has become clear that dietary oleic acid regulates many biological processes, the signaling pathway involved in these regulations remains poorly defined. In this work we tested the impact of an oleic acid-rich diet on hepatic gene expression. We were particularly interested in addressing the contribution of Liver X Receptors (LXR) in the control of genes involved in hepatic lipogenesis, an essential process in whole body energy homeostasis. We used wild-type mice and transgenic mice deficient for both α and β Liver X Receptor isoforms (LXR-/-) fed a control or an oleate enriched diet. We observed that hepatic-lipid accumulation was enhanced as well as the expression of lipogenic genes in the liver of wild-type mice fed the oleate enriched diet. In contrast, none of these changes occurred in the liver of LXR-/- mice. Strikingly, oleate-rich diet reduced cholesterolemia in wild-type mice and induced signs of liver inflammation and damage in LXR-/- mice but not in wild-type mice. This work suggests that dietary oleic acid reduces cholesterolemia while promoting LXR-dependent hepatic lipogenesis without detrimental effects to the liver.
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Affiliation(s)
- Simon Ducheix
- INRA, ToxAlim, Toulouse, France.,Université de Toulouse, INP, UPS, ToxAlim, Toulouse, France
| | - Alexandra Montagner
- INRA, ToxAlim, Toulouse, France.,Université de Toulouse, INP, UPS, ToxAlim, Toulouse, France
| | - Arnaud Polizzi
- INRA, ToxAlim, Toulouse, France.,Université de Toulouse, INP, UPS, ToxAlim, Toulouse, France
| | - Frédéric Lasserre
- INRA, ToxAlim, Toulouse, France.,Université de Toulouse, INP, UPS, ToxAlim, Toulouse, France
| | - Marion Régnier
- INRA, ToxAlim, Toulouse, France.,Université de Toulouse, INP, UPS, ToxAlim, Toulouse, France
| | - Alice Marmugi
- INRA, ToxAlim, Toulouse, France.,Université de Toulouse, INP, UPS, ToxAlim, Toulouse, France
| | - Fadila Benhamed
- INSERM, U1016, Institut Cochin, Paris, France.,CNRS, UMR8104, Paris, France
| | | | - Laila Mselli-Lakhal
- INRA, ToxAlim, Toulouse, France.,Université de Toulouse, INP, UPS, ToxAlim, Toulouse, France
| | - Nicolas Loiseau
- INRA, ToxAlim, Toulouse, France.,Université de Toulouse, INP, UPS, ToxAlim, Toulouse, France
| | - Pascal G Martin
- INRA, ToxAlim, Toulouse, France.,Université de Toulouse, INP, UPS, ToxAlim, Toulouse, France
| | - Jean-Marc Lobaccaro
- Clermont Université, Université Blaise Pascal, Génétique Reproduction et Développement, Clermont-Ferrand, France.,CNRS, UMR 6293, GReD, Aubière, France.,INSERM, U1103, GReD, Aubière, France.,Centre de Recherche en Nutrition Humaine d'Auvergne, Clermont-Ferrand, France
| | - Laurent Ferrier
- INRA, ToxAlim, Toulouse, France.,Université de Toulouse, INP, UPS, ToxAlim, Toulouse, France
| | - Catherine Postic
- INSERM, U1016, Institut Cochin, Paris, France.,CNRS, UMR8104, Paris, France.,Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Hervé Guillou
- INRA, ToxAlim, Toulouse, France.,Université de Toulouse, INP, UPS, ToxAlim, Toulouse, France
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32
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Kubicek-Sutherland JZ, Vu DM, Mendez HM, Jakhar S, Mukundan H. Detection of Lipid and Amphiphilic Biomarkers for Disease Diagnostics. BIOSENSORS-BASEL 2017; 7:bios7030025. [PMID: 28677660 PMCID: PMC5618031 DOI: 10.3390/bios7030025] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Revised: 06/27/2017] [Accepted: 06/30/2017] [Indexed: 12/24/2022]
Abstract
Rapid diagnosis is crucial to effectively treating any disease. Biological markers, or biomarkers, have been widely used to diagnose a variety of infectious and non-infectious diseases. The detection of biomarkers in patient samples can also provide valuable information regarding progression and prognosis. Interestingly, many such biomarkers are composed of lipids, and are amphiphilic in biochemistry, which leads them to be often sequestered by host carriers. Such sequestration enhances the difficulty of developing sensitive and accurate sensors for these targets. Many of the physiologically relevant molecules involved in pathogenesis and disease are indeed amphiphilic. This chemical property is likely essential for their biological function, but also makes them challenging to detect and quantify in vitro. In order to understand pathogenesis and disease progression while developing effective diagnostics, it is important to account for the biochemistry of lipid and amphiphilic biomarkers when creating novel techniques for the quantitative measurement of these targets. Here, we review techniques and methods used to detect lipid and amphiphilic biomarkers associated with disease, as well as their feasibility for use as diagnostic targets, highlighting the significance of their biochemical properties in the design and execution of laboratory and diagnostic strategies. The biochemistry of biological molecules is clearly relevant to their physiological function, and calling out the need for consideration of this feature in their study, and use as vaccine, diagnostic and therapeutic targets is the overarching motivation for this review.
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Affiliation(s)
- Jessica Z Kubicek-Sutherland
- Physical Chemistry and Applied Spectroscopy, Chemistry Division, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
| | - Dung M Vu
- Physical Chemistry and Applied Spectroscopy, Chemistry Division, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
| | - Heather M Mendez
- Department of Chemical and Biological Engineering, University of New Mexico, Albuquerque, NM 87131, USA.
- The New Mexico Consortium, Los Alamos, NM 87544, USA.
| | - Shailja Jakhar
- Physical Chemistry and Applied Spectroscopy, Chemistry Division, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
| | - Harshini Mukundan
- Physical Chemistry and Applied Spectroscopy, Chemistry Division, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
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33
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Leeper H, Viall A, Ruaux C, Bracha S. Preliminary evaluation of serum total cholesterol concentrations in dogs with osteosarcoma. J Small Anim Pract 2017; 58:562-569. [PMID: 28660727 DOI: 10.1111/jsap.12702] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2016] [Revised: 04/15/2017] [Accepted: 04/20/2017] [Indexed: 11/30/2022]
Abstract
OBJECTIVES To determine if total serum cholesterol concentrations were altered in dogs with osteosarcoma. To evaluate association of total serum cholesterol concentration with clinical outcomes in dogs with appendicular osteosarcoma. MATERIALS AND METHODS Retrospective, multi-institutional study on 64 dogs with osteosarcoma. Control population consisted of dogs with traumatic bone fractures (n=30) and healthy patients of similar age and weight as those of the osteosarcoma cases (n=31). Survival analysis was done on 35 appendicular osteosarcoma patients that received the current standard of care. Statistical associations were assessed by univariable and multi-variable analysis. Information about age, sex, primary tumour location, total cholesterol concentration, monocytes and lymphocyte counts and alkaline phosphatase were also included. RESULTS Total cholesterol was elevated above the reference interval (3·89 to 7·12 mmol/L) (150 to 275 mg/dL) in 29 of 64 (45·3%) osteosarcoma-bearing dogs, whereas similar elevations were found in only 3 of 30 (10%) fracture controls (P<0·0001) and 2 of 31 (6·5%) similar age/weight controls (P=0·0002). Elevated total cholesterol was significantly associated with a reduced hazard ratio (0·27, P=0·008) for overall mortality in dogs with osteosarcoma. CLINICAL SIGNIFICANCE These results suggest that elevated total cholesterol is associated with canine osteosarcoma and may have prognostic significance.
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Affiliation(s)
- H Leeper
- Veterinary Clinical Sciences, Oregon State University, 700 SW 30th Street, Corvallis, Oregon, 97331-4801, USA
| | - A Viall
- Department of Veterinary Pathology, College of Veterinary Medicine, Iowa State University, 1800 Christensen Drive, Ames, Iowa, 50011-1134, USA
| | - C Ruaux
- Veterinary Clinical Sciences, Oregon State University, 700 SW 30th Street, Corvallis, Oregon, 97331-4801, USA
| | - S Bracha
- Veterinary Clinical Sciences, Oregon State University, 700 SW 30th Street, Corvallis, Oregon, 97331-4801, USA
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34
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Raza S, Meyer M, Goodyear C, Hammer KDP, Guo B, Ghribi O. The cholesterol metabolite 27-hydroxycholesterol stimulates cell proliferation via ERβ in prostate cancer cells. Cancer Cell Int 2017; 17:52. [PMID: 28503095 PMCID: PMC5425984 DOI: 10.1186/s12935-017-0422-x] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Accepted: 05/02/2017] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND For every six men, one will be diagnosed with prostate cancer (PCa) in their lifetime. Estrogen receptors (ERs) are known to play a role in prostate carcinogenesis. However, it is unclear whether the estrogenic effects are mediated by estrogen receptor α (ERα) or estrogen receptor β (ERβ). Although it is speculated that ERα is associated with harmful effects on PCa, the role of ERβ in PCa is still ill-defined. The cholesterol oxidized metabolite 27-hydroxycholesterol (27-OHC) has been found to bind to ERs and act as a selective ER modulator (SERM). Increased 27-OHC levels are found in individuals with hypercholesterolemia, a condition that is suggested to be a risk factor for PCa. METHODS In the present study, we determined the extent to which 27-OHC causes deleterious effects in the non-tumorigenic RWPE-1, the low tumorigenic LNCaP, and the highly tumorigenic PC3 prostate cancer cells. We conducted cell metabolic activity and proliferation assays using MTS and CyQUANT dyes, protein expression analyses via immunoblots and gene expression analyses via RT-PCR. Additionally, immunocytochemistry and invasion assays were performed to analyze intracellular protein distribution and quantify transepithelial cell motility. RESULTS We found that incubation of LNCaP and PC3 cells with 27-OHC significantly increased cell proliferation. We also demonstrate that the ER inhibitor ICI 182,780 (fulvestrant) significantly reduced 27-OH-induced cell proliferation, indicating the involvement of ERs in proliferation. Interestingly, ERβ levels, and to a lesser extent ERα, were significantly increased following incubation of PCa cells with 27-OHC. Furthermore, in the presence of the ERβ specific inhibitor, PHTPP, 27-OHC-induced proliferation is attenuated. CONCLUSIONS Altogether, our results show for the first time that 27-OHC, through ER activation, triggers deleterious effect in prostate cancer cell lines. We propose that dysregulated levels of 27-OHC may trigger or exacerbate prostate cancer via acting on ERβ.
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Affiliation(s)
- Shaneabbas Raza
- Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, 501 North Columbia Road, Grand Forks, ND 58202 USA
| | - Megan Meyer
- Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, 501 North Columbia Road, Grand Forks, ND 58202 USA
| | - Casey Goodyear
- Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, 501 North Columbia Road, Grand Forks, ND 58202 USA
| | - Kimberly D P Hammer
- Department of Veteran Affairs, Fargo VA Health Care System, Fargo, ND 58102 USA
| | - Bin Guo
- Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58108 USA
| | - Othman Ghribi
- Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, 501 North Columbia Road, Grand Forks, ND 58202 USA
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Alfaqih MA, Nelson ER, Liu W, Safi R, Jasper JS, Macias E, Geradts J, Thompson JW, Dubois LG, Freeman MR, Chang CY, Chi JT, McDonnell DP, Freedland SJ. CYP27A1 Loss Dysregulates Cholesterol Homeostasis in Prostate Cancer. Cancer Res 2017; 77:1662-1673. [PMID: 28130224 PMCID: PMC5687884 DOI: 10.1158/0008-5472.can-16-2738] [Citation(s) in RCA: 87] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Revised: 01/10/2017] [Accepted: 01/10/2017] [Indexed: 11/16/2022]
Abstract
In this study, we used a bioinformatic approach to identify genes whose expression is dysregulated in human prostate cancers. One of the most dramatically downregulated genes identified encodes CYP27A1, an enzyme involved in regulating cellular cholesterol homeostasis. Importantly, lower CYP27A1 transcript levels were associated with shorter disease-free survival and higher tumor grade. Loss of CYP27A1 in prostate cancer was confirmed at the protein level by immunostaining for CYP27A1 in annotated tissue microarrays. Restoration of CYP27A1 expression in cells where its gene was silenced attenuated their growth in vitro and in tumor xenografts. Studies performed in vitro revealed that treatment of prostate cancer cells with 27-hydroxycholesterol (27HC), an enzymatic product of CYP27A1, reduced cellular cholesterol content in prostate cancer cell lines by inhibiting the activation of sterol regulatory-element binding protein 2 and downregulating low-density lipoprotein receptor expression. Our findings suggest that CYP27A1 is a critical cellular cholesterol sensor in prostate cells and that dysregulation of the CYP27A1/27HC axis contributes significantly to prostate cancer pathogenesis. Cancer Res; 77(7); 1662-73. ©2017 AACR.
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Affiliation(s)
- Mahmoud A Alfaqih
- Department of Surgery, Duke University, Durham, North Carolina
- Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina
| | - Erik R Nelson
- Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign; and University of Illinois Cancer Center, Chicago, Illinois
| | - Wen Liu
- Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina
| | - Rachid Safi
- Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina
| | - Jeffery S Jasper
- Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina
| | - Everardo Macias
- Department of Surgery, Duke University, Durham, North Carolina
- Department of Surgery and Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Joseph Geradts
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
| | - J Will Thompson
- Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina
- Department of Proteomics and Metabolomics Shared Resource, Duke University, Durham, North Carolina
| | - Laura G Dubois
- Department of Proteomics and Metabolomics Shared Resource, Duke University, Durham, North Carolina
| | - Michael R Freeman
- Department of Surgery and Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Ching-Yi Chang
- Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina
| | - Jen-Tsan Chi
- Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina
| | - Donald P McDonnell
- Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina.
| | - Stephen J Freedland
- Department of Surgery and Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
- Surgery Section, Durham VA Medical Center, Durham, North Carolina
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Bitzur R, Brenner R, Maor E, Antebi M, Ziv-Baran T, Segev S, Sidi Y, Kivity S. Metabolic syndrome, obesity, and the risk of cancer development. Eur J Intern Med 2016; 34:89-93. [PMID: 27545645 DOI: 10.1016/j.ejim.2016.08.019] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2016] [Revised: 07/10/2016] [Accepted: 08/10/2016] [Indexed: 10/21/2022]
Abstract
BACKGROUND Metabolic syndrome and its components are severe global health issues that are increasing in frequency as the prevalence of obesity increases. Various studies have established a correlation between metabolic syndrome and diseases including, diabetes mellitus, non-alcoholic fatty liver disease, cirrhosis, and cardiovascular disease. In recent years, correlations have also been detected between obesity and metabolic syndrome and the prevalence of certain types of cancer. The current study examines whether obesity and metabolic syndrome components are risk factors for cancer among the adult population in Israel. METHODS A cohort study analysis was performed of 24,987 initially healthy men and women who underwent yearly medical assessments at the Institute for Medical Screening in the Sheba Medical Center. Data from the Institute for Medical Screening database was correlated with that from the Israel Cancer Center in the Ministry of Health updated to December 2013. The correlation between metabolic syndrome, obesity, and the overall risk of cancer as well as the risks of specific types of cancer were examined. RESULTS Of 20,444 subjects for whom complete data were available, 1535 were diagnosed with cancer during the mean follow-up time of 104.3months. In a multi-variant analysis, no significant correlation was found between metabolic syndrome or obesity and the incidence of cancer. When the data were stratified by gender and cancer type, however, a significant association between metabolic syndrome and breast cancer in women was observed (P=0.03, HR=1.67, 95% CI=1.05-2.67). CONCLUSION Metabolic syndrome correlates with higher than expected breast cancer incidence in women.
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Affiliation(s)
- Rafael Bitzur
- The Bert W. Strassburger Lipid Center, Sheba Medical Center, 5265601 Tel Hashomer, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Israel
| | - Ronen Brenner
- Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Israel; Institute of Oncology, Wolfson Medical Center, Holon, Israel
| | - Elad Maor
- Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Israel; Leviev Heart Institute, The Chaim Sheba Medical Center, Tel Hashomer, Israel; The Dr. Pinchas Borenstein Talpiot Medical Leadership Program 2013, Sheba Medical Center, Tel Hashomer, Israel
| | - Maayan Antebi
- Department of Internal Medicine D, The Chaim Sheba Medical Center, Tel Hashomer, Israel
| | - Tomer Ziv-Baran
- Department of Epidemiology and Preventive Medicine, School of Public Health, Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Israel
| | - Shlomo Segev
- Institute for Medical Screening, Sheba Medical Center, Israel
| | - Yechezkel Sidi
- Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Israel; Department of Internal Medicine C, The Chaim Sheba Medical Center, Tel Hashomer, Israel
| | - Shaye Kivity
- Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Israel; The Dr. Pinchas Borenstein Talpiot Medical Leadership Program 2013, Sheba Medical Center, Tel Hashomer, Israel; Department of Internal Medicine A, The Chaim Sheba Medical Center, Tel Hashomer, Israel.
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Karantanos T, Karanika S, Gignac G. Uncontrolled diabetes predicts poor response to novel antiandrogens. Endocr Relat Cancer 2016; 23:691-8. [PMID: 27515296 DOI: 10.1530/erc-16-0222] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Accepted: 07/12/2016] [Indexed: 11/08/2022]
Abstract
Metabolic abnormalities including hyperglycemia and hyperlipidemia have been associated with worse prognosis of prostate cancer (PCa), but there are limited data regarding their impact on the prognosis of castrate-resistant prostate cancer (CRPC) and the response of novel antiandrogens, namely abiraterone acetate (AA) and enzalutamide. Retrospective analysis of 61 patients with CRPC on AA or enzalutamide, treated at the Boston Medical Center, was performed. We evaluated hemoglobin A1c (HbA1c), HDL, LDL, Triglycerides and BMI within 2months before the initiation of treatment with AA or enzalutamide and progression-free survival (PFS) under this treatment. Regression analysis and analysis of variance were used to evaluate the data. HbA1c levels were found to predict adversely the PFS on the novel agents (df (1, 37), P=0.00, R(2)=0.40, coeff=-3.28). The Kaplan-Meier analysis showed that there is significant difference in survival between the HbA1c 4.7-5.9% compared with patients with HbA1c 7.8-11.6% (6.72±1.3months, log rank test P<0.0001) LDL (P=0.07), HDL (P=0.14), and triglycerides (P=0.33) were not found to predict PFS. BMI predicted PFS positively (df (1.59), P=0.02, R(2)=0.09, coeff=0.03), but not independently of HbA1c (P=0.07). No significant implications of social and family history, previous chemotherapy regimen, and Gleason score with PFS were found. Multiple markers of patients' health state were not associated with HbA1c values. Uncontrolled diabetes can predict for poor response of CRPC patients to AA and enzalutamide determining PFS under this treatment. Elevated BMI can positively affect PFS at this stage of disease.
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Affiliation(s)
- Theodoros Karantanos
- General Internal Medicine DepartmentBoston Medical Center, Boston University School of Medicine, Boston, Massachusetts, USA
| | - Styliani Karanika
- Infectious Diseases DivisionWarren Alpert Medical School of Brown University, Providence, Rhode Island, USA
| | - Gretchen Gignac
- Hematology-Oncology DepartmentBoston Medical Center, Boston University School of Medicine, Boston, Massachusetts, USA
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Borgquist S, Butt T, Almgren P, Shiffman D, Stocks T, Orho-Melander M, Manjer J, Melander O. Apolipoproteins, lipids and risk of cancer. Int J Cancer 2016; 138:2648-56. [PMID: 26804063 DOI: 10.1002/ijc.30013] [Citation(s) in RCA: 152] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2015] [Revised: 12/14/2015] [Accepted: 01/05/2016] [Indexed: 12/21/2022]
Abstract
The epidemiological evidence for an obesity-cancer association is solid, whereas the association between obesity-associated lipoprotein levels and cancer is less evident. We investigated circulating levels of Apolipoprotein A1 (ApoA1), Apolipoprotein B (ApoB), LDL-cholesterol (LDL-C) and HDL-cholesterol (HDL-C) and association to risk of overall cancer and common cancer forms. The Malmö Diet and Cancer Study, a population-based prospective cohort study, enrolled 17,035 women and 11,063 men (1991-1996). Incident cancer cases were ascertained by record linkage with the Swedish Cancer Registry until end of follow-up, January 1, 2012. Baseline serum levels of ApoA1 and ApoB were analyzed for the entire cohort and HDL-C and LDL-C levels in 5,281 participants. Hazard ratios, with 95% confidence interval, were calculated using Cox's proportional hazards analysis. In the entire cohort, none of the exposures were related to overall cancer risk (HRadj ApoA1 = 0.98, 95%CI: 0.95,1.01; HRadj ApoB = 1.01, 95%CI: 0.98-1.04). Among men, ApoB was positively associated with cancer risk (HRadj ApoB = 1.06, 95%CI: 1.01,1.10). Female breast cancer risk was inversely associated with ApoB (HRadj = 0.92, 95%CI: 0.86,0.99). Among both genders, ApoA1 was inversely associated with lung cancer risk (HRadj = 0.88, 95%CI: 0.80,0.97), whereas high ApoB increased lung cancer risk (HRadj = 1.08, 95%CI: 0.99,1.18). Colorectal cancer risk was increased with high ApoB (HRadj = 1.08, 95%CI: 1.01,1.16) among both genders. Apolipoprotein levels were not associated with prostate cancer incidence. Circulating levels of apolipoproteins are associated with overall cancer risk in men and across both genders with breast, lung and colorectal cancer risk. Validation of these findings may facilitate future primary prevention strategies for cancer.
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Affiliation(s)
- Signe Borgquist
- Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Sweden.,Department of Oncology, Skåne University Hospital, Lund, Sweden
| | - Talha Butt
- Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Sweden
| | - Peter Almgren
- Division of Cardiology, Malmö, Lund University, Sweden.,Department of Clinical Sciences, Malmö, Lund University, Sweden
| | | | - Tanja Stocks
- Department of Clinical Sciences, Malmö, Lund University, Sweden.,Division of Diabetes and Cardiovascular Diseases, Genetic Epidemiology, Malmö, Lund University, Sweden
| | - Marju Orho-Melander
- Department of Clinical Sciences, Malmö, Lund University, Sweden.,Division of Diabetes and Cardiovascular Diseases, Genetic Epidemiology, Malmö, Lund University, Sweden
| | - Jonas Manjer
- Department of Clinical Sciences, Malmö, Lund University, Sweden.,Division of Surgery, Malmö, Lund University, Sweden
| | - Olle Melander
- Division of Cardiology, Malmö, Lund University, Sweden.,Department of Clinical Sciences, Malmö, Lund University, Sweden
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Zhang GM, Qin XJ, Zhang HL, Xiao WJ, Zhu Y, Gu CY, Dai B, Shi GH, Ye DW. Serum lipid profiles: novel biomarkers predicting advanced prostate cancer in patients receiving radical prostatectomy. Asian J Androl 2015; 17:239-44. [PMID: 25475662 PMCID: PMC4650485 DOI: 10.4103/1008-682x.142135] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
This study aimed to evaluate the role of serum lipid profiles as novel biomarkers in predicting pathological characteristics of prostate cancer (PCa). We retrospectively analyzed 322 consecutive patients with clinically localized PCa receiving radical prostatectomy (RP) and extended pelvic lymphadenectomy. Unconditional logistic regression was used to estimate the prostatectomy Gleason score (pGS), pathological stage and lymph node involvement (LNI) in RP specimens. Preoperative prostate-specific antigen (PSA) levels, biopsy GS (bGS), and preoperative tumor, node, metastasis staging were used as basic variables to predict postoperative pathological characteristics. Preoperative serum lipid profiles were introduced as potential predictors. A receiver operating characteristic (ROC) curve was used to determine predictive efficacy. Significant differences in pathological characteristics were observed among patients with normal and abnormal total cholesterol (TC), triglyceride (TG), and low-density lipoprotein (LDL) levels, with the exception of pGS in the TG group. Multivariable regression analysis revealed that the odds ratio for high levels of TC for LNI compared with normal TC levels was 6.386 (95% confidence interval [CI] 1.510–27.010), 3.270 (95% CI: 1.470–7.278) for high levels of TG for pT3–4 disease, and 2.670 (95% CI: 1.134–6.287) for high levels of LDL for pGS. The area under the ROC curve of the models with dyslipidemia was larger than that in models without dyslipidemia, in predicting pathological characteristics. Abnormal TC, TG, and LDL levels are significantly associated with postoperative pathological status in PCa patients. Together with preoperative PSA levels, bGS, and clinical stage, dyslipidemia is more accurate in predicting pathological characteristics.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Ding-Wei Ye
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China
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YuPeng L, YuXue Z, PengFei L, Cheng C, YaShuang Z, DaPeng L, Chen D. Cholesterol Levels in Blood and the Risk of Prostate Cancer: A Meta-analysis of 14 Prospective Studies. Cancer Epidemiol Biomarkers Prev 2015; 24:1086-93. [PMID: 25953767 DOI: 10.1158/1055-9965.epi-14-1329] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2014] [Accepted: 04/09/2015] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND As a neutral lipid and prominent component of the Western diet, cholesterol levels might be a risk factor for prostate cancer. However, current evidence has been inconsistent. This meta-analysis aimed to evaluate the association between blood cholesterol levels and the risk of prostate cancer. METHODS An extensive search was performed in MEDLINE and EMBASE for prospective studies that have reported the association between total cholesterol (TC), high-density lipoprotein cholesterol (HDL), and low-density lipoprotein cholesterol (LDL) levels in blood and risk of prostate cancer. Random-effects models were used to summarize the study-specific results. RESULTS Fourteen studies were included in this meta-analysis. In the meta-analysis, the summarized risk ratios (RR) for the highest to lowest cholesterol levels were as follows: 1.05 [95% confidence interval (CI), 0.97-1.14; P = 0.21] for TC, 0.93 (95% CI, 0.80-1.10; P = 0.40) for HDL, and 1.17 (95% CI, 0.88-1.55; P = 0.51) for LDL. When restricting to high-grade prostate cancer, the pooled RR was 1.32 (95% CI, 0.93-1.87; P = 0.13) for TC. In dose-response analyses, a 1 mmol/L increment in blood TC, HDL, and LDL level conferred an RR of 1.01 (95% CI, 0.99-1.02; P = 0.38), 0.98 (95% CI, 0.91-1.07; P = 0.72), and 1.04 (95% CI, 0.98-1.10; P = 0.24), respectively. CONCLUSION In this meta-analysis of 14 large prospective studies, blood TC, HDL, and LDL levels were not associated with the risk of either overall prostate cancer or high-grade prostate cancer. IMPACT Our findings did not appear to support the hypothesis that hypercholesterolemia increases the risk of prostate cancer.
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Affiliation(s)
- Liu YuPeng
- Department of Epidemiology, School of Public Health, Harbin Medical University, Harbin, China
| | - Zhang YuXue
- Department of Preventive Medicine, School of Public Health, Harbin Medical University, Harbin, China
| | - Li PengFei
- Department of Medical Oncology, The third Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Cheng Cheng
- Laboratory Center, Heilongjiang Entry-Exit Inspection and Quarantine Bureau, Harbin, China
| | - Zhao YaShuang
- Department of Epidemiology, School of Public Health, Harbin Medical University, Harbin, China
| | - Li DaPeng
- Department of Epidemiology, School of Public Health, Harbin Medical University, Harbin, China.
| | - Du Chen
- Department of Urology Oncology, The third Affiliated Hospital, Harbin Medical University, Harbin, China.
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Kang M, Jeong CW, Ku JH, Kwak C, Kim HH. Hypertriglyceridemia is a potential preoperative predictor for biochemical recurrence after radical prostatectomy. PLoS One 2015; 10:e0122438. [PMID: 25803284 PMCID: PMC4372604 DOI: 10.1371/journal.pone.0122438] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2014] [Accepted: 02/13/2015] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVES Many previous studies have suggested that the outcome of prostate cancer (PCa) may be closely related to abnormal lipid metabolism. Therefore, in this study, we evaluated the preoperative lipid profiles of patients with clinically localized prostate cancer (PCa) who underwent radical prostatectomy (RP), with particular emphasis on the relationship between these profiles and biochemical recurrence (BCR). PATIENTS AND METHODS We evaluated 715 consecutive men with clinically localized PCa who underwent RP at our institution between January 2011 and December 2013. We defined hypertriglyceridemia as a fasting serum triglyceride (TG) level greater than 200 mg/dL. We used the Kaplan-Meier method to predict BCR-free survival and applied the log-rank test to determine the statistical significance between survival curves. Cox proportional hazard ratio (HR) models were used to identify the significant predictors of BCR according to clinicopathological variables. RESULTS Of 663 patients who underwent RP for clinically localized PCa, 66 (10.0%) showed BCR during a median follow-up period of 21 months. Patients without BCR had higher levels of serum TG, and patients with hypertriglyceridemia were significantly more likely to achieve BCR-free survival in the Kaplan-Meier analysis (log-rank test, P = 0.009). In the multivariable analysis, the presence of hypertriglyceridemia (HR 0.22), pathologic Gleason score (≥ 8; HR 2.85), pathologic T stage (≥ pT3; HR 3.44), and a positive surgical margin (HR, 2.39) were still significant BCR predictors. CONCLUSIONS We found that preoperative hypertriglyceridemia was associated with a lower risk of BCR after RP in patients with clinically localized PCa. Our results could help to clarify the currently conflicting evidence on the relationship between serum lipid profiles, particularly the presence of hypertriglyceridemia, and the risk of BCR in PC a patients after surgery.
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Affiliation(s)
- Minyong Kang
- Department of Urology, Seoul National University Hospital, Seoul, Republic of Korea
| | - Chang Wook Jeong
- Department of Urology, Seoul National University Hospital, Seoul, Republic of Korea
| | - Ja Hyeon Ku
- Department of Urology, Seoul National University Hospital, Seoul, Republic of Korea
| | - Choel Kwak
- Department of Urology, Seoul National University Hospital, Seoul, Republic of Korea
| | - Hyeon Hoe Kim
- Department of Urology, Seoul National University Hospital, Seoul, Republic of Korea
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Tan JTM, Ng MKC, Bursill CA. The role of high-density lipoproteins in the regulation of angiogenesis. Cardiovasc Res 2015; 106:184-93. [PMID: 25759067 DOI: 10.1093/cvr/cvv104] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2014] [Accepted: 02/22/2015] [Indexed: 02/07/2023] Open
Abstract
Angiogenesis is important for postnatal physiological processes including tissue neovascularization in response to an ischaemic injury. Conversely, uncontrolled inflammatory-driven angiogenesis can accelerate atherosclerotic plaque and tumour growth. Angiogenesis-associated diseases are highly prevalent globally, with cardiovascular-related disorders and cancer being the leading causes of mortality worldwide. A vast amount of research has been conducted on the vasculoprotective effects of high-density lipoproteins (HDLs) and while current HDL-raising therapies to date have not yielded the desired benefits clinically, its role in angiogenesis is yet to be fully elucidated. Epidemiological studies report positive correlations between elevated HDL levels and improved prognosis in both ischaemia- and inflammatory-driven pathologies, in which angiogenesis plays a key role. This review focuses on current evidence from epidemiological and prospective studies, coupled with animal models and mechanistic studies that highlight the ability of HDL to conditionally regulate angiogenesis.
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Affiliation(s)
- Joanne T M Tan
- The Heart Research Institute, 7 Eliza Street, Newtown, Sydney, New South Wales 2042, Australia Sydney Medical School, University of Sydney, Sydney, Australia
| | - Martin K C Ng
- The Heart Research Institute, 7 Eliza Street, Newtown, Sydney, New South Wales 2042, Australia Sydney Medical School, University of Sydney, Sydney, Australia Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia
| | - Christina A Bursill
- The Heart Research Institute, 7 Eliza Street, Newtown, Sydney, New South Wales 2042, Australia Sydney Medical School, University of Sydney, Sydney, Australia
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Alioui A, Celhay O, Baron S, Lobaccaro JMA. Lipids and prostate cancer adenocarcinoma. ACTA ACUST UNITED AC 2014. [DOI: 10.2217/clp.14.51] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
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Kayali M, Balci M, Aslan Y, Bilgin O, Guzel O, Tuncel A, Atan A. The Relationship Between Prostate Cancer and Presence of Metabolic Syndrome and Late-onset Hypogonadism. Urology 2014; 84:1448-52. [DOI: 10.1016/j.urology.2014.07.015] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2014] [Revised: 06/25/2014] [Accepted: 07/05/2014] [Indexed: 10/24/2022]
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45
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Allott EH, Howard LE, Cooperberg MR, Kane CJ, Aronson WJ, Terris MK, Amling CL, Freedland SJ. Serum lipid profile and risk of prostate cancer recurrence: Results from the SEARCH database. Cancer Epidemiol Biomarkers Prev 2014; 23:2349-56. [PMID: 25304929 DOI: 10.1158/1055-9965.epi-14-0458] [Citation(s) in RCA: 103] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Evidence for an association between total cholesterol, low- and high-density lipoproteins (LDL and HDL, respectively), triglycerides, and prostate cancer is conflicting. Given that prostate cancer and dyslipidemia affect large proportions of Western society, understanding these associations has public health importance. METHODS We conducted a retrospective cohort analysis of 843 radical prostatectomy (RP) patients who never used statins before surgery within the Shared Equal Access Regional Cancer Hospital (SEARCH) database. Multivariable Cox proportional hazards analysis was used to investigate the association between cholesterol, LDL, HDL, and triglycerides and biochemical recurrence risk. In secondary analysis, we explored these associations in patients with dyslipidemia, defined using National Cholesterol Education Program guidelines. RESULTS Elevated serum triglycerides were associated with increased risk of prostate cancer recurrence [HRper 10 mg/dl, 1.03; 95% confidence interval (CI), 1.01-1.05] but associations between total cholesterol, LDL and HDL, and recurrence risk were null. However, among men with dyslipidemia, each 10 mg/dl increase in cholesterol and HDL was associated with 9% increased recurrence risk (HR, 1.09; 95% CI, 1.01-1.17) and 39% reduced recurrence risk (HR, 0.61; 95% CI, 0.41-0.91), respectively. CONCLUSIONS Elevated serum triglycerides were associated with increased risk of prostate cancer recurrence. Cholesterol, LDL, or HDL were not associated with recurrence risk among all men. However, among men with dyslipidemia, elevated cholesterol and HDL levels were associated with increased and decreased risk of recurrence, respectively. IMPACT These findings, coupled with evidence that statin use is associated with reduced recurrence risk, suggest that lipid levels should be explored as a modifiable risk factor for prostate cancer recurrence.
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Affiliation(s)
- Emma H Allott
- Division of Urology, Department of Surgery, Duke University School of Medicine, Durham, North Carolina. Cancer Prevention, Detection, and Control Program, Duke Cancer Institute, Durham, North Carolina. Division of Urology, Veterans Affairs Medical Center Durham, Durham, North Carolina
| | - Lauren E Howard
- Division of Urology, Department of Surgery, Duke University School of Medicine, Durham, North Carolina. Division of Urology, Veterans Affairs Medical Center Durham, Durham, North Carolina. Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, North Carolina
| | - Matthew R Cooperberg
- Department of Urology, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California
| | - Christopher J Kane
- Urology Department, University of California San Diego Health System, San Diego, California
| | - William J Aronson
- Urology Section, Department of Surgery, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California. Department of Urology, UCLA School of Medicine, Los Angeles, California
| | - Martha K Terris
- Section of Urology, Veterans Affairs Medical Center, Augusta, Georgia. Section of Urology, Medical College of Georgia, Augusta, Georgia
| | | | - Stephen J Freedland
- Division of Urology, Department of Surgery, Duke University School of Medicine, Durham, North Carolina. Division of Urology, Veterans Affairs Medical Center Durham, Durham, North Carolina. Department of Pathology, Duke University School of Medicine, Durham, North Carolina.
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Liu J, Xian G, Li M, Zhang Y, Yang M, Yu Y, Lv H, Xuan S, Lin Y, Gao L. Cholesterol oxidase from Bordetella species promotes irreversible cell apoptosis in lung adenocarcinoma by cholesterol oxidation. Cell Death Dis 2014; 5:e1372. [PMID: 25118932 PMCID: PMC4454300 DOI: 10.1038/cddis.2014.324] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2014] [Revised: 06/24/2014] [Accepted: 06/26/2014] [Indexed: 12/28/2022]
Abstract
Cholesterol oxidase (COD), an enzyme catalyzing the oxidation of cholesterol, has been applied to track the distribution of membrane cholesterol. Little investigations about the effect of COD on tumor cells have been performed. In the present study, we provided evidence that COD from Bordetella species (COD-B), induced apoptosis of lung cancer cells in vitro and in vivo. COD-B treatment inhibited Akt and ERK1/2 phosphorylation in dose- and time-dependent manner, which was not reversed and was even aggravated by cholesterol addition. Further investigation indicated that COD-B treatment promoted the generation of reactive oxygen species (ROS) and that cholesterol addition further elevated ROS levels. Moreover, COD-B treatment resulted in JNK and p38 phosphorylation, downregulation of Bcl-2, upregulation of Bax, activated caspase-3 and cytochrome C release, which likely responded to freshly produced hydrogen peroxide that accompanied cholesterol oxidation. Catalase pretreatment could only partially prevent COD-B-induced events, suggesting that catalase inhibited H2O2-induced signal transduction but had little effect on signal pathways involved in cholesterol depletion. Our results demonstrated that COD-B led to irreversible cell apoptosis by decreasing cholesterol content and increasing ROS level. In addition, COD-B may be a promising candidate for a novel anti-tumor therapy.
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Affiliation(s)
- J Liu
- Department of General Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China
| | - G Xian
- Department of General Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China
| | - M Li
- Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China
| | - Y Zhang
- Department of Obstetrics, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China
| | - M Yang
- Department of Ultrasound, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China
| | - Y Yu
- Department of Ultrasound, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China
| | - H Lv
- Department of Obstetrics, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China
| | - S Xuan
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong Province 250021, China
| | - Y Lin
- Department of Center Laboratory, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China
| | - L Gao
- 1] Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong Province 250021, China [2] Department of Center Laboratory, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China
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Zhang GM, Zhu Y, Ye DW. Metabolic syndrome and renal cell carcinoma. World J Surg Oncol 2014; 12:236. [PMID: 25069390 PMCID: PMC4118156 DOI: 10.1186/1477-7819-12-236] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2013] [Accepted: 07/20/2014] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Metabolic syndrome (MS) is a cluster of metabolic abnormalities, which has been regarded as a pivotal risk factor for cardiovascular diseases. Recent studies focusing on the relationship between MS and cancer have recognized the significant role of MS on carcinogenesis. Likewise, growing evidence suggests that MS has a strong association with increased renal cell carcinoma (RCC) risk. This review outlines the link between MS and RCC, and some underlying mechanisms responsible for MS-associated RCC. MATERIALS AND METHODS A National Center for Biotechnology Information PubMed search (http://www.pubmed.gov) was conducted using medical subject headings 'metabolic syndrome', 'obesity', 'hypertension', 'diabetes', 'dyslipidemia', and 'renal cell carcinoma'. RESULTS This revealed that a variety of molecular mechanisms secondary to MS are involved in RCC formation, progression, and metastasis. A deeper understanding of these molecular mechanisms may provide some strategies for the prevention and treatment of RCC. CONCLUSIONS In summary, there is a large body of evidence regarding the link between MS and RCC, within which each component of MS is considered to have a close causal association with RCC.
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Affiliation(s)
| | | | - Ding-Wei Ye
- Department of Urology, Fudan University Shanghai Cancer Center, No, 270, Dongan Rd, Shanghai 200032, China.
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Karunasinghe N, Bishop K, Murray P, Xu Y, Goudie M, Ng L, Zhu S, Han DY, Ferguson LR, Masters J, Benjamin B, Holmes M. Role of β-microseminoprotein from prostate cancer initiation to recurrence: A mini-review. World J Clin Urol 2014; 3:20-30. [DOI: 10.5410/wjcu.v3.i1.20] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2013] [Revised: 12/19/2013] [Accepted: 02/18/2014] [Indexed: 02/06/2023] Open
Abstract
Medline/Pubmed articles relevant to this topic were considered using the search terms β-microseminoprotein, MSMB, prostate secretory protein of 94 amino acids and PSP94. Full articles were retrieved when the abstract was considered relevant. In addition, other data related to this topic including our own are discussed. Summary of findings-β-microseminoprotein (MSMB) is increasingly being considered as a marker for prostate cancer, as reduced levels have been associated with the disease. Here we review various aspects of this protein including its biological and physiological variants, binding proteins and immune modulation; its importance as a marker for biochemical recurrence of prostate cancer; prostate cancer related splice variants and its therapeutic utility. Two of the most important properties of MSMB are related to anticancer functions and immune modulation. Predominant expression of two (short and full-length) splice variants of MSMB has been observed from normal prostate and several other tissues. In benign prostate hyperplasia the short isoform is dominant, constituting 98% of this isoform, whereas in prostate cancer 96% constitute the full-length isoform. The MSMB promoter single nucleotide polymorphism rs10993994 with the C allele functions as an activated cyclic adenosine monophosphate response element binding protein binding site. This C variant of rs10993994 could be responsible for the production of splice variants under variable conditions. MSMB has binding motifs to a few known proteins including immunoglobulin G and several Cysteine-rich secretory proteins family proteins. MSMB bound to these proteins is considered as immune modulating. Use of MSMB as a urinary marker for detecting aggressive prostate cancers that could resist radiation and surgical treatments, seems possible, but needs further investigation. The ratio of MSMB splice variants could also be a possible approach in understanding prostate cancers, with higher ratios indicating severe disease.
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Zhang GM, Zhu Y, Luo L, Zhang HL, Gu CY, Sun LJ, Ye DW. Prevalence of dyslipidaemia in patients with renal cell carcinoma: a case-control study in China. BJU Int 2014; 113:E75-81. [PMID: 24274674 DOI: 10.1111/bju.12581] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
OBJECTIVE To examine the prevalence of dyslipidaemia in patients with renal cell carcinoma (RCC) in a Chinese population. PATIENTS AND METHODS In all, 550 histologically confirmed RCC cases and 570 controls, matched for age and sex were included. Total cholesterol, triglyceride, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) were assessed before treatment using standard techniques. The lipid profiles were defined as 'normal', 'borderline high', 'high' and 'low' according to Chinese Guidelines on Adult Dyslipidaemia. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression in both unadjusted and adjusted models. RESULTS Abnormal LDL elevation was common in RCC cases compared with controls (P < 0.001). Results for total cholesterol, triglyceride and HDL levels between groups were insignificant. The OR for RCC for high levels of LDL (≥160 mg/dL) compared with those with a normal LDL profile was 4.675 (95% CI 1.900-11.500). After adjustment for age, gender, body mass index, smoking status, hypertension, diabetes, total cholesterol and triglyceride, the coexistence of high levels of LDL and RCC was large and statistically significant (OR 8.955, 95% CI 3.371-23.786). There was a significant coexistence of RCC for participants with high LDL levels when subgroups of cases with clear cell subtypes and advanced T stages were compared with controls. CONCLUSION Abnormal LDL elevation was prevalent in Chinese patients with RCC. The results remain to be evaluated in prospective cohorts.
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Affiliation(s)
- Gui-Ming Zhang
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
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Vílchez JA, Martínez-Ruiz A, Sancho-Rodríguez N, Martínez-Hernández P, Noguera-Velasco JA. The real role of prediagnostic high-density lipoprotein cholesterol and the cancer risk: a concise review. Eur J Clin Invest 2014; 44:103-14. [PMID: 24111547 DOI: 10.1111/eci.12185] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2013] [Accepted: 09/24/2013] [Indexed: 12/14/2022]
Abstract
BACKGROUND In several observational and clinical studies, the association between serum cholesterol levels and cancer is still unsettled although serum total cholesterol has been associated with increased mortality from cancer. Moreover, the importance of abnormal levels of serum lipid components as the main features of dyslipidemia and the risk of individual cancers is unclear. The prevalence of dyslipidemia is increasing worldwide but, the precise aetiology of the link between risk of cancer and the behaviour of lipid profile, prior diagnosis, has yet to be determinated. Low levels of high-density lipoprotein cholesterol (HDL) at baseline of many of the studies analyzed has to be taken into account, and continued low levels of HDL without explanation should be considered by clinicians. AIMS The main aim of this review was to undertake the assessment of the most recent studies implying the lipid profile and cancer risk, and focused on low HDL levels at baseline and follow up, and also analyzing this behaviour on the different cancer types. MATERIAL AND METHODS A literature search was performed to identify publications. The most recent prospective and case-control studies with multivariate Cox models were analyzed and also were considered some recent meta-analyses. RESULTS AND CONCLUSIONS The findings exposed in this review suggest that the association with low HDL levels at baseline of different studies of cancer risk is shared among many types of cancer, and it is mainly linked to obesity and inflammation, suggesting a common pathway.
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Affiliation(s)
- Juan A Vílchez
- Department of Clinical Analysis, University Hospital Virgen de la Arrixaca, Murcia, Spain; Department of Cardiology, University Hospital Virgen de la Arrixaca, Murcia, Spain
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