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(2015) 36:35733582
DOI 10.1007/s13277-014-2994-6
RESEARCH ARTICLE
Received: 17 October 2014 / Accepted: 17 December 2014 / Published online: 8 January 2015
# International Society of Oncology and BioMarkers (ISOBM) 2015
Abstract Clinical and epidemiological data suggest coronary and PC-3 in a dose-dependent manner. The results of phos-
artery disease shares etiology with prostate cancer (PCa). The phoprotein microarray illustrated that ox-LDL could influence
aim of this work was to assess the effects of several serum multiple signaling pathways of PC-3. Activation of prolifera-
markers reported in cardiovascular disease on PCa. Serum tion promoting signaling pathways (including -catenin,
markers (oxidized low-density lipoprotein [ox-LDL], apoli- cMyc, NF-B, STAT1, STAT3) as well as apoptosis-
poprotein [apo] B100, and apoB48) in peripheral blood sam- associating signaling pathways (including p27, caspase-3)
ples from 50 patients from Fudan University Shanghai Cancer demonstrated that ox-LDL had complicated effects on pros-
Center (FUSCC) with localized or lymph node metastatic PCa tate cancer. Increased serum ox-LDL level and OLR1 expres-
were investigated in this study. Twenty-five samples from sion may indicate advanced-stage PCa and lymph node me-
normal individuals were set as controls. We first conducted tastasis. Moreover, ox-LDL could stimulate PCa proliferation,
enzyme-linked immunosorbent assay analysis to select candi- migration, and invasion in vitro.
date markers that were significantly different between these
patients and controls. Then, the clinical relevance between
OLR1 (the ox-LDL receptor) expression and PCa was ana- Keywords Ox-LDL . OLR1 . Cell migration . Prostate
lyzed in The Cancer Genome Atlas (TCGA) cohort. We also cancer . Proliferation
investigated the function of ox-LDL in PCa cell lines in vitro.
Phosphorylation protein chips were used to analyze cell sig-
naling pathways in ox-LDL-treated PC-3 cells. The ox-LDL
level was found to be significantly correlated with N stage of Introduction
prostate cancer. OLR1 expression was correlated with lymph
node metastasis in the TCGA cohort. In vitro, ox-LDL stim- In developed countries, prostate cancer (PCa) is the most
ulated the proliferation, migration, and invasion of LNCaP common malignancy in men and the second leading cause
of cancer-related mortality [1]. In recent years, the incidence
Fangning Wan and Xiaojian Qin contributed equally to this work. of PCa has gradually increased in the Peoples Republic of
Electronic supplementary material The online version of this article China. According to the latest Chinese Cancer Registry An-
(doi:10.1007/s13277-014-2994-6) contains supplementary material, nual Report (2012), PCa has become the sixth most prevalent
which is available to authorized users. cancer and the ninth leading cause of cancer-related mortality
F. Wan : X. Qin : G. Zhang : X. Lu : Y. Zhu : H. Zhang : B. Dai : in men, especially in urban areas [2].
G. Shi : D. Ye (*) Large cohort studies and meta-analyses suggest a poten-
Department of Urology, Fudan University Shanghai Cancer Center,
tially beneficial effect of statins on PCa patients treated with
Shanghai, Peoples Republic of China
e-mail: dwyeli@163.com radiotherapy. Statin usage was associated with improved free-
dom from biochemical failure, freedom from salvage andro-
F. Wan : X. Qin : G. Zhang : X. Lu : Y. Zhu : H. Zhang : B. Dai : gen deprivation therapy, and relapse-free survival in these
G. Shi : D. Ye
patients [3, 4]. Data show that men with coronary artery
Department of Oncology, Shanghai Medical College, Fudan
University, No. 270, Dongan Road, Shanghai 200032, Peoples disease were more likely to have diabetes, hypertension, and
Republic of China hypercholesterolemia, and this was associated with a 35 %
3574 Tumor Biol. (2015) 36:35733582
increased risk of PCa diagnosis, so it is reasonable to speculate in a previous study [16]. Only patients with intact tumor
that coronary artery disease shares etiology with PCa [5]. expression data were included in this study. Detailed
Oxidative stress is often cited as playing an important role demographics of these patients, characterized by the TCGA
in cardiovascular outcomes [68]. In PCa, oxidative stress, an consortium, are shown in Table 1.
innate and key event characterized by supraphysiological
concentrations of reactive oxygen species, has been identified In vitro studies
as one of the hallmarks of the aggressive disease phenotype.
Specifically, oxidative stress is associated with PCa develop- Cell lines
ment, progression, and response to therapy [911].
Oxidized low-density lipoprotein (ox-LDL) is an important Prostate cancer cell lines, LNCaP (CRL-1740) and PC-3
prognostic marker in the serum of atherosclerosis patients (CLR-1435), were purchased from American Type Culture
[12]. It is suggested that ox-LDL plays a more important role Collection (Manassas, VA, USA). LNCaP and PC-3 were
in the genesis and progression of atherosclerosis than native respectively cultured in RPMI 1640 (L0495, Biowest LCC,
LDL [4, 13], and ox-LDL is a biomarker associated with Kansas City, MI, USA) and F-12 K (21127-022, Life
oxidative stress in pathophysiological processes and is linked Technologies, Carlsbad, CA, USA) with 10 % fetal bovine
to atherogenesis and tumorigenesis [14, 15]. However, there serum (S181P, Biowest LCC) at 37 C in an atmosphere of
are insufficient studies on ox-LDL and its relevance with 5 % CO2.
respect to PCa behavior.
Western blot
Materials and methods Cell lysates of LNCaP and PC-3 were harvested following 0-,
6-, 12-, 24-, 48-, and 96-h treatments with ox-LDL. Western
Patients and samples blot analysis of OLR1 expression was performed as per de-
scribed methods [17]. Primary antibodies including anti-
This study received Institutional Review Board approval from OLR1 (ab85839, Abcam, Cambridge, UK), anti-GAPDH
Fudan University Shanghai Cancer Center (FUSCC), and (AP7873a, Abgent Inc., San Diego, CA, USA), and anti-
written informed consent was obtained from all subjects. A rabbit IgG peroxidase-conjugated antibody (LP1001b,
total of 75 patients including 50 PCa patients and 25 benign Abgent Inc.) were used for western blot analysis.
prostatic hyperplasia (BPH) patients were retrospectively col-
lected from 2008 to 2011. Pathology diagnoses were con- Cell viability assays
firmed by experienced pathologists. Baseline characteristics,
such as age, history of hypertension or diabetes mellitus, body The effects of ox-LDL on cell viability were assessed by Cell
mass index (BMI), smoking status, lipid profiles, statin usage, Counting Kit-8 (CCK-8) assays [17]. Cells were plated on 96-
prostate-specific antigen (PSA) levels, Gleason score (GS), well plates at a concentration of 5000 cells per well in tripli-
and stage at diagnosis (tumor, node, metastasis [TNM] clas- cate. After seeding for 12 h, cells were exposed to a series of
sification), were obtained from electronic records and medical concentrations of ox-LDL diluted in complete medium (0, 4,
charts. Blood samples of these patients were obtained from 20, and 100 g/ml). Next, 10 l of CCK-8 reagent was added
routine tests, and sera were separated by centrifugation and to each well 24, 48, and 96 h after adding ox-LDL. Cells were
immediately stored at 70 C in the tissue bank of FUSCC. incubated at 37 C for 2 h and measured at 450 nm on a plate
Sandwich enzyme-linked immunosorbent assay (ELISA) kits reader. Results were calculated and plotted with GraphPad
(ABIN417290, ABIN1371105, ABIN456069, ABIN414494, Prism software (GraphPad Software Inc., version 5.01, La
Antibodies-Online Inc., Atlanta, GA, USA) were used to Jolla, CA, USA). Experiments were repeated a minimum of
detect apoprotein B48 (APOB48), apoprotein B100 three times and representative results are shown.
(APOB100), anti-oxidized LDL antibody (OLAb), and ox-
LDL levels in blood serum with protocols and reagents sup- Cell migration and invasion
plied by the manufacturer.
OLR1 expression and clinical data were acquired from The Transwell assays were performed to evaluate cell migration
Cancer Genome Atlas (TCGA) database. The data are avail- and invasion [9]. For invasion analysis, 60 l of Matrigel (BD
able from the Cancer Genomics Browser of the University of Biosciences, Mississauga, ON, Canada) diluted in a serum-
California, Santa Cruz (UCSC) (https://genome-cancer.ucsc. free medium (1:5) was added to the upper compartment of the
edu/). In total, 256 primary prostate tumors from male patients chamber. Next, 5104 LNCaP and PC-3 cells were suspended
with detailed OLR1 expression data were chosen from the in 200 l of serum-free medium with a series of ox-LDL
updated TCGA database according to parameters mentioned concentrations (0, 4, 20, and 100 g/ml) and seeded into the
3574 Tumor Biol. (2015) 36:35733582
increased risk of PCa diagnosis, so it is reasonable to speculate in a previous study [16]. Only patients with intact tumor
that coronary artery disease shares etiology with PCa [5]. expression data were included in this study. Detailed
Oxidative stress is often cited as playing an important role demographics of these patients, characterized by the TCGA
in cardiovascular outcomes [68]. In PCa, oxidative stress, an consortium, are shown in Table 1.
innate and key event characterized by supraphysiological
concentrations of reactive oxygen species, has been identified In vitro studies
as one of the hallmarks of the aggressive disease phenotype.
Specifically, oxidative stress is associated with PCa develop- Cell lines
ment, progression, and response to therapy [911].
Oxidized low-density lipoprotein (ox-LDL) is an important Prostate cancer cell lines, LNCaP (CRL-1740) and PC-3
prognostic marker in the serum of atherosclerosis patients (CLR-1435), were purchased from American Type Culture
[12]. It is suggested that ox-LDL plays a more important role Collection (Manassas, VA, USA). LNCaP and PC-3 were
in the genesis and progression of atherosclerosis than native respectively cultured in RPMI 1640 (L0495, Biowest LCC,
LDL [4, 13], and ox-LDL is a biomarker associated with Kansas City, MI, USA) and F-12 K (21127-022, Life
oxidative stress in pathophysiological processes and is linked Technologies, Carlsbad, CA, USA) with 10 % fetal bovine
to atherogenesis and tumorigenesis [14, 15]. However, there serum (S181P, Biowest LCC) at 37 C in an atmosphere of
are insufficient studies on ox-LDL and its relevance with 5 % CO2.
respect to PCa behavior.
Western blot
Materials and methods Cell lysates of LNCaP and PC-3 were harvested following 0-,
6-, 12-, 24-, 48-, and 96-h treatments with ox-LDL. Western
Patients and samples blot analysis of OLR1 expression was performed as per de-
scribed methods [17]. Primary antibodies including anti-
This study received Institutional Review Board approval from OLR1 (ab85839, Abcam, Cambridge, UK), anti-GAPDH
Fudan University Shanghai Cancer Center (FUSCC), and (AP7873a, Abgent Inc., San Diego, CA, USA), and anti-
written informed consent was obtained from all subjects. A rabbit IgG peroxidase-conjugated antibody (LP1001b,
total of 75 patients including 50 PCa patients and 25 benign Abgent Inc.) were used for western blot analysis.
prostatic hyperplasia (BPH) patients were retrospectively col-
lected from 2008 to 2011. Pathology diagnoses were con- Cell viability assays
firmed by experienced pathologists. Baseline characteristics,
such as age, history of hypertension or diabetes mellitus, body The effects of ox-LDL on cell viability were assessed by Cell
mass index (BMI), smoking status, lipid profiles, statin usage, Counting Kit-8 (CCK-8) assays [17]. Cells were plated on 96-
prostate-specific antigen (PSA) levels, Gleason score (GS), well plates at a concentration of 5000 cells per well in tripli-
and stage at diagnosis (tumor, node, metastasis [TNM] clas- cate. After seeding for 12 h, cells were exposed to a series of
sification), were obtained from electronic records and medical concentrations of ox-LDL diluted in complete medium (0, 4,
charts. Blood samples of these patients were obtained from 20, and 100 g/ml). Next, 10 l of CCK-8 reagent was added
routine tests, and sera were separated by centrifugation and to each well 24, 48, and 96 h after adding ox-LDL. Cells were
immediately stored at 70 C in the tissue bank of FUSCC. incubated at 37 C for 2 h and measured at 450 nm on a plate
Sandwich enzyme-linked immunosorbent assay (ELISA) kits reader. Results were calculated and plotted with GraphPad
(ABIN417290, ABIN1371105, ABIN456069, ABIN414494, Prism software (GraphPad Software Inc., version 5.01, La
Antibodies-Online Inc., Atlanta, GA, USA) were used to Jolla, CA, USA). Experiments were repeated a minimum of
detect apoprotein B48 (APOB48), apoprotein B100 three times and representative results are shown.
(APOB100), anti-oxidized LDL antibody (OLAb), and ox-
LDL levels in blood serum with protocols and reagents sup- Cell migration and invasion
plied by the manufacturer.
OLR1 expression and clinical data were acquired from The Transwell assays were performed to evaluate cell migration
Cancer Genome Atlas (TCGA) database. The data are avail- and invasion [9]. For invasion analysis, 60 l of Matrigel (BD
able from the Cancer Genomics Browser of the University of Biosciences, Mississauga, ON, Canada) diluted in a serum-
California, Santa Cruz (UCSC) (https://genome-cancer.ucsc. free medium (1:5) was added to the upper compartment of the
edu/). In total, 256 primary prostate tumors from male patients chamber. Next, 5104 LNCaP and PC-3 cells were suspended
with detailed OLR1 expression data were chosen from the in 200 l of serum-free medium with a series of ox-LDL
updated TCGA database according to parameters mentioned concentrations (0, 4, 20, and 100 g/ml) and seeded into the
Tumor Biol. (2015) 36:35733582 3575
phosphorylation of untreated cells. This experiment was car- two groups (all p > 0.05). However, abnormal TC was
ried out once. more commonly seen in PCa patients (p<0.05). Besides,
we screened four more relative biomarkers in patient
Statistical analyses serum. ApoB48 and ApoB100 were found to be strongly
co-expressed, but did not show a significant increase in
Statistical analyses were performed with SPSS software (ver- primary or metastatic PCa. Similarly, OLAB was not
sion 17.0, IBM Corp., Armonk, NY, USA) using independent associated with PCa. However, ox-LDL was significantly
t tests (for continuous variables) and Pearsons 2 tests (for increased in PCa patients and even higher in metastatic
categorical variables). Logistic regression was used to deter- PCa patients (Fig. 1).
mine the correlation between OLR1 expression level and
clinicopathological characteristics in the TCGA cohorts. Sta-
tistical significance was based on two-sided p values of <0.05. OLR1 was associated with high Gleason score and lymph
node metastasis
were found to be independent predictors of high Gleason Ox-LDL increased the migration and invasion capabilities
score (Table 3). of LNCaP and PC-3
2.45) and STAT3 (phospho-Tyr705, fold change 1.63) activa- lymph node metastasis. Moreover, we found that ox-LDL
tion could stimulate expression of downstream genes respon- might promote PC-3 and LNCaP proliferation, migration,
sible for progressive PCa. Apoptosis-associated protein and invasion and stimulate OLR1 expression in a dose- and
caspase-3 (phospho-Ser150, fold change 1.99) is activated in time-dependent manner in PC-3 cells. Taken together, our
ox-LDL-treated cells (Fig. 5). Activation of these signaling study demonstrated that ox-LDL could be a pivotal factor
pathways might be responsible for ox-LDL-induced tumor for advanced PCa and also a hallmark of PCa progression
proliferation, migration, and apoptosis. and prognosis. Furthermore, patients with high expression of
OLR1 are more likely to have lymph node metastasis; thus,
extended lymph node dissection and closer examination of
surgical margins should be performed for patients with high
Discussion serum ox-LDL levels.
A recent study linked metabolic disorders to the sophisti-
Our study revealed that the ox-LDL level in serum was cated nature of cancer phenotypes. Thanks to previous ath-
associated with PCa aggressiveness. In addition, overexpres- erosclerosis and hyperlipidemia studies, our study on ox-LDL
sion of OLR1 was associated with higher Gleason score and and PCa was inspired. Ox-LDL promoted proliferation,
Tumor Biol. (2015) 36:35733582 3579
Fig. 3 Ox-LDL promoted PC-3 migration and stimulated the expression dependent manner. b Wound healing percentages were normalized to
of OLR1. a Representative images of the wound healing assay showed controls and plotted. c Ox-LDL can increase OLR1 levels in a dose-
that ox-LDL could promote the migration capabilities of PC-3 in a dose- and time-dependent manner
accelerated cell cycle, stimulated cell migration, and promoted ox-LDL can stimulate OLR1 expression and is responsible for
PCa in our study. To our knowledge, few studies have ex- proliferation, migration, and apoptosis.
plored the role of ox-LDL and its mechanisms on PCa. OLR1, High Gleason score, lymph node metastasis, and bone
the ox-LDL receptor, was highly expressed in PC-3 compared metastasis are typically seen in aggressive PCa, implying
with LNCaP cells. Interestingly, PC-3 cells are more aggres- decreased survival and poor quality of life. As a complex
sive than LNCaP with respect to many biological behaviors, process, PCa metastasis begins with a cell tropism to invasion
such as proliferation [19, 20] and drug resistance to docetaxel and is driven by extracellular signals [24]. Ox-LDL level is
[21]. This phenomenon inspired us to investigate OLR1 ex- always high in obese and atherosclerotic patients [25], who
pression with respect to PCa invasion and migration. also suffer from metabolic syndromes, such as hypertension,
OLR1, a lectin-like scavenger receptor, is capable of rec- diabetes mellitus, and dyslipidemia. The association between
ognizing several ligands, including the ox-LDL protein moi- metabolic syndrome and the risk of biochemical recurrence
ety [22]. Overexpression of OLR1 has already been found in after radical prostatectomy in patients with PCa is well
the cellular components of atherosclerotic lesions [23]. Recent established [26]. These results may explain why statin usage
studies also showed that OLR1 might act as an oncogene by was reported to be beneficial for PCa patients [3, 13].
activating of NF-kB target genes responsible for proliferation, In this study, we show, for the first time, that ox-LDL is a
migration, and inhibition of apoptosis [22] and analogous to new marker for metastatic PCa. Khaidakov reported that ox-
our microarray findings. In addition to NF-kB activation, in LDL triggers pro-oncogenic signaling in human breast mam-
our study, exogenous ox-LDL increased cellular P27, c-Myc, mary epithelial cells via stimulation of MiR-21 [27]. Ox-LDL
-catenin, and caspase-3 levels. These findings illustrate that has also been reported as an independent factor differentiating
3580 Tumor Biol. (2015) 36:35733582
patients with pancreatic cancer from patients with chronic 6. Li N, Hao M, Phalen RF, Hinds WC, Nel AE. Particulate air pollut-
ants and asthma. A paradigm for the role of oxidative stress in PM-
pancreatitis [28]. In this study, we discovered that ox-LDL
induced adverse health effects. Clin Immunol. 2003;109:25065.
might promote proliferation through stimulating cell cycle and 7. Araujo JA, Nel AE. Particulate matter and atherosclerosis: role of
did not interfere with apoptosis at low concentrations. Al- particle size, composition and oxidative stress. Particle Fibre Toxicol.
though p-Akt decreased in ox-LDL-treated PC-3 cells, p-Akt 2009;6:24.
8. Ghio AJ, Carraway MS, Madden MC. Composition of air pollution
inhibited P27 increases, and the MAPK/c-Myc pathway and
particles and oxidative stress in cells, tissues, and living systems. J
NF-B were activated. Toxic Environ Health B, Crit Rev. 2012;15:121.
There are several limitations to this study. For instance, this 9. Kumar B, Koul S, Khandrika L, Meacham RB, Koul HK. Oxidative
was a single-center research study with limited cases, and stress is inherent in prostate cancer cells and is required for aggressive
phenotype. Cancer Res. 2008;68:177785.
thus, possible selection bias was unavoidable. Furthermore,
10. Nguyen HL, Zucker S, Zarrabi K, Kadam P, Schmidt C, Cao J.
the TCGA cohort of PCa patients is incomplete because many Oxidative stress and prostate cancer progression are elicited by
data are currently unavailable. Therefore, further validation of membrane-type 1 matrix metalloproteinase. Mol Cancer Res:
our work at other centers, including patients of other races and MCR. 2011;9:130518.
11. Paschos A, Pandya R, Duivenvoorden WC, Pinthus JH. Oxidative
re-analysis with updated TCGA data, is needed. Moreover,
stress in prostate cancer: changing research concepts towards a novel
further validation of our protein microarray results in other paradigm for prevention and therapeutics. Prostate Cancer Prostatic
PCa cell lines and studies evaluating crosstalk after ox-LDL Dis. 2013;16:21725.
treatment are required. The role of ox-LDL in apoptosis of 12. Lubrano V, Balzan S. LOX-1 and ROS, inseparable factors in the
PCa cells was not clearly defined yet. However, this study process of endothelial damage. Free Radic Res. 2014;119.
13. DAmico AV. Statin use and the risk of prostate-specific antigen recur-
revealed a novel serum protein marker related to obesity and rence after radiation therapy with or without hormone therapy for pros-
oxidization stress that contributes to PCa metastasis. Our tate cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2010;28:26512.
research may facilitate further research on how ox-LDL can 14. Shen Y, Yang T, Guo S, Li X, Chen L, Wang T, et al. Increased serum
trigger PCa invasion or metastasis and elucidate the underly- ox-LDL levels correlated with lung function, inflammation, and
oxidative stress in COPD. Mediat Inflamm. 2013;2013:972347.
ing mechanisms of this relationship. 15. Lu J, Mitra S, Wang X, Khaidakov M, Mehta JL. Oxidative stress and
lectin-like ox-LDL-receptor LOX-1 in atherogenesis and tumorigen-
esis. Antioxid Redox Signal. 2011;15:230133.
Conclusion 16. Jiang YZ, Yu KD, Zuo WJ, Peng WT, Shao ZM. GATA3 mutations
define a unique subtype of luminal-like breast cancer with improved
survival. Cancer. 2014;120:132937.
Increased serum ox-LDL levels and OLR1 expression may 17. Ye L, Yao XD, Wan FN, Qu YY, Liu ZY, Shen XX, et al. MS4A8B
indicate advanced-stage PCa and lymph node metastasis. Ox- promotes cell proliferation in prostate cancer. Prostate. 2014;74:91122.
LDL can stimulate prostate cancer proliferation, migration, 18. Eke I, Schneider L, Forster C, Zips D, Kunz-Schughart LA, Cordes
N. EGFR/JIP-4/JNK2 signaling attenuates cetuximab-mediated
and invasion in vitro, and exogenous ox-LDL can activate radiosensitization of squamous cell carcinoma cells. Cancer Res.
multiple signaling pathways in PC-3 cells in vitro. 2013;73:297306.
19. Kalin TV, Wang IC, Ackerson TJ, Major ML, Detrisac CJ,
Kalinichenko VV, et al. Increased levels of the FoxM1 transcription
factor accelerate development and progression of prostate carcino-
mas in both TRAMP and LADY transgenic mice. Cancer Res.
References 2006;66:171220.
20. Saraon P, Musrap N, Cretu D, Karagiannis GS, Batruch I, Smith C,
et al. Proteomic profiling of androgen-independent prostate cancer
1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cell lines reveals a role for protein S during the development of high
cancer statistics. CA Cancer J Clin. 2011;61:6990. grade and castration-resistant prostate cancer. J Biol Chem.
2. He J, Chen W. Chinese cancer registry annual report. Beijing: 2012;287:3401931.
Military Medical Science Press; 2012. 21. Muenchen HJ, Poncza PJ, Pienta KJ. Different docetaxel-induced
3. Gutt R, Tonlaar N, Kunnavakkam R, Karrison T, Weichselbaum RR, apoptotic pathways are present in prostate cancer cell lines LNCaP
Liauw SL. Statin use and risk of prostate cancer recurrence in men and PC-3. Urology. 2001;57:36670.
treated with radiation therapy. J Clin Oncol Off J Am Soc Clin Oncol. 22. Khaidakov M, Mitra S, Kang BY, Wang X, Kadlubar S, Novelli G,
2010;28:26539. et al. Oxidized LDL receptor 1 (OLR1) as a possible link between
4. Park HS, Schoenfeld JD, Mailhot RB, Shive M, Hartman RI, obesity, dyslipidemia and cancer. PLoS One. 2011;6:e20277.
Ogembo R, et al. Statins and prostate cancer recurrence following 23. Chen M, Kakutani M, Minami M, Kataoka H, Kume N, Narumiya S,
radical prostatectomy or radiotherapy: a systematic review and meta- et al. Increased expression of lectin-like oxidized low density lipo-
analysis. Ann Oncol Off J Eur Soc Med Oncol / ESMO. 2013;24: protein receptor-1 in initial atherosclerotic lesions of Watanabe her-
142734. itable hyperlipidemic rabbits. Arterioscler Thromb Vasc Biol.
5. Thomas 2nd JA, Gerber L, Banez LL, Moreira DM, Rittmaster RS, 2000;20:110715.
Andriole GL, et al. Prostate cancer risk in men with baseline history 24. Muralidharan A, Smith MT. Pathobiology and management of pros-
of coronary artery disease: results from the REDUCE study. Cancer tate cancer-induced bone pain: recent insights and future treatments.
Epidemiol Biomarkers Prev: Publ Am Assoc Cancer Res Inflammopharmacology. 2013;21:33963.
cosponsored by the American Society of Preventive Oncology. 25. Syvaranta S, Alanne-Kinnunen M, Oorni K, Oksjoki R, Kupari M,
2012;21:57681. Kovanen PT, et al. Potential pathological roles for oxidized low-
3582 Tumor Biol. (2015) 36:35733582
density lipoprotein and scavenger receptors SR-AI, CD36, and LOX- 27. Khaidakov M, Mehta JL. Oxidized LDL triggers pro-oncogenic
1 in aortic valve stenosis. Atherosclerosis. 2014;235:398407. signaling in human breast mammary epithelial cells partly via stim-
26. Shiota M, Yokomizo A, Takeuchi A, Imada K, Kiyoshima K, ulation of MiR-21. PLoS One. 2012;7:e46973.
Inokuchi J, Tatsugami K, Naito S. The feature of metabolic syndrome 28. Kodydkova J, Vavrova L, Stankova B, Macasek J, Krechler T, Zak A.
is a risk factor for biochemical recurrence after radical prostatectomy. Antioxidant status and oxidative stress markers in pancreatic cancer
J Surg Oncol. 2014 and chronic pancreatitis. Pancreas. 2013;42:61421.