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Human Papillomavirus Genotyping and p16INK4a Expression in Cervical Lesions: A Combined Test to Avoid Cervical Cancer Progression.

Yassine ZOUHEIR ; Taoufiq FECHTALI ; Nadia ELGNAOUI

Journal of Cancer Prevention.2016;21(2):121-125. doi:10.15430/JCP.2016.21.2.121

Cervical cancer is a major public health problem in Morocco. The cervical cancer has a long precancerous period that provides an opportunity for the screening and treatment. Improving screening tests is a priority goal for the early diagnosis of cervical cancer. This study was conducted to evaluate the combination of p16INK4a protein expression, human papillomavirus (HPV) typing, and histopathology for the identification of cervical lesions with high risk to progress to cervical cancer among Moroccan women. A total of 96 cervical biopsies were included in this study. Signal amplification in situ hybridization with biotinylated probes was used to detect HPV. Immunohistochemistry was used to evaluate the expression of p16INK4a protein. HPV DNA was detected in 74.0% of the biopsies (71/96). Of the seventy-one positive HPV cases, we detected 67.6% (48/71) of high risk (HR)-HPV (HPV 16 and 18), 24% of low risk-HPV (HPV 6 and 11), 1.4% intermediate risk-HPV (HPV 31, 33, and 35), and 7% coinfections (HPV 6/11 and 16/18). Overexpression of p16INK4a protein was observed in 72.9% (70/96) of the biopsies. In addition, p16INK4a protein detection was closely correlated with recovery of HR HPV. Our result showed that p16INK4a expression level is correlated with HR-HPV status.
Biopsy ; Coinfection ; Cyclin-Dependent Kinase Inhibitor p16 ; DNA ; Early Diagnosis ; Female ; Humans* ; Immunohistochemistry ; In Situ Hybridization ; Mass Screening ; Morocco ; Public Health ; Uterine Cervical Neoplasms*

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A Multi-stage Carcinogenesis Model to Investigate Caloric Restriction as a Potential Tool for Post-irradiation Mitigation of Cancer Risk.

Shusuke TANI ; Benjamin John BLYTH ; Yi SHANG ; Takamitsu MORIOKA ; Shizuko KAKINUMA ; Yoshiya SHIMADA

Journal of Cancer Prevention.2016;21(2):115-120. doi:10.15430/JCP.2016.21.2.115

The risk of radiation-induced cancer adds to anxiety in low-dose exposed populations. Safe and effective lifestyle changes which can help mitigate excess cancer risk might provide exposed individuals the opportunity to pro-actively reduce their cancer risk, and improve mental health and well-being. Here, we applied a mathematical multi-stage carcinogenesis model to the mouse lifespan data using adult-onset caloric restriction following irradiation in early life. We re-evaluated autopsy records with a veterinary pathologist to determine which tumors were the probable causes of death in order to calculate age-specific mortality. The model revealed that in both irradiated and unirradiated mice, caloric restriction reduced the age-specific mortality of all solid tumors and hepatocellular carcinomas across most of the lifespan, with the mortality rate dependent more on age owing to an increase in the number of predicted rate-limiting steps. Conversely, irradiation did not significantly alter the number of steps, but did increase the overall transition rate between the steps. We show that the extent of the protective effect of caloric restriction is independent of the induction of cancer from radiation exposure, and discuss future avenues of research to explore the utility of caloric restriction as an example of a potential post-irradiation mitigation strategy.
Animals ; Anxiety ; Autopsy ; Caloric Restriction* ; Carcinogenesis* ; Carcinoma, Hepatocellular ; Cause of Death ; Life Style ; Mental Health ; Mice ; Models, Theoretical ; Mortality ; Neoplasms, Radiation-Induced ; Radiation Exposure

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Suppression of β-catenin Signaling Pathway in Human Prostate Cancer PC3 Cells by Delphinidin.

Wooje LEE ; Jung Mi YUN

Journal of Cancer Prevention.2016;21(2):110-114. doi:10.15430/JCP.2016.21.2.110

Delphinidin possesses strong anti-oxidant, anti-inflammatory, and anti-cancer properties. Suppression of the Wnt/β-catenin signaling pathway is a potential strategy for chemoprevention and therapy. As aberrant activation of the β-catenin signaling pathway contributes to prostate cancer progression, we evaluated the effect of delphinidin on this pathway in human PC3 prostate cancer cells. An MTT assay showed that treatment with delphinidin (15-180 μM, 72 hours) resulted in a dose-dependent growth inhibition of cells. Treatment with delphinidin increased the phosphorylation of serine or threonine residues on β-catenin and decreased the levels of cytoplasmic β-catenin. Moreover, treatment with delphinidin inhibited the nuclear translocation of β-catenin and the expression of β-catenin target genes such as cyclin D1, c-myc, Axin-2, and T cell factor-1. Delphinidin also induced the phosphorylation of glycogen synthase kinase 3β and the expression of adenomatous polyposis coli and Axin proteins. Our results indicate that inhibition of cell growth by delphinidin is mediated, at least in part, through modulation of the β-catenin signaling pathway. We suggest that delphinidin is a potent inhibitor of Wnt/β-catenin signaling in prostate cancer cells.
Adenomatous Polyposis Coli ; Anthocyanins ; Axin Protein ; beta Catenin ; Chemoprevention ; Cyclin D1 ; Cytoplasm ; Glycogen Synthase Kinases ; Humans* ; Phosphorylation ; Prostate* ; Prostatic Neoplasms* ; Serine ; Threonine

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Human Papillomavirus Prevalence and Type Distribution Among 968 Women in South Korea.

Kyeong A SO ; Jin Hwa HONG ; Jae Kwan LEE

Journal of Cancer Prevention.2016;21(2):104-109. doi:10.15430/JCP.2016.21.2.104

BACKGROUND: Geographic variation in the prevalence of carcinogenic types and human papillomavirus (HPV) genotype distribution is closely associated with the impact of HPV prophylactic vaccines. We determined the prevalence and distribution of HPV genotypes among healthy women in Korea. METHODS: This study included 968 healthy women who were examined at a health promotion center of the Korea University Guro Hospital between January and June 2013. Each participant had a Pap test and a HPV DNA test using the Anyplex™ II HPV 28 Detection system, which detects 19 high-risk HPVs (HR HPVs) and 9 low-risk HPVs (LR HPVs). Women with abnormal cytology and/or positivity for HR HPVs were referred to colposcopic biopsy. RESULTS: Overall HR HPV prevalence based on the assay was 33.7%. Among them, 225 women had single infection and 101 women had multiple infection. The most frequently occurring HR HPV types were 53 (6.5%), 52 (6.1%), 58 (4.8%), 16 (4.5%), and 68 (4.2%). The most frequently occurring LR HPV types were 54 (5.4%), 70 (3.8%), 42 (3.6%), 61 (3.4%), and 44 (3.1%). The prevalence of HPV 16 was highest (17.6%) among women with cervical intraepithelial neoplasia (CIN) and HPV 16 was strongly associated with a diagnosis of CIN2/3 (odds ratio = 20.5; 95% confidence interval: 3.9-107.1; P < 0.0001). CONCLUSIONS: HPV 53, 52, 58, 16, and 68 were common HR HPV types among healthy Korean women. HPV16 was the most common type in high-grade CIN lesions, as shown in most studies worldwide. The results might be useful information for cervical cancer prevention in South Korea.
Biopsy ; Cervical Intraepithelial Neoplasia ; Diagnosis ; Female ; Genotype ; Health Promotion ; Human papillomavirus 16 ; Human Papillomavirus DNA Tests ; Humans* ; Korea* ; Papanicolaou Test ; Prevalence* ; Uterine Cervical Neoplasms ; Vaccines

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High-fat Diet Accelerates Intestinal Tumorigenesis Through Disrupting Intestinal Cell Membrane Integrity.

Mi Young PARK ; Min Young KIM ; Young Rok SEO ; Jong Sang KIM ; Mi Kyung SUNG

Journal of Cancer Prevention.2016;21(2):95-103. doi:10.15430/JCP.2016.21.2.95

BACKGROUND: Excess energy supply induces chronic low-grade inflammation in association with oxidative stress in various tissues including intestinal epithelium. The objective of this study was to investigate the effect of high-fat diet (HFD) on intestinal cell membrane integrity and intestinal tumorigenesis in ApcMin/+ mice. METHODS: Mice were fed with either normal diet (ND) or HFD for 12 weeks. The number of intestinal tumors were counted and biomarkers of endotoxemia, oxidative stress, and inflammation were determined. Changes in intestinal integrity was measured by fluorescein isothiocyanate (FITC)-dextran penetration and membrane gap junction protein expression. RESULTS: HFD group had significantly higher number of tumors compared to ND group (P < 0.05). Blood total antioxidant capacity was lower in HFD group, while colonic 8-hydroxy-2'-deoxyguanosine level, a marker of oxidative damage, was higher in HFD group compared to that of ND group (P < 0.05). The penetration of FITC-dextran was substantially increased in HFD group (P < 0.05) while the expressions of membrane gap junction proteins including zonula occludens-1, claudin-1, and occludin were lower in HFD group (P < 0.05) compared to those in ND group. Serum concentration of lipopolysaccharide (LPS) receptor (CD14) and colonic toll-like receptor 4 (a LPS receptor) mRNA expression were significantly higher in HFD group than in ND group (P < 0.05), suggesting that significant endotoxemia may occur in HFD group due to the increased membrane permeability. Serum interleukin-6 concentration and myeloperoxidase activity were also higher in HFD group compared to those of ND group (P < 0.05). CONCLUSIONS: HFD increases oxidative stress disrupting intestinal gap junction proteins, thereby accelerating membrane permeability endotoxemia, inflammation, and intestinal tumorigenesis.
Animals ; Biomarkers ; Carcinogenesis* ; Cell Membrane* ; Claudin-1 ; Colon ; Colonic Neoplasms ; Connexins ; Diet ; Diet, High-Fat* ; Endotoxemia ; Fluorescein ; Inflammation ; Interleukin-6 ; Intestinal Mucosa ; Membranes ; Mice ; Occludin ; Oxidative Stress ; Permeability ; Peroxidase ; RNA, Messenger ; Toll-Like Receptor 4

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The Inhibitory Effects of Forsythia Koreana Extracts on the Metastatic Ability of Breast Cancer Cells and Bone Resorption by Osteoclasts.

Yu Li KIM ; Sun Kyoung LEE ; Kwang Kyun PARK ; Won Yoon CHUNG

Journal of Cancer Prevention.2016;21(2):88-94. doi:10.15430/JCP.2016.21.2.88

BACKGROUND: Breast cancer is the most common malignant disease in women. The patients with advanced breast cancer develop metastasis to bone. Bone metastasis and skeletal-related events by breast cancer are frequently associated with the invasiveness of breast cancer cells and osteoclasts-mediated bone resorption. Forsythia koreana is used in oriental traditional medicine to treat asthma, atopy, and allergic diseases. The aim of this study was to evaluate the inhibitory effects of F. koreana extracts on the invasion of breast cancer cells and bone resorption by osteoclasts. METHODS: Cell viability was measured by an MTT assay and the migration and invasion of MDA-MB-231 cells were detected by a Boyden chamber assay. The formation of osteoclasts and pit was detected using tartrate-resistant acid phosphatase staining and calcium phosphate-coated plates, respectively. The activities of matrix metalloproteinases (MMPs) and cathepsin K were evaluated by gelatin zymography and a cathepsin K detection kit. RESULTS: The fruit and leaf extracts of F. koreana significantly inhibited the invasion of MDA-MB-231 cells at noncytotoxic concentrations. The fruit extract of F. koreana reduced the transforming growth factor β1-induced migration, invasion and MMPs activities of MDA-MB-231 cells. In addition, the fruit, branch, and leaf extracts of F. koreana also inhibited the receptor activator of nuclear factor kappa-B ligand-induced osteoclast formation and osteoclast-mediated bone-resorbing activity by reducing the activities of MMPs and cathepsin K. CONCLUSIONS: The extracts of F. koreana may possess the potential to inhibit the breast cancer-induced bone destruction through blocking invasion of breast cancer cells, osteoclastogenesis, and the activity of mature osteoclasts.
Acid Phosphatase ; Asthma ; Bone Resorption* ; Breast Neoplasms* ; Breast* ; Calcium ; Cathepsin K ; Cell Survival ; Female ; Forsythia* ; Fruit ; Gelatin ; Humans ; Matrix Metalloproteinases ; Medicine, East Asian Traditional ; Neoplasm Metastasis ; Osteoclasts* ; Transforming Growth Factors

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Chrysophanic Acid Induces Necrosis but not Necroptosis in Human Renal Cell Carcinoma Caki-2 Cells.

Joon Seok CHOI

Journal of Cancer Prevention.2016;21(2):81-87. doi:10.15430/JCP.2016.21.2.81

BACKGROUND: Chrysophanic acid, also known as chrysophanol, has a number of biological activities. It enhances memory and learning abilities, raises superoxide dismutase activity, and has anti-cancer effects in several model systems. According to previous reports, chrysophanic acid-induced cell death shares features of necrotic cell death. However, the molecular and cellular processes underlying chrysophanic acid-induced cell death remain poorly understood. METHODS: Chrysophanic acid-induced cell death was monitored by cell viability assay and Annexin V-propidium iodide (PI) staining of renal cell carcinoma Caki-2 cells. The induction of intracellular reactive oxygen species (ROS) by chrysophanic acid and the suppression of ROS by anti-oxidants were evaluated by 2',7'-dichlorofluorescin diacetate staining. The expression and phosphorylation of proteins that are involved in apoptosis and necroptosis were detected by immunoblotting. RESULTS: The extent of chrysophanic acid-induced cell death was concentration and time dependent, and dead cells mainly appeared in the PI-positive population, which is a major feature of necrosis, upon fluorescence-activated cell sorting analysis. Chrysophanic acid-induced cell death was associated with the generation of intracellular ROS, and this effect was reversed by pretreatment with N-acetyl cysteine. Chrysophanic acid-induced cell death was not associated with changes in apoptotic or necroptotic marker proteins. CONCLUSIONS: The cell death induced by chrysophanic acid resembled neither apoptotic nor necroptotic cell death in human renal cell carcinoma Caki-2 cells.
Apoptosis ; Carcinoma, Renal Cell* ; Cell Death ; Cell Survival ; Cysteine ; Flow Cytometry ; Humans* ; Immunoblotting ; Learning ; Memory ; Necrosis* ; Phosphorylation ; Reactive Oxygen Species ; Superoxide Dismutase

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Nano-mechanical Phenotype as a Promising Biomarker to Evaluate Cancer Development, Progression, and Anti-cancer Drug Efficacy.

Soyeun PARK

Journal of Cancer Prevention.2016;21(2):73-80. doi:10.15430/JCP.2016.21.2.73

Since various bio-mechanical assays have been introduced for studying mechanical properties of biological samples, much progress has been made in cancer biology. It has been noted that enhanced mechanical deformability can be used as a marker for cancer diagnosis. The relation between mechanical compliances and the metastatic potential of cancer cells has been suggested to be a promising prognostic marker. Although it is yet to be conclusive about its clinical application due to the complexity in the tissue integrity, the nano-mechanical compliance of human cell samples has been evaluated by several groups as a promising marker in diagnosing cancer development and anticipating its progression. In this review, we address the mechanical properties of diverse cancer cells obtained by atomic force microscopy-based indentation experiments and reiterate prognostic relations between the nano-mechanical compliance and cancer progression. We also review the nano-mechanical responses of cancer cells to the anti-cancer drug treatment in order to interrogate a possible use of nano-mechanical compliance as a means to evaluate the effectiveness of anti-cancer drugs.
Antineoplastic Agents ; Biology ; Compliance ; Diagnosis ; Elastic Modulus ; Humans ; Microscopy, Atomic Force ; Neoplasm Metastasis ; Phenotype*

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Regulation of Inflammation by Sucrose Isomer, Turanose, in Raw 264.7 Cells.

Joo Yeon CHUNG ; Yoo Sun KIM ; Yuri KIM ; Sang Ho YOO

Journal of Cancer Prevention.2017;22(3):195-201. doi:10.15430/JCP.2017.22.3.195

Increased sugar consumption has been proposed to be a risk factor for obesity-related metabolic disorders. The objective of this study was to investigate the anti-inflammatory effect of turanose in Raw 264.7 macrophages. Turanose (3-O-α-D-glucosyl-D-fructose), an isomer of sucrose, naturally exists in honey. For these studies, macrophages were treated with total glucose (Glu), 50% Glu/50% turanose (T50), 25% Glu/75% turanose (T75), and 100% turanose (T100), each with a total concentration of 25 mM in cell media. Expressions of inflammatory enzymes and cytokines were analyzed. Cell viability was not affected in the turanose treated groups compared to the Glu group. Lipopolysaccharide and glucose-induced nitric oxide production, protein expression of inducible nitric oxide synthase, COX-2, and superoxide dismutase 2, and mRNA expression levels of interleukin (IL)-1β and IL-18 were significantly suppressed by turanose treatment. These results demonstrate that turanose exerts anti-inflammatory effects in vitro, and possesses potential to serve therapeutic functional sweetener for testing in vivo and in clinical trials.
Cell Survival ; Cytokines ; Glucose ; Honey ; In Vitro Techniques ; Inflammation* ; Interleukin-18 ; Interleukins ; Macrophages ; Nitric Oxide ; Nitric Oxide Synthase Type II ; RAW 264.7 Cells* ; Risk Factors ; RNA, Messenger ; Sucrose* ; Superoxide Dismutase ; Sweetening Agents

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Peroxisome Proliferator-activated Receptor-gamma Inhibits the Activation of STAT3 in Cerulein-stimulated Pancreatic Acinar Cells.

Kyung Don JU ; Joo Weon LIM ; Hyeyoung KIM

Journal of Cancer Prevention.2017;22(3):189-194. doi:10.15430/JCP.2017.22.3.189

Cerulein-induced pancreatitis is similar to human edematous pancreatitis, characterized by the dysregulation of digestive enzyme production, edema formation, and an infiltration of inflammatory cells into the pancreas. We previously showed that the Janus kinase 2 (JAK2)/STAT3 pathway mediates inflammatory signaling in cerulein-stimulated pancreatic acinar cells. PPAR-γ has been implicated in the regulation of inflammatory responses in several cells. In the present study, we investigated the role of PPAR-γ in cerulein-induced activation of JAK2/STAT3 in pancreatic acinar cells. Treatment with cerulein induced the activation of JAK2/STAT3 and PPAR-γ expression in AR42J cells. Cerulein-induced PPAR-γ expression was inhibited by AG490, a JAK2/STAT3 inhibitor, in AR42J cells. An immunoprecipitation analysis showed that PPAR-γ binds to STAT3 in cerulein-stimulated AR42J cells. Down-regulation of PPAR-γ by siRNA increased STAT3 phosphorylation in AR42J cells stimulated with cerulein. These results show that PPAR-γ inactivates STAT3 by directly interacting with STAT3 in cerulein-stimulated pancreatic acinar cells. Overexpression of PPAR-γ may be beneficial for preventing pancreatitis by suppressing the activation of STAT3 in pancreatic acinar cells.
Acinar Cells* ; Ceruletide ; Down-Regulation ; Edema ; Humans ; Immunoprecipitation ; Janus Kinase 2 ; Pancreas ; Pancreatitis ; Peroxisomes* ; Phosphorylation ; RNA, Small Interfering

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