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1.  Chemopreventive Effects of Korean Red Ginseng Extract on Rat Hepatocarcinogenesis 
Journal of Cancer  2015;6(1):1-8.
The objective of this study was to determine a chemopreventive activity of Korean red ginseng extract (KRG) in diethylnitrosamine (DEN) induced hepatocarcinogenesis in rats. After acclimatization for a week, Sprague-Dawley rats were randomized into five groups (n = 15) and fed either KRG (0.5, 1 or 2%) or control diets for 10 weeks. After two weeks of starting of experimental diets, the rats were initiated hepatocarcinogenesis by injection of DEN and were then subjected to two-thirds partial hepatectomy at five-week for developing the medium-term bioassay system. Both 0.5 and 1% KRG diets suppressed the area (55 and 60%; p= 0.0251 and 0.0144) and number (39 and 59%; p= 0.0433 and 0.0012) of glutathione S-transferase placental form (GST-P) positive foci when compared to the DEN-control group. The production of thiobarbituric acid reactive substances (TBARS) was significantly reduced in 0.5 and 1% KRG-treated rats. The supplementation of 1% KRG diet significantly elevated the levels of total glutathione (tGSH) and glutathione-related enzymes including cytosolic glutathione S-transferase (GST) and glutathione peroxidase (GPx) activities. It was also observed in cDNA microarray that the gene expressions (Cyp2c6, Cyp2e1, Cyp3a9, and Mgst1) involved in the xenobiotics metabolism via cytochrome P450 signaling pathway were down-regulated in the 1% KRG diet-treated group when compared to the DEN-control. The chemopreventive effects of KRG could be affected by 1) the decrease of lipid peroxidation, 2) the increase of tGSH content and GSH-dependent enzyme activities, and 3) the decrease of the gene expression profile involved in cytochrome P450 signaling pathway. These results suggest that KRG may prove to be a therapeutic agent against hepatocarcinogenesis.
doi:10.7150/jca.10353
PMCID: PMC4278909  PMID: 25553083
Korean red ginseng; rat; glutathione S-transferase placental form positive foci; hepatocarcinogenesis; antioxidant.
2.  Use of Proteins as Biomarkers and Their Role in Carcinogenesis 
Journal of Cancer  2015;6(1):9-18.
Summary: Improved diagnostic methods and medical therapies are necessary for early detection and treatment and an improved prognosis. It is thus vital to both examine and evaluate the role of the various existing proteins as biomarkers in carcinogenesis and to assess the contribution of these proteins in anti-cancer activity, for consideration in therapeutic strategies. It is essential to both examine and evaluate the role of the various existing proteins as biomarkers in carcinogenesis and to assess the contribution of these proteins in anti-cancer activity, for consideration in therapeutic strategies. The purpose of this review is twofold. Firstly, it is to evaluate recent data about which proteins can be utilized as biomarkers in carcinogenesis. The proteins reviewed include: CPTP, IL-6, CCN, and S100. Secondly, it is to evaluate the contribution of dietary proteins in cancer activity. Specifically, how whey protein, soy proteins and lectin, a phytochemical could be useful in cancer prevention and treatment.
Recent Findings: Whey protein, present in dairy products, is an excellent source of the sulphur amino acid cysteine, the rate limiting substrate in glutathione synthesis. Notably, this protein survives digestion and has been shown to have anti-carcinogenic properties in animal studies. Lectins are phytochemicals present in plant foods, and have active components which alters cancer initiation, promotion and progression. Lectins have been characterized as a useful tool in biochemistry, cell biology, immunology and in diagnostic and therapeutic purposes in cancer research. Soy proteins contain various compounds, including isoflavones, protease inhibitors and protein kinase inhibitors, which have been proven effective in tumor growth inhibition. They have therefore, been greatly emphasized in cancer prevention and treatment. It has been proved that soy food consumption was associated with decreased risk of death and recurrence of breast cancer. CPTP is a recently discovered protein whose main role is to transport C1P, a pro-inflammatory molecule. The discovery of CPTP may shine a light on the mechanism of inflammatory diseases, and hopefully offer a potential target for therapeutic purposes in cancer research. Interleukin-6 is a multifunctional cytokine that affects the activity of cancer cells. It is involved in tumor growth, and elevated levels is associated with an increased risk of cancer. S100B is a well-established biomarker for malignant melanoma, and useful in assessing tumor load, stage and prognosis for patients with this disease. Other members of this family of proteins include S100A4, which has been associated with several malignancies and S100A2, which has been found to be decreased in some cancers. CCN are a group of regulatory proteins, located in the extracellular matrix (maricellular). They are involved in cellular adhesion, mitogenesis, chemotaxis, cell survival, and wound healing. CCN proteins are also able to modulate the signals of several proteins, which may also influence skeletal development and angiogenesis. Many of the functions of these proteins are thus also related to tumor growth. Furthermore, CCN interacts with estrogen in the development of cancer, and is implicated in some breast and ovarian cancers.
doi:10.7150/jca.10560
PMCID: PMC4278910  PMID: 25553084
biomarkers; proteins; lung cancer.
3.  Upregulation of miRNA3195 and miRNA374b Mediates the Anti-Angiogenic Properties of Melatonin in Hypoxic PC-3 Prostate Cancer Cells 
Journal of Cancer  2015;6(1):19-28.
Recently microRNAs (miRNAs) have been attractive targets with their key roles in biological regulation through post-transcription to control mRNA stability and protein translation. Though melatonin was known as an anti-angiogenic agent, the underlying mechanism of melatonin in PC-3 prostate cancer cells under hypoxia still remains unclear. Thus, in the current study, we elucidated the important roles of miRNAs in melatonin-induced anti-angiogenic activity in hypoxic PC-3 cells. miRNA array revealed that 33 miRNAs (>2 folds) including miRNA3195 and miRNA 374b were significantly upregulated and 16 miRNAs were downregulated in melatonin-treated PC-3 cells under hypoxia compared to untreated control. Melatonin significantly attenuated the expression of hypoxia-inducible factor (HIF)-1 alpha, HIF-2 alpha and vascular endothelial growth factor (VEGF) at mRNA level in hypoxic PC-3 cells. Consistently, melatonin enhanced the expression of miRNA3195 and miRNA 374b in hypoxic PC-3 cells by qRT-PCR analysis. Of note, overexpression of miRNA3195 and miRNA374b mimics attenuated the mRNA levels of angiogenesis related genes such as HIF-1alpha, HIF-2 alpha and VEGF in PC-3 cells under hypoxia. Furthermore, overexpression of miRNA3195 and miRNA374b suppressed typical angiogenic protein VEGF at the protein level and VEGF production induced by melatonin, while antisense oligonucleotides against miRNA 3195 or miRNA 374b did not affect VEGF production induced by melatonin. Also, overexpression of miR3195 or miR374b reduced HIF-1 alpha immunofluorescent expression in hypoxic PC-3 compared to untreated control. Overall, our findings suggest that upregulation of miRNA3195 and miRNA374b mediates anti-angiogenic property induced by melatonin in hypoxic PC-3 cells.
doi:10.7150/jca.9591
PMCID: PMC4278911  PMID: 25553085
melatonin; miRNA3195; miRNA374b; VEGF; HIF-1 alpha; PC-3 cells.
4.  Cancer: We Should Not Forget The Past 
Journal of Cancer  2015;6(1):29-39.
Cancer has been in existence longer than human beings, and man has been facing the illness ever since he made his appearance on Earth. Amazingly, the first human cancer gene was cloned only thirty years ago. This, and other extraordinary scientific goals achieved by molecular cancer research in the last 30 years, seems to suggest that definitive answers and solutions to this severe disease have been finally found. This was not the case, as cancer still remains to be defeated. To do so, cancer must be first understood.
This review highlights how cancer onset and progression has been tackled from ancient times to present day. Old theories and achievements have provided the pillars of cancer understanding, in laying the basis of 'modern era' cancer research, are discussed. The review highlights the discovery of oncogenes and suppressor tumor genes, underlining the crucial role of these achievements in cancer diagnosis and therapies. Finally, an overview of how the modern technologies have given impetuous to expedite these goals is also considered.
doi:10.7150/jca.10336
PMCID: PMC4278912  PMID: 25553086
Cancer theories; oncogenes; genomics.
5.  Differentiation between Malignant and Benign Solitary Lesions in the Liver with 18FDG PET/CT: Accuracy of Age-related Diagnostic Standard 
Journal of Cancer  2015;6(1):40-47.
Objective: This study was to determine the reliability of age-stratified diagnostic index in differential diagnosis of malignant and benign solitary lesions in the liver using fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18FDG PET/CT).
Methods: The enrolled 272 patients with solitary lesions in the liver were divided into three age groups, younger group (under 50 years), middle-aged group (50-69 years), and elderly group (70 years and above). Patients' ages were compared, and the optimal cut-offs of the standard uptake value (SUV) ratio (tumor-to-non-tumor ratio of the SUV), as well as areas under the curves (AUC), were evaluated in terms of malignant and benign lesions in each age group by using receiver operating characteristic (ROC) analysis. Based on optimal cut-offs, the sensitivity, specificity, accuracy were calculated, and the diagnostic accordance rate was compared between each age group and all patients, supported by 18FDG PET/CT imaging data.
Results: There was a significant age difference between the malignant and benign groups (t=3.905 p=0.0001). ROC analysis showed that the optimal cut-off value in all patients, younger group, middle-aged group and elderly group was 1.25, 1.17, 1.45 and 1.25 for SUVratio, and 0.856, 0.962, 0.650, 0.973 for AUC. The chi-square test proved that diagnostic accordance rate of 18FDG PET/CT in younger group and elderly group were superior to that in all patients (χ2=13.352, P=0.0003) and (χ2=8.494, P=0.0036). Conversely, overall diagnostic accordance rate in all patient group was higher than that in middle-aged group (χ2=9.057, P=0.0026). Representative 18FDG PET/CT imaging findings are demonstrated.
Conclusion: This study indicates that diagnostic optimal cut-offs of SUVratio of liver solitary lesions of 18FDG PET/CT were different in each age group. In addition, the diagnostic performance of SUVratio was better in younger and elderly groups than that in all patients, and was poorer in middle-aged group than that in all patients. Therefore, age difference appears to be one of the important factors for discriminating malignant liver lesions from benign ones using 18 FDG PET/CT.
doi:10.7150/jca.10422
PMCID: PMC4278913  PMID: 25553087
Positron emission tomography/computed tomography (PET/CT); Standardized up take value (SUV); Solitary hepatic lesion; Age-related.
6.  Upregulation of Acetylcholinesterase Mediated by p53 Contributes to Cisplatin-Induced Apoptosis in Human Breast Cancer Cell 
Journal of Cancer  2015;6(1):48-53.
Background: The expression of acetylcholinesterase (AChE) could be induced during apoptosis in various cell types. And reduced AChE expression either by siRNA could prevent apoptosis. However, the detailed mechanisms underlying the AChE regulation are largely unknown in human breast cancer cell.
Material and methods: MCF-7 cells were cultured and treated by cisplatin in the absence or presence of p53 siRNA.
Results: In this study, the regulation of AChE expression during apoptosis induced by cisplatin, a current used anticancer drug, was investigated in human breast cancer cell line MCF-7. Exposure of MCF-7 cells to cisplatin resulted in apoptosis in a time- and concentration-dependent manner. Meanwhile, the upregulated AChE and p53 were also observed during apoptosis. Silencing interfering RNA directed against p53 blocked the expression of AChE.
Conclusion: Taken together, these results suggested that AChE expression could be upregulated by the activation of p53 during apoptosis induced by cisplatin in MCF-7 cells.
doi:10.7150/jca.10521
PMCID: PMC4278914  PMID: 25553088
acetylcholinesterase; apoptosis; p53; cisplatin; breast cancer.
7.  Pathway and Network Approaches for Identification of Cancer Signature Markers from Omics Data 
Journal of Cancer  2015;6(1):54-65.
The advancement of high throughput omic technologies during the past few years has made it possible to perform many complex assays in a much shorter time than the traditional approaches. The rapid accumulation and wide availability of omic data generated by these technologies offer great opportunities to unravel disease mechanisms, but also presents significant challenges to extract knowledge from such massive data and to evaluate the findings. To address these challenges, a number of pathway and network based approaches have been introduced. This review article evaluates these methods and discusses their application in cancer biomarker discovery using hepatocellular carcinoma (HCC) as an example.
doi:10.7150/jca.10631
PMCID: PMC4278915  PMID: 25553089
Biological pathways; system biology; high-throughput omics data; cancer biomarker.
8.  Spatial and Temporal Fracture Pattern in Breast and Gynecologic Cancer Survivors 
Journal of Cancer  2015;6(1):66-69.
Objective(s): To assess skeletal wide fracture location and time of fracture after cancer treatment
Study Design: One hundred thirty-nine women diagnosed with breast or gynecologic cancer between 2003 and 2012 that subsequently had a radiologic diagnosis of fracture were identified retrospectively using electronic medical records. Results were compared with skeletal fracture pattern previously reported for a general population.
Results: Skeletal fractures in cancer patients occur throughout the entire skeleton similar to general population. The most common sites were vertebrae (16%), feet and toes (15%), ribs (12%), hands and fingers (10%), and pelvis (8%). Fracture incidence was observed starting within the first year of survivorship, and continued to after five years. The median time from cancer diagnosis to fracture varied by age (p<0.01), from a high of 3.2 years for ages 50-59 to a low of 1.2 years for patients older than 70.
Conclusion: The pattern of skeletal fracture is similar between cancer survivor and general population. Contrary to general assumption, survivors can experience skeletal fracture early after cancer treatment, especially at an older age. Thus, cancer survivorship care should include assessment of early time points with improved management of cancer treatment related bone injury.
doi:10.7150/jca.10288
PMCID: PMC4278916  PMID: 25553090
Bone loss; chemotherapy; radiation; quantitative computed tomography.
9.  ERCC1 Induction after Oxaliplatin Exposure May Depend on KRAS Mutational Status in Colorectal Cancer Cell Line: In Vitro Veritas 
Journal of Cancer  2015;6(1):70-81.
Introduction: Oxaliplatin (Oxa) is widely used in metastatic colorectal cancer (mCRC), but currently there are not valid predictors of response to this drug. In the control arms both of OPUS and PRIME studies Oxa seems more active in patients with mCRC with mutated (mt) KRAS than in those with wild type (wt) KRAS. Recently we have retrospectively confirmed this suggestion, therefore we have hypothesized that the mutational status of KRAS could influence the expression of ERCC1, one of the main mechanisms of Oxa resistance.
Material and Methods: We used four cell lines of colorectal cancer: two KRAS wild type (wt) (HCT-8 and HT-29) and two KRAS mt (SW620 and SW480). We evaluated the sensitivity of these cell lines to Oxa by MTT-test as well the ERCC1 levels before and after 24 h exposure to Oxa by Real-Time PCR. We silenced KRAS in a KRAS mt cell line (SW620LV) to evaluate the impact on Oxa sensitivity and ERCC1 levels. Lastly, ERCC1 was also silenced in order to confirm the importance of this protein as an Oxa resistance factor.
Results: The KRAS mt cell lines resulted more sensitive to Oxa (OR 2.68; IC 95% 1.511-4.757 p<0.001). The basal levels of ERCC1 did not show significant differences between KRAS mt and wt cell lines, however, after 24 h exposure to Oxa, only the wt KRAS lines showed the ability to induce ERCC1, with a statistically significant difference (OR 42.9 IC 95% 17.260-106.972 p<0.0005). By silencing KRAS, sensitivity to Oxa was reduced in mt KRAS cell lines and this effect was associated with the acquisition of ability to induce ERCC1. Silencing of ERCC1, in turn, enhanced the sensitivity to Oxa in wt KRAS cell lines and restored sensitivity to Oxa in SW620LV cell line.
Conclusion: KRAS mutated cell lines were more sensitive to Oxa. This feature seems secondary to the inability of these cells to induce ERCC1 after exposure to Oxa. Thus, KRAS mutational status might be a predictor of response to Oxa in CRC surrogating the cell ability to induce ERCC1.
doi:10.7150/jca.10478
PMCID: PMC4278917  PMID: 25553091
Oxaliplatin; KRAS; ERCC1; colorectal cancer cells.
10.  Changes in Bone Density after Cancer Treatment in Patients with Cervical and Endometrial Cancer 
Journal of Cancer  2015;6(1):82-89.
OBJECTIVE: This study aimed to evaluate the impact of cancer treatment on bone mineral density (BMD) in the lumbar spine (LS) and femur in the postmenopausal women with cervical or endometrial cancer without bone metastasis compared to normal control postmenopausal women.
METHODS: We retrospectively evaluated the BMD data in the LS, femur neck (FN) and trochanter (FT) by dual-energy X-ray absorptiometry and laboratory data of bone turnover markers at baseline and after one year in 130 patients with cervical cancer, 68 patients with endometrial cancer, and 225 healthy controls.
RESULTS: There were no significant differences in the T-scores of basal BMD in LS and femur between patients with endometrial cancer and controls, and only T-score of basal BMD at the fourth lumbar vertebra (L4) was significantly lower in patients with cervical cancer compared to controls. One year later, T-scores of BMD at all LS sites and FN in patients with cervical cancer and T-scores of BMD at L3, L4, FN, and FT in those with endometrial cancer after cancer treatment were significantly lower compared to controls. Lower proportions of normal BMD at all skeletal sites except L2 in patients with endometrial cancer and those at L1, L4, and FN in patients with cervical cancer were observed compared to controls after cancer treatment.
CONCLUSIONS: Our results suggest that cancer treatment increase bone loss in postmenopausal women with cervical and endometrial cancer.
doi:10.7150/jca.10679
PMCID: PMC4278918  PMID: 25553092
Bone mineral density; Cervical cancer; Endometrial cancer; Osteoporosis.
11.  Discovery of Invasion Routes for Nasopharyngeal Adenoid Cystic Carcinoma 
Journal of Cancer  2015;6(1):90-97.
The aim of this study is to discover regional invasion routes for nasopharyngeal adenoid cystic carcinoma (NACC) through analyses of the magnetic resonance (MR) images and comparison with keratinizing squamous cell carcinoma (KSCC). Both MR results and clinical records were retrospectively reviewed for 18 patients with NACC and 182 patients with KSCC. The metastasis routes of NACC were identified by analysis of MR images of patients who underwent magnetic resonance imaging (MRI). There were significant differences in skull base invasion and cavernous sinus invasion (p = 0.020 and 0.028, respectively) while parapharyngeal space invasion rate was not. The laryngopharynx invasion rate and external pterygoid muscle invasion rate were higher in NACC patients than that in KSCC patients (16.7% vs. 0.5 %, p = 0.002; 27.8% vs. 11.0%, p = 0.040, respectively). Paralysis of the cranial nerves had a significant higher incidence in the NACC group compared to the KSCC group (66.7% vs. 8.2%, p < 0.001). There was significant difference in invasion to the neural foramen between the NACC and KSCC groups (66.7% vs. 36.3%, p = 0.020). Foramen ovale was a common invasion site, significantly higher in NACC patients than in KSCC patients (50.0% vs. 24.1%, p = 0.018). Based on the MRI findings, a regional invasion model of NACC with two possible routes has been built, including aggressive local infiltration along submucosa to laryngopharynx or external pterygoid muscle, and extension from pharyngonasal cavity, through cranial nerve canal to cavernous sinus. The significant difference in overall survival (OS) time between the two different invasion routs and the recurrent rates in different regions also supported the validity of the invasion model.
doi:10.7150/jca.10739
PMCID: PMC4278919  PMID: 25553093
nasopharyngeal adenoid cystic carcinoma; keratinizing squamous cell carcinoma; invasion routes; MRI; paralyzed cranial nerve.
12.  Fibronectin Matrix Formation is a Prerequisite for Colonization of Kidney Tumor Cells in Fibrin 
Journal of Cancer  2015;6(2):98-104.
Fibrin plays an important role in lung metastasis. Here we show that fibrin promotes colony formation in primary kidney tumor cells from patients with kidney metastasis. In addition, we found that inhibition of fibrin formation with the thrombin inhibitor hirudin in nude mice in vivo significantly reduced the metastatic outgrowth of kidney tumor cells. Colony formation was significantly more efficient in tumor cells embedded in fibrin compared to matrigel and this effect correlates with the capacity of tumor cells to assemble a fibronectin matrix and generate stress fibers. Interestingly, stress fiber formation in fibrin was a specific function of metastatic kidney tumor cells while non-metastatic cells remained round. Inhibition of stress fiber formation with the Rho kinase inhibitor Y-27632, in turn, reduced fibronectin matrix assembly and colony formation in fibrin suggesting that spreading is a critical mechanism for the outgrowth of metastatic kidney tumor cells. Overall, our results indicate that adhesive interactions with fibrin play an important role for the progression of renal cell carcinoma and that inhibiting these interactions could be a promising strategy for treatment and prevention of kidney cancer metastasis.
doi:10.7150/jca.10496
PMCID: PMC4280391  PMID: 25561973
Fibronectin; Metastasis; Fibrin.
13.  Colon Cancer Associated Transcript-1 (CCAT1) Expression in Adenocarcinoma of the Stomach 
Journal of Cancer  2015;6(2):105-110.
Background: Long non-coding RNAs (lncRNAs) have been shown to have functional roles in cancer biology and are dys-regulated in many tumors. Colon Cancer Associated Transcript -1 (CCAT1) is a lncRNA, previously shown to be significantly up-regulated in colon cancer. The aim of this study is to determine expression levels of CCAT1 in gastric carcinoma (GC).
Methods: Tissue samples were obtained from patients undergoing resection for gastric carcinoma (n=19). For each patient, tumor tissue and normal appearing gastric mucosa were taken. Normal gastric tissues obtained from morbidly obese patients, undergoing laparoscopic sleeve gastrectomy served as normal controls (n=19). A human gastric carcinoma cell line (AGS) served as positive control. RNA was extracted from all tissue samples and CCAT1 expression was analyzed using quantitative real time-PCR (qRT-PCR).
Results: Low expression of CCAT1 was identified in normal gastric mucosa samples obtained from morbidly obese patients [mean Relative Quantity (RQ) = 1.95±0.4]. AGS human gastric carcinoma cell line showed an elevated level of CCAT1 expression (RQ=8.02). Expression levels of CCAT1 were approximately 10.8 fold higher in GC samples than in samples taken from the negative control group (RQ=21.1±5 vs. RQ=1.95±0.4, respectively, p<0.001). Interestingly, CCAT1 expression was significantly overexpressed in adjacent normal tissues when compared to the negative control group (RQ = 15.25±2 vs. RQ=1.95±0.4, respectively, p<0.001). Tissues obtained from recurrent GC cases showed the highest expression levels (RQ = 88.8±31; p<0.001). Expression levels increased with tumor stage (T4- 36.4±15, T3- 16.1±6, T2- 4.7±1), however this did not reach statistical significance (p=0.2). There was no difference in CCAT1 expression between intestinal and diffuse type GC (RQ=22.4±7 vs. 22.4±16, respectively, p=0.9). Within the normal gastric tissue samples, no significant difference in CCAT1 expression was observed in helicobacter pylori negative and positive patients (RQ= 2.4±0.9 vs. 0.93±0.2, respectively, p=0.13).
Conclusion: CCAT1 is up-regulated in gastric cancer, and may serve as a potential bio-marker for early detection and surveillance.
doi:10.7150/jca.10568
PMCID: PMC4280392  PMID: 25561974
Gastric cancer; CCAT1; gastrectomy; biomarker; long non-coding RNA.
14.  Identification of Stably Expressed lncRNAs as Valid Endogenous Controls for Profiling of Human Glioma 
Journal of Cancer  2015;6(2):111-119.
Background: Recent research indicates that long non-coding RNAs (lncRNA) represent a new family of RNAs that is of fundamental importance for controlling transcription and translation. Thereby, there is increasing evidence that lncRNAs are also important in tumourigenesis. Thereby valid expression profiling using quantitative PCR requires suitable, stably expressed normalisers to achieve reliable and reproducible data. However, no systematic analysis of suitable references in lncRNA studies in human glioma has been performed yet.
Methods: In this study, we investigated 90 lncRNAs in 30 tissue specimen for the expression stability in human diffuse astrocytoma (WHO-Grade II), anaplastic astrocytoma (WHO-Grade III) and glioblastoma (WHO-Grade IV) both alone as well as in comparison with normal white matter. Our identification procedure included a rigorous bioinformatical selection process that resulted in the inclusion of only highly abundant, equally expressed lncRNAs for further analysis. Additionally, lncRNAs were classified according to their stability value using the NormFinder algorithm.
Results: We identified 24 appropriate normalisers suitable for studies in diffuse astrocytoma, 22 for studies in anaplastic astrocytoma and 12 for studies in glioblastoma. Comparing all three glioma entities 7 lncRNAs showed stable expression levels. Addition of normal brain tissue resulted in only 4 suitable lncRNAs.
Conclusions: Our findings indicate that 4 lncRNAs (HOXA6as, H19 upstream conserved 1 and 2, Zfhx2as and BC200) are suitable as normalisers in glioma and normal brain. These lncRNAs may thus be regarded as universal references being applicable for the accurate normalisation of lncRNA expression profiling in various glioma (WHO-Grades II-IV) alone and in combination with brain tissue. This enables to perform valid longitudinal studies, e.g. of glioma before and after malignisation to identify changes of lncRNA expressions probably driving malignant transformation.
doi:10.7150/jca.10867
PMCID: PMC4280393  PMID: 25561975
long non-coding RNA; lncRNA; Glioma; References; qPCR; Profiling.
15.  Three-Step Hand-Assisted Laparoscopic D2 Radical Gastrectomy for Chinese Obese Patients: A Highly Efficient and Feasible Surgical Approach 
Journal of Cancer  2015;6(2):120-127.
Three-step hand-assisted laparoscopic D2 radical gastrectomy (HALG) is a modified surgical procedure that has achieved satisfactory results for obese patients in our surgical center. To fully elucidate the advantages of this procedure, in this study, comprehensive and in-depth comparative analyses were performed to assess clinical data from obese gastric cancer patients who underwent HALG, laparoscopic-assisted D2 radical gastrectomy (LAG), and open D2 radical gastrectomy (OG) in our surgical center during a specific time period. For the 3 groups, incision length was 1.25 cm longer for the HALG group than for the LAG group but was significantly shorter for the HALG group than for the OG group (P =0.00). The rate of conversion to laparotomy , the pneumoperitoneum time and the number of recovered lymph nodes were significantly better for the HALG group than for the LAG group (P <0.05). The pain score at day 2 after surgery, intestinal function recovery time, and duration of postoperative hospital stay were not significantly different for the HALG and LAG groups ( P >0.05) but were significantly better for the HALG group than for the OG group (P <0.05). There were significantly fewer postoperative complications for the HALG group than for the LAG and OG groups (P =0.049). According to the results, the “three-step HALG method” incorporates both the thoroughness of the radical OG approach and the minimal invasiveness of the LAG approach for obese patients. Thus, the HALG approach is a relatively safe and extremely feasible surgical procedure for the treatment of these patients.
doi:10.7150/jca.10639
PMCID: PMC4280394  PMID: 25561976
hand-assisted laparoscopic D2 radical gastrectomy; laparoscopy-assisted D2 radical gastrectomy; open D2 radical gastrectomy; obese patients.
16.  The Quantum of Initial Transformed Cells Potentially Modulates the Type of Local Inflammation Mechanism Elicited by Surrounding Normal Epithelial Tissues and Systemic Immune Pattern for Tumor Arrest or Progression 
Journal of Cancer  2015;6(2):128-138.
The immune/ inflammation system potentially serves to arrest, eliminate or promote tumor development. Nonetheless, factors that dictate the choice are not comprehensively known yet. Using a B16/F1 syngeneic wild type model, we evaluated the essentiality of initial transformed cells' density for overt tumor development, the molecular trends of inflammatory mediators in the normal tumor-adjacent epithelial tissues (NTAT), and how such local events may reflect systematically in the host. Overt tumors developed, within an observatory period of at least 45 days and 90 days at most, only in mice inoculated with cancer cells above a limiting threshold of 1× 103 cells. Immunoblots showed early, intense and transient presence of IL-1β, IFN-γ, and both the all-thiol and disulfide forms of HMGB1 in the NTAT of non-tumor bearing mice. However, all-thiol form of HMGB1 and delayed but aberrant IL-6 expression characterized chronic inflammation in tumor bearing hosts. These local epithelial tissue events uniquely reflected in host's systemic cytokines dynamics where stable Th1/Th2 signature (IFN-γ/ IL-4) coupled with early Th1 cells polarization (IL-12/ IL-4) evidenced in non-tumor hosts but highly fluctuating Th1/ Th2 profile in tumor hosts, even before tumors became overt. This hypothesizes that the physical quantum of transformed cells that may either spontaneously arise or accrue at a locus may be crucial in orchestrating the mechanism for the type of local epithelial tissue and systemic immune/ inflammatory responses essential for tumor progression or arrest.
doi:10.7150/jca.10787
PMCID: PMC4280395  PMID: 25561977
Cancer cell density; minimum tumorigenic threshold; inflammation; overt tumor; Th1/Th2/Th17 cytokines.
17.  The Quality of Tumor Size Assessment by Contrast-Enhanced Spectral Mammography and the Benefit of Additional Breast MRI 
Journal of Cancer  2015;6(2):144-150.
Background - Contrast-enhanced spectral mammography (CESM) is a promising new breast imaging modality that is superior to conventional mammography for breast cancer detection. We aimed to evaluate correlation and agreement of tumor size measurements using CESM. As additional analysis, we evaluated whether measurements using an additional breast MRI exam would yield more accurate results.
Methods - Between January 1st 2013 and April 1st 2014, 87 consecutive breast cancer cases that underwent CESM were collected and data on maximum tumor size measurements were gathered. In 57 cases, tumor size measurements were also available for breast MRI. Histopathological results of the surgical specimen served as gold standard in all cases.
Results - The Pearson's correlation coefficients (PCC) of CESM versus histopathology and breast MRI versus histopathology were all >0.9, p<0.0001. For the agreement between measurements, the mean difference between CESM and histopathology was 0.03 mm. The mean difference between breast MRI and histopathology was 2.12 mm. Using a 2x2 contingency table to assess the frequency distribution of a relevant size discrepancy of >1 cm between the two imaging modalities and histopathological results, we did not observe any advantage of performing an additional breast MRI after CESM in any of the cases.
Conclusion - Quality of tumor size measurement using CESM is good and matches the quality of these measurement assessed by breast MRI. Additional measurements using breast MRI did not improve the quality of tumor size measurements.
doi:10.7150/jca.10705
PMCID: PMC4280397  PMID: 25561979
breast cancer; mammography; CESM; CEDM; MRI.
18.  Effects of Mitochondrial Translocation of Telomerase on Drug Resistance in Hepatocellular Carcinoma Cells 
Journal of Cancer  2015;6(2):151-159.
Hepatocellular carcinoma (HCC) cells exhibit multidrug resistance (MDR), but the underlying mechanisms remain unclear. Cancer cells that overexpress telomerase are resistant to chemotherapeutic drugs. This study aimed to determine the effects of mitochondrial translocation of telomerase on MDR in HCC cells. HepG2 cells were transfected with negative plasmid and PTPN11 (Shp-2) short hairpin RNA (ShRNA) plasmid to establish HepG2-negative (HepG2 transfected with negative plasmid) and HepG2-ShShp-2 (HepG2 transfected with Shp-2 ShRNA plasmid) cells. Sensitivity to chemotherapeutic drugs was assessed by Cell Counting Kit-8 (CCK-8) assays. Distribution of human telomerase reverse transcriptase (hTERT) within mitochondria was detected by western blotting and immunofluorescence combined with laser scanning confocal microscopy. Mitochondrial reactive oxygen species (ROS) generation was demonstrated by flow cytometry with the mitochondrial superoxide (Mito-Sox) indicator. The frequency of damaged mitochondrial DNA (mtDNA) was illustrated by quantitative real-time polymerase chain reaction (Q-PCR). Expression of mitochondrial respiratory chain complex subunits ND1 and COXII were also demonstrated by western blotting. Knockdown of Shp-2 in HepG2 cells resulted in upregulation of mitochondrial TERT expression and increased resistance to cisplatin (CDDP) and 5-fluorouracil (5-FU) (resistance indices, 2.094 and 1.863, respectively). In addition, both the mitochondrial ROS and the frequency of mtDNA damage were decreased, and COXII expression was upregulated. Our results suggest that Mitochondrial translocation of hTERT may lead to chemotherapeutic resistance in HCC cells. Mitochondrial hTERT contributes to the drug resistance of tumor cells by reducing ROS production and mtDNA damage, and exerting a protective effect on the mitochondrial respiratory chain.
doi:10.7150/jca.10419
PMCID: PMC4280398  PMID: 25561980
telomerase; mitochondria; multidrug resistance; hepatocellular carcinoma.
19.  The Assessment of Tumor Response by Measuring the Single Largest Lesion per Organ in Metastatic Tumors: A Pooled Analysis of Previously Reported Data 
Journal of Cancer  2015;6(2):169-176.
Background: The RECIST 1.1 adopted a total of five target lesions to be measured, with a maximum of two lesions per organ. To the best of our knowledge, the criterion of two target lesions per organ in the RECIST 1.1 is arbitrary and has not been supported by any objective evidence. Recently, we reported that the modified RECIST 1.1 (measuring the single largest lesion in each organ) showed a high level of concordance with the original RECIST 1.1 in patients with advanced or metastatic non-small cell lung cancer (NSCLC), gastric cancer (GC), and colorectal cancer (CRC). However, each study had a major limitation of a small number of patients.
Methods: We conducted a pooled analysis using the data from the three individual studies to improve statistical power. Tumor responses were compared according to the RECIST 1.1 and modified RECIST 1.1 (mRECIST 1.1).
Results: A total of 153 patients who had at least two target lesions in any organ according to the RECIST 1.1 were included in this pooled study: 64 with NSCLC, 51 with GC, and 38 with CRC. Regardless of primary sites, the number of target lesions according to the mRECIST 1.1 was significantly lower than that according to the RECIST 1.1 (P<0.001). The assessment of tumor responses showed a high concordance between the two criteria (k = 0.908). Only eight patients (5.2%) showed disagreement in the tumor response assessment between the two criteria. The overall response rates of chemotherapy were not significantly different between the two criteria (33.3% versus 33.3%, P=1.0).
Conclusions: The modified RECIST 1.1 was comparable to the original RECIST 1.1 in the tumor response assessment of patients with advanced or metastatic NSCLC, GC, and CRC. Our results suggest that it may be possible to measure the single largest lesion per organ for assessing tumor response in clinical practice.
doi:10.7150/jca.10912
PMCID: PMC4280400  PMID: 25561982
RECIST 1.1; modified RECIST 1.1; Target lesion; Tumor response; Single-lesion measurement
20.  Brain and Central Nervous System Cancer Incidence in Navarre (Spain), 1973-2008 and Projections for 2014 
Journal of Cancer  2015;6(2):177-183.
Different studies have pointed out Navarre as one of the regions of Spain with the highest incidence rates of brain and other central nervous system (CNS) cancer. Trend analysis for cancer incidence rates for long periods of time, might help determining risk factors as well as, assessing prevention actions involved in this disease. The objective of this study was to describe the incidence of brain and CNS cancer using data from the population-based cancer registry of Navarre, (Spain) during the period 1973-2008 and provide forecast figures up to-2014. Crude and age-standardized (world population) incidence rates of brain cancer per 100,000 person-years were calculated by the direct method separately by gender, area (Pamplona and others), and age-groups. Penalized splines for smoothing rates in the temporal dimensions were applied in order to estimate and forecast cancer incidence rates. Age-adjusted incidence rates showed an increase over the study and forecast periods in both sexes more marked in women than in men. Higher incidence rates were observed in men compared with women but the differences became smaller with time. The increase was due to the rise of rates in the oldest age groups since the rates for younger age groups remained stable or decreased over time. As the entire aetiology of brain and other CNS cancer is not still clear, keep promoting healthful lifestyles for cancer primary prevention among the whole population is necessary.
doi:10.7150/jca.10482
PMCID: PMC4280401  PMID: 25561983
Brain Cancer Incidence; Trend analysis; Projections; Population-based cancer registries; Spain
21.  Could GLUT12 be a Potential Therapeutic Target in Cancer Treatment? A Preliminary Report 
Journal of Cancer  2015;6(2):139-143.
Background: Recent studies proposed GLUT12 to be a major glucose transporter involved in the glycolytic metabolism of cancer cells.
Methods: GLUT12 expression was determined by immunohistochemistry in a selection of cancer cell lines and a tumour spheroid model.
Results: GLUT12 expression was high in A549 and RH-36; low in HT29; and absent in NB-EB cancer cell lines. GLUT12 expression was located in the necrotic centre of HT29 spheroids, which is characterised by anaerobic metabolism.
Conclusion: The data supports the involvement of GLUT12 in the glycolytic metabolism of cancer cells and therefore, its potential as a novel therapeutic target for cancer treatment.
doi:10.7150/jca.10429
PMCID: PMC4280396  PMID: 25561978
GLUT12; Cancer cell lines; Spheroid; Immunohistochemistry; Glycolytic metabolism.
22.  The Analysis of the Relationship between Multiple Myeloma Cells and Their Microenvironment 
Journal of Cancer  2015;6(2):160-168.
The bone marrow microenvironment plays a key role in the stimulation of growth and survival of multiple myeloma (MM) cells. We investigated whether membrane microfragments (MFBs) exert a stimulatory effect on mesenchymal stem cell (MSC) gene expression or differentiation. MSCs from patients with multiple myeloma (MMBM-MSCs) proliferated at a slower rate than MSCs from healthy volunteers (BM-MSCs), and fewer MMBM-MSCs adhered to the substrate as compared to BM-MSCs. Phenotypic analysis revealed that MMBM-MSCs and BM-MSCs differed significantly in terms of their CD166 and CXCR4 expressions. In conclusion, our comparative analysis of mesenchymal cells from MM patients and healthy volunteers revealed differences in the genetic and phenotypic profiles of these two populations, their potential for osteodifferentiation, and expression of surface antigens. Moreover, we showed that membrane MFBs may alter the genetic profile of MSCs, leading to disorders of their osteodifferentiation, and interact with the WNT pathway via presentation of the DKK-1 protein.
doi:10.7150/jca.10873
PMCID: PMC4280399  PMID: 25561981
bone marrow; genotype; membrane microfragments; microenvironment; multiple myeloma; osteodifferentiation
23.  MiR-217 Promotes Tumor Proliferation in Breast Cancer via Targeting DACH1 
Journal of Cancer  2015;6(2):184-191.
Objective: The expression of DACH1 was frequently lost in human breast cancer, which significantly correlated with poor prognosis. Herein, we aim to investigate its underlying mechanisms.
Methods: The expression of miR-217 was detected by Taqman PCR. The mRNA and protein level of DACH1 were investigated by real time PCR and western blot. The dual-luciferase reporter system was used to determine the direct interaction between miR-217 and DACH1. A series of gain&loss of function assays were performed to measure the affects of miR-217 on tumor proliferation and cell cycle distribution.
Results: Compared to that in normal breast samples, the expression of miR-217 was significantly upregulated in breast cancer tissues. High level of miR-217 was notably correlated with highly histological grade, the triple negative subtype and advanced tumor stage. Moreover, the expression of miR-217 was negatively correlated with the expression of DACH1. The results of dual-luciferase reporter assay demonstrated that miR-217 directly targets and inhibits the transcriptive activity of DACH1. In vitro, treatment with miR-217 mimics significantly suppressed the proliferation of MCF-7 cells, induced G1 phase arrest and inhibited the expression of cyclin D1; while these effects were significantly reversed by the restoration of DACH1. In MDA-MB-231 cells, treatment with miR-217 inhibitors enhanced the cellular proliferation, promoted cell cycle progression and upregulated the expression of cyclin D1, which were neutralized by the pre-treatment of siRNA-DACH1. In vivo, inhibition of miR-217 significantly suppressed the xenografts growth and downregulated the expression of cyclin D1.
Conclusion: We found that miR-217 was commonly overexpressed in breast cancer, which could enhance tumor proliferation via promoting cell cycle progression. Moreover, the DACH1 (the cell fate determination factor) was identified as a novel target of miR-217. Our results proposed inhibiting miR-217 to be a potent therapeutic strategy for breast cancer.
doi:10.7150/jca.10822
PMCID: PMC4314667  PMID: 25653720
DACH1; miR-217; breast cancer; proliferation; cell cycle
24.  Clinico-Pathological Correlation of β-Catenin and Telomere Dysfunction in Head and Neck Squamous Cell Carcinoma Patients 
Journal of Cancer  2015;6(2):192-202.
Background: Tumorigenesis is a complex process of accumulated alteration in function of multiple genes and pathways. Wnt signalling pathway is involved in various differentiation events during embryonic development and is conserved in various species.
Objective: A multicentre collaborative initiative is undertaken to study the occurrence, prognosis and molecular mechanism of HNSCC (Head and Neck Squamous Cell Carcinoma) which is highly prevalent in eastern parts of India. From a large cohort of HNSCC tissue repository, 67 cases were selected for multi-parametric investigation.
Results: 67 cases showed stable β-catenin expression. We have seen correlation, if any, of the transcription factor - β-catenin, telomere maintenance and shelterin complex proteins - TRF2, Rap1 and hTert with respect to tumor differentiation and telomere dysfunction. Immunohistochemistry of β-catenin protein showed stable and high expression in tumor when compared to stroma. MDSCC (Moderately Differentiated Squamous cell carcinoma) cases expressed nuclear expression of β-catenin in invasive fronts and showed increased genomic instability. Higher frequency of Anaphase bridges was observed ranging from <3% in normal cut margin to 13% in WDSCC (Well differentiated squamous cell carcinoma) and 18% in MDSCC (Moderately differentiated Squamous cell carcinoma). There was significant decrease in telomere length in MDSCC (<4) when compared to the normal cut margin samples (<7). Quantitative Real Time-PCR confirmed a significant correlationship between stable β-catenin expression and poor clinical and pathological outcome.
Conclusion: The Stabilisation and accumulation of β-catenin was significant and correlated well with de-differentiation process as well as prognosis and therapy outcome of the patients in the cohort. Expression status of molecular markers such as β-catenin, hTert, TRF2 and RAP1 correlate significantly with the process of tumorigenesis and prognosis and may play a role in therapeutic management of Head and neck patients.
doi:10.7150/jca.9558
PMCID: PMC4314668  PMID: 25653721
HNSCC; Genomic instability; Wnt/β-catenin; Dedifferentiation; MDSCC; WDSCC.
25.  Immune Suppression during Oncolytic Virotherapy for High-Grade Glioma; Yes or No? 
Journal of Cancer  2015;6(3):203-217.
Oncolytic viruses have been seriously considered for glioma therapy over the last 20 years. The oncolytic activity of several oncolytic strains has been demonstrated against human glioma cell lines and in in vivo xenotransplant models. So far, four of these stains have additionally completed the first phase I/II trials in relapsed glioma patients. Though safety and feasibility have been demonstrated, therapeutic efficacy in these initial trials, when described, was only minor. The role of the immune system in oncolytic virotherapy for glioma remained much less studied until recent years. When investigated, the immune system, adept at controlling viral infections, is often hypothesized to be a strong hurdle to successful oncolytic virotherapy. Several preclinical studies have therefore aimed to improve oncolytic virotherapy efficacy by combining it with immune suppression or evasion strategies. More recently however, a new paradigm has developed in the oncolytic virotherapy field stating that oncolytic virus-mediated tumor cell death can be accompanied by elicitation of potent activation of innate and adaptive anti-tumor immunity that greatly improves the efficacy of certain oncolytic strains. Therefore, it seems the three-way interaction between oncolytic virus, tumor and immune system is critical to the outcome of antitumor therapy. In this review we discuss the studies which have investigated how the immune system and oncolytic viruses interact in models of glioma. The novel insights generated here hold important implications for future research and should be incorporated into the design of novel clinical trials.
doi:10.7150/jca.10640
PMCID: PMC4317755  PMID: 25663937
glioblastoma; oncolytic virotherapy; antitumor immunity

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