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The incidence of colorectal cancer (CRC) has increased significantly in the past decade. Early diagnosis and new therapeutics are still urgently needed for CRC in clinical practice. Human α-defensin 6 (HD6) plays a defense role against microbes in the gastrointestinal tract. However, the role and mechanism of HD6 in CRC is still unresolved. Specimens from CRC patients with higher HD6 showed better outcomes. Overexpressed HD6 in CRC cells caused a reduction of cell proliferative, migratory, and invasive ability in vitro and in vivo. HD6-overexpressed caused S phase arrest through changes in cyclin-A and B and CDK2 levels. In addition, serpine-1 may be negatively regulated by HD6 altering the translocation of c-Jun N-terminal kinases (JNK), extracellular regulated protein kinases (ERK), and p38. Higher HD6 and lower serpine-1 levels in CRC patients reflected better outcomes. Finally, we found that HD6 interacts directly with epidermal growth factor receptor (EGFR) by co-immunoprecipitated assay. EGF treatment caused an increase of the level of serpine-1 and pEGFR levels and then increased growth activity in HD6 overexpressing cells. Together, our study shows that HD6 may compete with EGF to bind to EGFR and interrupt cancer progression in CRC. We believe these findings may give new insights for HD6 in CRC therapy.

Introduction Breast cancer is a common malignancy worldwide. Smartphones have gradually become indispensable to our modern lives and have already changed lifestyles of human beings. To our best knowledge, no study has investigated the relationship between smartphone use and breast cancer. This case-control study purposely investigated the relationship between smartphone use and breast cancer risk. Materials and methods This was a case-control study comprising 894 healthy controls and 211 patients with breast cancer. All participants were asked to respond to standard questionnaires to collect information on sleep quality, smartphone addiction, and smartphone use. Results Participants with smartphone addiction had a significantly higher 1.43-fold risk of breast cancer. Individuals with the habitual behavior of smartphone use >4.5 minutes before bedtime had a significantly increased 5.27-fold risk of breast cancer compared to those who used a smartphone for ≤4.5 minutes before bedtime. Additionally, a closer distance between the smartphone and the breasts when using the smartphone exhibited a significantly increased 1.59-fold risk. Participants who carried their smartphone near their chest or waist-abdomen area had significantly increased 5.03-fold and 4.06-fold risks of breast cancer, respectively, compared to those who carried the smartphone below the waist. Moreover, there was a synergistic effect of smartphone addiction and smartphone use of >4.5 minutes before bedtime which increased the breast cancer risk. Conclusion Excessive smartphone use significantly increased the risk of breast cancer, particularly for participants with smartphone addiction, a close distance between the breasts and smartphone, and the habit of smartphone use before bedtime.

Oxaliplatin resistance is a major issue in the treatment of p53 mutant colorectal cancer (CRC). Finding the specific biomarkers would improve therapeutic efficacy of patients with CRC. In order to figure out the biomarker for CRC patients with mutant p53 access oxaliplatin, a Gene Expression Omnibus dataset (GSE42387) was used to determine differentially expressed genes (DEGs). The Search Tool for the Retrieval of Interacting Genes (STRING) and Cytoscape software were used to predict protein-protein interactions. The Database for Annotation, Visualization, and Integrated Discovery online tool was used to group the DEGs into their common pathways. 138 DEGs were identified with 46 upregulated and 92 downregulated. In the PPI networks, 7 of the upregulated genes and 13 of the downregulated genes were identified as hub genes (high degrees). Four hub genes, aldehyde dehydrogenase 2 family member (ALDH2), aldo-keto reductase family 1 member B1 (AKR1B1), aldo-keto reductase family 1 member B10 (AKR1B10), and monoglyceride lipase (MGLL) were enriched in the most significant pathway, glycerolipid metabolism. Further, we found that low expression of ALDH2 is correlated with poor overall survival and oxaliplatin resistance. Finally, we found that combined treatment with ALDH2 inhibitor and oxaliplatin will reduce the sensitivity to oxaliplatin in p53 mutant HT29 cells. In conclusion, we demonstrate that ALDH2 may be a biomarker for oxaliplatin resistance status in CRC patients and bring new insight into treatment strategy for p53 mutant CRC patients.

Background:Approximately 25% of patients with early-stage breast cancer experience cancer progression throughout the disease course. Alterations in TMEM240 in breast cancer were identified and investigated to monitor treatment response and disease progression.Methods:Circulating methylated TMEM240 in the plasma of breast cancer patients was used to monitor treatment response and relapse events. Illumina methylation arrays were used to identify novel hypermethylated CpG sites and genes related to poor hormone therapy response. Quantitative methylation-specific real-time polymerase chain reaction (QMSP), quantitative real-time reverse transcription PCR, and immunohistochemical analyses were performed to measure DNA methylation, mRNA and protein expression levels in 335 breast samples from Taiwanese and Korean patients. Kaplan–Meier curves, Cox proportional hazards regression and receiver operating characteristic curves were used to analyze 10-year survival and disease progression. The Cancer Genome Atlas (TCGA) dataset was used to investigate TMEM240 alterations in Western countries. Transient transfection and knockdown of TMEM240 were performed to determine its biological functions and its relationship to hormone drug treatment response in breast cancer cells.Results: Aberrant methylated TMEM240 was identified in breast cancer patients with poor hormone therapy response using genome-wide methylation analysis in the Taiwan and TCGA breast cancer cohorts. A cell model showed that TMEM240, which is localized to the cell membrane and cytoplasm, represses breast cancer cell proliferation and cell migration. TMEM240 protein expression was observed in normal breast tissues, but not detected in 88.2% (67/76) of breast tumors and in 90.0% (9/10) of metastatic tumors from breast cancer patients. Almost all triple-negative breast cancer patients (95.7%, 22/23) had deficient TMEM240 protein expression. QMSP revealed that in 54.5% (55/101) of Taiwanese breast cancer patients, the methylation level of TMEM240 was at least 2-fold higher in tumor tissues than in the matched normal breast tissues. Patients with hypermethylation of TMEM240 had poor 10-year overall survival (p = 0.003) and poor treatment response, especially hormone therapy response (p < 0.001). Prediction of disease progression based on circulating methylated TMEM240 was found to have 87.5% sensitivity, 93.1% specificity, and 90.2% accuracy, better than the currently used biomarkers CEA and CA-153.Conclusions: Circulating methylated TMEM240 is a potential biomarker for treatment response and disease progression monitoring in breast cancer.

Simple Summary The dysregulation of UPS exacerbates the tumor microenvironment and drives malignant transformation. As the largest family of E3 ligases, the SCFF-boxes promotes BRCA progression. FBXL8 was recently identified to be a novel SCF E3 ligase that potently promotes BRCA. Here, we profiled the transcriptome of BRCA patient tissues by global NGS RNA-Seq and TCGA database analyses. A signature of four SCFF-box E3 ligases (FBXL8, FBXO43, FBXO15, CCNF) was found to be pivotal for BRCA advancement. Knockdown of FBXL8 and FBXO43 reduced cancer cell viability and proliferation, suggesting their pro-tumorigenic roles. However, the overexpression of CCNF inhibited cancer cell progression, indicating its anti-tumorigenic role. FBXL8 and FZR1 pulled down CCNF, and double knockdown of FBXL8 and FZR1 caused CCNF accumulation. Additionally, CCNF partnered with a pro-tumorigenic factor, RRM2, and overexpression of CCNF reduced RRM2. Our findings suggest a potential for drugging CCNF in co-modulatory partnership with FBXL8 and FZR1, for anti-BRCA therapy. Abstract Breast cancer (BRCA) malignancy causes major fatalities amongst women worldwide. SCF (Skp1-cullin-F-box proteins) E3 ubiquitin ligases are the most well-known members of the ubiquitination–proteasome system (UPS), which promotes cancer initiation and progression. Recently, we demonstrated that FBXL8, a novel F-box protein (SCFF-boxes) of SCF E3 ligase, accelerates BRCA advancement and metastasis. Since SCFF-boxes is a key component of E3 ligases, we hypothesized that other SCFF-boxes besides FBXL8 probably collaborate in regulating breast carcinogenesis. In this study, we retrospectively profiled the transcriptome of BRCA tissues and found a notable upregulation of four SCFF-box E3 ligases (FBXL8, FBXO43, FBXO15, and CCNF) in the carcinoma tissues. Similar to FBXL8, the knockdown of FBXO43 reduced cancer cell viability and proliferation, suggesting its pro-tumorigenic role. The overexpression of CCNF inhibited cancer cell progression, indicating its anti-tumorigenic role. Unexpectedly, CCNF protein was markedly downregulated in BRCA tissues, although its mRNA level was high. We showed that both E3 ligases, FBXL8 and FZR1, pulled down CCNF. Double knockdown of FBXL8 and FZR1 caused CCNF accumulation. On the other hand, CCNF itself pulled down a tumorigenic factor, RRM2, and CCNF overexpression reduced RRM2. Altogether, we propose a signature network of E3 ligases that collaboratively modulates CCNF anti-cancer activity. There is potential to target BRCA through modulation of the partnership axes of (i) CCNF-FBXL8, (ii) CCNF-FZR1, and (iii) CCNF-RRM2, particularly, via CCNF overexpression and activation and FBXL8/FZR1 suppression.

Colorectal cancer (CRC) arises from chromosomal instability, resulting from aberrant hypermethylation in tumor suppressor genes. This study identified hypermethylated genes in CRC and investigated how they affect clinical outcomes. Methylation levels of specific genes were analyzed from The Cancer Genome Atlas dataset and 20 breast cancer, 16 esophageal cancer, 33 lung cancer, 15 uterine cancer, 504 CRC, and 9 colon polyp tissues and 102 CRC plasma samples from a Taiwanese cohort. In the Asian cohort, Eps15 homology domain-containing protein 3 (EHD3) had twofold higher methylation in 44.4% of patients with colonic polyps, 37.3% of plasma from CRC patients, and 72.6% of CRC tissues, which was connected to vascular invasion and high microsatellite instability. Furthermore, EHD3 hypermethylation was detected in other gastrointestinal cancers. In the Asian CRC cohort, low EHD3 mRNA expression was found in 45.1% of patients and was connected to lymph node metastasis. Multivariate Cox proportional-hazards survival analysis revealed that hypermethylation in women and low mRNA expression were associated with overall survival. In the Western CRC cohort, EHD3 hypermethylation was also connected to overall survival and lower chemotherapy and antimetabolite response rates. In conclusion, EHD3 hypermethylation contributes to the development of CRC in both Asian and Western populations.

The present systematic review and meta-analysis investigated the association between exposure to radiofrequency radiation and the risk of breast cancer. The published studies that were available in PubMed, Embase, Cochrane Library, Ovid MEDLINE, CINAHL Plus, Web of Science, Airiti Library, Networked Digital Library of Theses and Dissertations and ProQuest until May 2020 were investigated. A total of eight studies (four case-control and four cohort studies) were eligible for quantitative analysis. A significant association between radiofrequency radiation exposure and breast cancer risk was detected [pooled relative risk (RR)=1.189; 95% confidence interval (CI), 1.056-1.339]. Subgroup analyses indicated that radiofrequency radiation exposure significantly increased the risk of breast cancer susceptibility among subjects aged ≥50 years (RR=2.179; 95% CI, 1.260-3.770). Pooled estimates revealed that the use of electrical appliances, which emit radiofrequency radiation, such as mobile phones and computers, significantly increased breast cancer development (RR=2.057; 95% CI, 1.272-3.327), while occupational radiofrequency exposure and transmitters did not increase breast cancer development (RR=1.274; 95% CI, 0.956-1.697; RR=1.133; 95% CI, 0.987-1.300, respectively). It was concluded that radiofrequency radiation exposure significantly increased the risk of breast cancer, especially in women aged ≥50 years and in individuals who used electric appliances, such as mobile phones and computers. In accordance with Preferred Reporting Items for Systematic Reviews and Meta-analysis, an evaluation protocol was prepared and registered with the PROSPERO database (registration no. CRD42018087283).

Developing treatment strategies for triple-negative breast cancer (TNBC) has become an important clinical challenge. Currently, taxane-based chemotherapy is one of the standard treatments for TNBC. However, determining the key factor of taxane-resistance is urgently in need for clinical treatment for breast cancer. We used GEO data to generate paclitaxel resistance in two basal-like TNBC cell lines (SUM149 and MDA-MB-468). Seventy-one common upregulated differentially expressed genes (DEGs) and 11 downregulated DEGs were found to be related to paclitaxel resistance. By constructing protein-protein interactions, 28 hub proteins with a degree cutoff criterion of ≥1 were found. Nine hub genes (COL4A6, COL4A5, IL6, PDGFA, LPAR1, FYB, IL20, IL18R1 and INHBA) are involved in important signaling pathways. We found that upregulated PDGFA and downregulated COL4A6 were significantly associated with an insensitive response to neoadjuvant paclitaxel-based therapy. A Kaplan-Meier plot was created to check the prognostic values of 11 hub DEGs in terms of recurrence-free survival. High expressions of PDGFA and LAMB3 were correlated with poor recurrence-free survival, while low levels of FYB, IL18R1, and RASGRP1 indicated poorer relapse-free survival. Our results suggest that PDGFA, COL4A6, LPAR1, FYB, COL4A5, and RASGRP1 might be candidate target genes for taxane-based therapy in basal-like TNBC.

The present systematic review and meta-analysis investigated the association between exposure to radiofrequency radiation and the risk of breast cancer. The published studies that were available in PubMed, Embase, Cochrane Library, Ovid MEDLINE, CINAHL Plus, Web of Science, Airiti Library, Networked Digital Library of Theses and Dissertations and ProQuest until May 2020 were investigated. A total of eight studies (four case-control and four cohort studies) were eligible for quantitative analysis. A significant association between radiofrequency radiation exposure and breast cancer risk was detected [pooled relative risk (RR)=1.189; 95% confidence interval (CI), 1.056-1.339]. Subgroup analyses indicated that radiofrequency radiation exposure significantly increased the risk of breast cancer susceptibility among subjects aged ≥50 years (RR=2.179; 95% CI, 1.260-3.770). Pooled estimates revealed that the use of electrical appliances, which emit radiofrequency radiation, such as mobile phones and computers, significantly increased breast cancer development (RR=2.057; 95% CI, 1.272-3.327), while occupational radiofrequency exposure and transmitters did not increase breast cancer development (RR=1.274; 95% CI, 0.956-1.697; RR=1.133; 95% CI, 0.987-1.300, respectively). It was concluded that radiofrequency radiation exposure significantly increased the risk of breast cancer, especially in women aged ≥50 years and in individuals who used electric appliances, such as mobile phones and computers. In accordance with Preferred Reporting Items for Systematic Reviews and Meta-analysis, an evaluation protocol was prepared and registered with the PROSPERO database (registration no. CRD42018087283).

The initiation and progression of breast cancer (BRCA) is associated with inflammation and immune-overactivation, which is critically modulated by the E3 ubiquitin ligase. However, the underlying mechanisms and key factors involved in BRCA formation and disease advancement remains under-explored. By retrospective studies of BRCA patient tissues, and gene knockdown and gain/loss-of-function studies, we uncovered a novel E3 ligase, FBXL8, in BRCA. A signature expression profile of F-box factors that specifically target and degrade proteins involved in cell death/survival, was identified. FBXL8 emerged as a prominent member of the F-box factors. Ex vivo analysis of 1349 matched BRCA tissues indicated that FBXL8 promotes cell survival and tumorigenesis, and its level escalates with BRCA progression. Knockdown of FBXL8 caused: (i) intrinsic apoptosis, (ii) inhibition of cell migration and invasion, (iii) accumulation of two tumor-suppressors, CCND2 and IRF5, and (iv) downregulation of cancer-promoting cytokines/chemokines, all of which curtailed the tumor microenvironment and displayed potential to suppress cancer progression. Co-IP study suggests that two tumor-suppressors, CCND2 and IRF5 are part of the immune-complex of FBXL8. The protein levels of CCND2 and IRF5 inversely correlated with FBXL8 expression, implying that FBXL8 E3 ligase was associated with the degradation of CCND2 and IRF5. Altogether, we propose the exploitation of the ubiquitin signaling axis of FBXL8-CCND2-IRF5 for anti-cancer strategies and potential therapeutics.

The initiation and progression of breast cancer (BRCA) is associated with inflammation and immune-overactivation. The E3 ubiquitin ligase is known to subtly balance immune-overactivation and pro-tumorigenesis. Here, by global transcriptional profiling of BRCA patient tissues, we identified a signature expression profile of F-box factors, of which FBXL8 emerged as a novel key component of E3 ligase. Our ex vivo studies (n=1349) indicate that FBXL8 promotes tumorigenesis and its level escalates with BRCA advancement. Knockdown of FBXL8 caused: (i) accumulation of two tumor-suppressors,CCND2 and IRF5, suggesting their collaborative regulation of BRCA status, (ii) intrinsic apoptosis in BRCA, (iii) inhibition of cell migration and invasion and (iv) downregulation of cancer-promoting cytokines/ chemokines; all of these effects curtailed the tumor microenvironment and suppressed cancer progression. Our findings highlight the translational impact of exploiting FBXL8 and its interaction partners (CCND2 and IRF5) for developing anti-cancer strategies and potential therapeutics to limit BRCA progression.

Background Gene silencing by aberrant DNA methylation of promoter regions remains the most dominant phenomenon occurring during tumorigenesis. Improving the early diagnosis, prognosis, and recurrence prediction of colorectal cancer using noninvasive aberrant DNA methylation biomarkers has encouraging potential. The aim of this study is to characterize the DNA methylation of the promoter region of TMEM240, as well as gene expression and its effect on cell biological functions and its applications in early detection and outcome prediction. Results Highly methylated CpG sites were identified in the TMEM240 gene by Illumina methylation 450K arrays in 26 Taiwanese patient paired samples and 38 paired samples from The Cancer Genome Atlas (TCGA) colorectal cancer dataset. Transient transfection and knockdown of TMEM240 were performed to demonstrate the role of TMEM240 in colorectal cancer cells. The data showed that TMEM240 could lead to G1 cell cycle arrest, repress cancer cell proliferation, and inhibit cancer cell migration. The quantitative methylation-specific real-time polymerase chain reaction (PCR) results revealed that 87.8% (480 of 547) of the colorectal cancer tumors had hypermethylated TMEM240, and this was also found in benign tubular adenomas (55.6%). Circulating cell-free methylated TMEM240 was detected in 13 of 25 (52.0%) Taiwanese colorectal cancer patients but in fewer (28.6%) healthy controls. In 72.0% (85/118) of tissue samples, TMEM240 mRNA expression was lower in Taiwanese CRC tumor tissues than in normal colorectal tissues according to real-time reverse transcription PCR results, and this was also found in benign tubular adenomas (44.4%). The TMEM240 protein was analyzed in South Korean and Chinese CRC patient samples using immunohistochemistry. The results exhibited low protein expression in 91.7% (100/109) of tumors and 75.0% (24/32) of metastatic tumors but exhibited high expression in 75.0% (6/8) of normal colon tissues. Multivariate Cox proportional hazards regression analysis found that mRNA expression of TMEM240 was significantly associated with overall, cancer-specific, and recurrence-free survival (p = 0.012, 0.007, and 0.022, respectively). Conclusions Alterations in TMEM240 are commonly found in Western and Asian populations and can potentially be used for early prediction and as poor prognosis and early-recurrence biomarkers in colorectal cancer.

Additional file 1: Figure S1. Differentially methylated CpG heatmap of TMEM240 in paired colon cancer, esophageal cancer, gastric cancer, pancreatic cancer, rectal cancer, and liver cancer tissues. Methylation levels (average β values) at differentially methylated loci were identified using an Illumina Methylation 450K array-based assay. Figure S2. TMEM240 mRNA expression was analyzed in two colon cancer cell lines and two human normal colon tissues. Figure S3. Representative figures of TMEM240 methylation levels determined by QMSP in 78 adjacent normal colon tissues and 78 CRC tumors. Experiments were performed with three technical replicates. Figure S4. Representative figures of TMEM240 mRNA expression determined by gene specific probe based real-time RT-PCR in 21 adjacent normal colon tissues and 21 CRC tumors. Experiments were performed with three technical replicates. Data are presented as the mean ± SD, * p ≤ 0.05, ** p ≤ 0.01, *** p ≤ 0.001. A t-test was used to calculate group differences in all experiments. Experiments were performed with at least two biological duplicates and three technical replicates. Figure S5. The Kaplan-Meier survival curves for (A) overall survival in Taiwanese colorectal carcinoma (CRC) patients and (B) cancer-specific survival in Taiwanese females are shown. TMEM240 was considered to have low expression when the expression level in CRC tumors was 5-fold lower than that in normal tissues. Table S1. TMEM240 mRNA expression and promoter hypermethylation in relation to the clinical parameters of the TCGA CRC dataset. Table S2: List of primers sequences and their reaction conditions used in the present study.

// Chin-Sheng Hung 1, 2, 3, * , Chien-Yu Huang 2, 4, * , Chia-Hwa Lee 5 , Wei-Yu Chen 6, 7 , Ming-Te Huang 2, 4 , Po-Li Wei 2, 3, 8, 9, 10, 11 and Yu-Jia Chang 1, 2, 3, 11 1 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC 2 Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC 3 Division of General Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei, Taiwan, ROC 4 Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan, ROC 5 School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan, ROC 6 Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC 7 Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan, ROC 8 Division of Colorectal Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan, ROC 9 Translational Laboratory, Department of Medical Research, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan, ROC 10 Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan, ROC 11 Cancer Research Center, Taipei Medical University Hospital, Taipei, Taiwan, ROC * These authors contributed equally to this work Correspondence to: Po-Li Wei, email: poliwei@tmu.edu.tw Yu-Jia Chang, email: r5424012@tmu.edu.tw Keywords: HCC, Hsp27, IGFBP2 Received: February 08, 2017 Accepted: June 18, 2017 Published: July 05, 2017 ABSTRACT Heat shock protein 27 (Hsp27) is a key chaperone that interacts with over 200 client proteins. The expression of Hsp27 might be correlated with poor outcome in many types of cancer. Previous study indicated that Hsp27 might be an important biomarker in hepatocellular carcinoma (HCC). However, the detailed mechanism is less well understood. The shRNA-mediated silencing of Hsp27 decreased the proliferation, migration and invasion of HCC cells. In a xenograft model, the silencing of Hsp27 reduced tumor progression. We revealed that the silencing of Hsp27 led to a reduction in insulin-like growth factor binding protein 2 (IGFBP2), which might mediate proliferation and metastasis through vimentin, snail and beta-catenin. The overexpression of IGFBP2 reversed the reductions in cell growth, migration and invasion. The tissue array results showed that HCC patients with high Hsp27 expression exhibited poor prognosis and increased metastasis. The Hsp27 expression was highly correlated with IGFPB2 in CRC specimen. ChIP and luciferase assays showed that Hsp27 does not directly bind the IGFBP2 promoter region to regulate the transcription of IGFBP2. In conclusion, our study demonstrated that Hsp27 is a key mediator of HCC progression and metastasis and that Hsp27 might regulate proliferation and metastasis through IGFBP2. This pathway might provide a new direction for the development of a novel therapeutic strategy for HCC.

Multiple common variants identified by genome-wide association studies showed limited evidence of the risk of breast cancer in Taiwan. In this study, we analyzed the breast cancer risk in relation to 13 individual single-nucleotide polymorphisms (SNPs) identified by a GWAS in an Asian population. In total, 446 breast cancer patients and 514 healthy controls were recruited for this case–control study. In addition, we developed a polygenic risk score (PRS) including those variants significantly associated with breast cancer risk, and also evaluated the contribution of PRS and clinical risk factors to breast cancer using receiver operating characteristic curve (AUC). Logistic regression results showed that nine individual SNPs were significantly associated with breast cancer risk after multiple testing. Among all SNPs, six variants, namely FGFR2 (rs2981582), HCN1 (rs981782), MAP3K1 (rs889312), TOX3 (rs3803662), ZNF365 (rs10822013), and RAD51B (rs3784099), were selected to create PRS model. A dose–response association was observed between breast cancer risk and the PRS. Women in the highest quartile of PRS had a significantly increased risk compared to women in the lowest quartile (odds ratio 2.26; 95% confidence interval 1.51–3.38). The AUC for a model which contained the PRS in addition to clinical risk factors was 66.52%, whereas that for a model which with established risk factors only was 63.38%. Our data identified a genetic risk predictor of breast cancer in Taiwanese population and suggest that risk models including PRS and clinical risk factors are useful in discriminating women at high risk of breast cancer from those at low risk.

The early detection of cancer can reduce cancer-related mortality. There is no clinically useful noninvasive biomarker for early detection of breast cancer. The aim of this study was to develop accurate and precise early detection biomarkers and a dynamic monitoring system following treatment. We analyzed a genome-wide methylation array in Taiwanese and The Cancer Genome Atlas (TCGA) breast cancer (BC) patients. Most breast cancer-specific circulating methylated CCDC181, GCM2 and ITPRIPL1 biomarkers were found in the plasma. An automatic analysis process of methylated ccfDNA was established. A combined analysis of CCDC181, GCM2 and ITPRIPL1 (CGIm) was performed in R using Recursive Partitioning and Regression Trees to establish a new prediction model. Combined analysis of CCDC181, GCM2 and ITPRIPL1 (CGIm) was found to have a sensitivity level of 97% and an area under the curve (AUC) of 0.955 in the training set, and a sensitivity level of 100% and an AUC of 0.961 in the test set. The circulating methylated CCDC181, GCM2 and ITPRIPL1 was also significantly decreased after surgery (all p &lt, 0.001). The aberrant methylation patterns of the CCDC181, GCM2 and ITPRIPL1 genes means that they are potential biomarkers for the detection of early BC and can be combined with breast imaging data to achieve higher accuracy, sensitivity and specificity, facilitating breast cancer detection. They may also be applied to monitor the surgical treatment response.

Gastric cancer is an important health issue worldwide. Currently, improving the therapeutic efficacy of chemotherapy drugs is an important goal of cancer research. Alpha-7 nicotine acetylcholine receptor (A7-nAChR) is the key molecule that mediates gastric cancer progression, metastasis, and therapy responses; however, the role of A7-nAChR in the therapeutic efficacy of ixabepilone remains unclear. A7-nAChR expression was silenced by small interfering RNA (siRNA) technology. The cytotoxicity of ixabepilone was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and ixabepilone-induced apoptosis was analyzed by flow cytometry and annexin V/propidium iodide (PI) apoptotic assay. The expression patterns of anti-apoptotic proteins (AKT, phospho-AKT, Mcl-1, and Bcl-2) and pro-apoptotic proteins (Bad and Bax) were determined by western blot. Our study found that A7-nAChR knockdown (A7-nAChR-KD) AGS cells were more sensitive to ixabepilone administration than scrambled control AGS cells. We found that A7-nAChR knockdown enhanced ixabepilone-induced cell death as evidenced by the increased number of annexin V-positive (apoptotic) cells. After scrambled control and A7-nAChR-KD cells were treated with ixabepilone, we found that pAKT and AKT levels were significantly reduced in both groups of cells. The levels of Bcl-2 and the anti-apoptotic Mcl-1 isoform increased dramatically after ixabepilone treatment in scrambled control cells but not in A7-nAChR-KD cells. Bad and Bax levels did not change between the treatment group and vehicle group in both A7-nAChR-KD and scrambled control cells, whereas cleaved PARP levels dramatically increased in ixabepilone-treated A7-nAChR-KD cells. Our results demonstrated that knockdown of A7-nAChR enhanced the sensitivity of gastric cancer cells to ixabepilone administration. Thus, the A7-nAChR expression level in patients with gastric cancer may be a good indicator of ixabepilone sensitivity.

Background/aim Androgen deprivation therapy remains the principal treatment for patients with advanced prostate cancer, though, most patients will eventually develop hormone-refractory prostate cancer (HRPC). Androgen ablation mediated maspin-induction has been identified in cancer patients. However, the role of maspin on the anticancer activity of curcumin derived from turmeric (Curcuma longa) in HRPC cells has not been elucidated. Materials and methods The anticancer action of curcumin in hormone-independent prostate cancer cells (DU145, and PC-3) was determined by measures of cell survival rate. The cause of maspin silencing on the anti-tumor abilities of curcumin in PC-3 cells was evaluated by measures of cell survival rate, cell-cycle distribution, and apoptosis signaling analysis. Results Our present study showed that PC-3 cells (with higher maspin expression) were more sensitive than DU145 cells to curcumin treatment (with lower maspin expression). RNA interference-mediated maspin silencing reduced curcumin sensitivity of PC-3 cells, as evidenced by reduced apoptotic cell death. After exposure to curcumin, maspin-knockdown cells showed lower expression levels of pro-apoptotic proteins, Bad and Bax, as compared with control cells. Conclusion Maspin can enhance the sensitivity of HRPC cells to curcumin treatment.

Glucose-regulated protein 78 (GRP78) is the key regulator of endoplasmic reticular (ER) function. Expression of GRP78 was correlated with malignancy in different cancers. However, the role of GRP78 in the cytotoxic effect of curcumin on colon cancer cells is still unclear. A silencing RNA (siRNA) technique was used to knock down GRP78 expression. The anticancer effects of curcumin were assessed by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, a flow cytometric cell cycle analysis, and a terminal dexynucleotidyl transferase-mediated nick end labeling (TUNEL) assay. HT-29 cells expressed lower GRP78 compared with DLD-1 cells. The MTT assay revealed that HT-29 cells were more resistant to curcumin treatment than DLD-1 cells. GRP78KD cells showed more resistance to curcumin treatment compared with scrambled control cells. Overexpressed GRP78 in HT-29 cells increased the sensitivity to curcumin treatment. According to the cell cycle analysis and TUNEL assay, we found that apoptosis dramatically increased in scrambled control cells compared to GRP78KD DLD-1 cells after curcumin treatment. Finally, we evaluated levels of Bcl-2, BAX, and Bad and found that an increase of Bcl-2 level was observed in GRP78KD cells treated with curcumin. Those results were consistent with the increasing of resistance to curcumin after silencing of GRP78. The levels of GRP78 expression might determine the therapeutic efficacy of curcumin against colon cancer cells.

Laparoscopic surgery has become the standard for treating appendicitis. The cosmetic benefits of using single-incision laparoscopy are well known, but its duration, complications and time to recovery have not been well documented. We compared 2 laparoscopic approaches for treating appendicitis and evaluated postoperative pain, complications and time to full recovery.We retrospectively reviewed the cases of consecutive patients with appendicitis and compared those who underwent conventional laparoscopic appendectomy (CLA) performed using 3 incisions and those who underwent single-incision laparoscopic appendectomy (SILA). During SILA, the single port was prepared to increase visibility of the operative site.Our analysis included 688 consecutive patients: 618 who underwent CLA and 70 who underwent SILA. Postsurgical complications occurred more frequently in the CLA than the SILA group (18.1% v. 7.1%, p = 0.018). Patients who underwent SILA returned to oral feeding sooner than those who underwent CLA (median 12 h v. 22 h, p0.001). These between-group differences remained significant after controlling for other factors. Direct comparison of only nonperforated cases, which was determined by pathological examination, revealed that SILA was significantly longer than CLA (60 min v. 50 min, p0.001). Patients who underwent SILA had longer in-hospital stays than those who underwent CLA (72 v. 55 h, p0.001); however, they had significantly fewer complications (3.0% v. 14.4%, p = 0.006).In addition to its cosmetic advantages, SILA led to rapid recovery and no increase in postsurgical pain or complications.La chirurgie laparoscopique est devenue la norme pour le traitement de l’appendicite. Les avantages de la laparoscopie à simple incision au plan esthétique sont bien connus, mais la durée de l’intervention, ses complications et le temps de récupération n’ont pas été adéquatement documentés. Nous avons comparé 2 approches laparoscopiques pour le traitement de l’appendicite et évalué la douleur et les complications postopératoires, de même que le temps de récupération complète.Nous avons passé en revue de manière rétrospective les dossiers de patients consécutifs atteints d’appendicite et comparé ceux qui ont subi une appendicectomie laparoscopique classique (ALC) à 3 incisions à ceux qui ont subi une appendicectomie laparoscopique à simple incision (ALSI). Durant l’ALSI, l’incision était préparée de manière à améliorer la visibilité du champ opératoire.Notre analyse a inclus 688 patients consécutifs : 618 qui ont subi une ALC et 70, une ALSI. Les complications postopératoires ont été plus nombreuses dans le groupe soumis à l’ALC qu’à l’ALSI (18,1 % c. 7,1 %,En plus de ses avantages au plan esthétique, l’ALSI a permis une récupération rapide, sans accroissement de la douleur ou des complications postopératoires.

Laparoscopic rectal cancer surgery is regarded as more complex because of its technical difficulties in pelvic exposure, dissection, and sphincter preservation. This study therefore aimed to investigate the feasibility of laparoscopic resection for low rectal cancer using intersphincteric resection (ISR) and to assess its short-term oncological outcomes. Further, we intended to analyze the learning curve for laparoscopic surgery and identify the factors influencing the learning curve.Patients with low rectal cancer who received open or laparoscopic ISR were retrospectively chart reviewed. The surgical and oncological outcomes were evaluated. Comparisons of operating time, estimated blood loss, surgical outcomes, and histopathologic status were analyzed. Also, operating time was used as a technical indicator for learning curve analysis.The mean estimated blood loss was 265 mL (range, 100-800 mL) in the open group and 104 mL (range, 30-250 mL) in the laparoscopic group. There was a significant difference between these two groups (P 0.001). Operative experience analysis showed that the mean operating time was 402.1 min (range, 210-570 min) in the first stage and 331.4 min (range, 210-450 min) in the second stage, and on pathologic examination the mean number of lymph nodes harvested was 11.1 (range, 5-21) in the first stage and 18.3 (range, 11-31) in the second stage, with statistical differences between these two stages (P = 0.034 and P = 0.004, respectively). Multifactorial analysis showed that operating time was associated with surgeons' experience (18 or ≥18 cases) (odds ratio = 2.918, 95% CI 1.078-7.902). Protective stoma creation was also associated with surgeons' experience (odds ratio = 3.999, 95% CI 1.153-13.86).Our data show that laparoscopic ISR for low rectal cancer is feasible and safe. Surgeons' experience improved operating time and postoperative complications.

MRI provides a highly sensitive technique for early detection of abnormal breast tissue. It is useful for identifying a status of proliferation, angiogenesis, and microvascular permeability, which may indicate early breast neoplasm formation. We retrospectively studied 2005 breast MRI images from Taiwanese women and classified them as either healthy or unhealthy according to BI-RADS categories. A subgroup of our study patients had received estrogen supplements, containing estrogen components or phytoestrogen, for at least 3 months. These patients’ images were also classified into the healthy and unhealthy groups. These two groups were compared and a significant difference was found between them (P

Introduction Laparoscopic techniques are commonly used in abdominal and gynecologic surgery, while breast cancer surgery has remained largely unchanged. In Asia, especially in Japan, many surgeons have started to use endoscopic surgery for breast cancer. In Taiwan, endoscopy-assisted breast surgery started in 2010. The benefits of this surgical method include smaller incisions, an axillary anatomic approach, clear vision, no oncologic compromise, and good cosmetic outcomes. This is the first report to discuss the learning curve of endoscopy-assisted breast surgery, including the difficulties experienced. Materials and methods From June 2011 to December 2013, data were collected from 134 patients who received an endoscopic total mastectomy at the Taipei Medical University Hospital (TMUH) or Changhua Christian Hospital (CCH). We divided these patients into a learning group (TMUH, n = 15; CCH, n = 15) and a mature group (TMUH, n = 50; CCH, n = 54). Patient data and perioperative variables were recorded by retrospective chart review. Variables were compared using the χ2 test and Student’s t-test. Results There was a significant difference in operation time (275.3 vs. 228.9 minutes, p < 0.01) between the learning and mature groups. Perioperative variables (lymph node dissection method, nipple preservation, and reconstruction method) were also analyzed, but there were no demographic differences between the groups. The complication rate was higher in the learning group, although this difference was also not statistically significant. Conclusion Our study is the first to discuss the learning curve of endoscopic total mastectomy. The operation time decreased significantly after 15 cases at each hospital. Although the operation is still more time-consuming than traditional methods, it has the benefit of smaller wounds and improved cosmetic outcomes if combined with immediate reconstruction.

Background Breast magnetic resonance imaging (MRI) is extremely sensitive for detecting lesions, but certain characteristics of malignancies, such as the washout pattern of kinetic curves, are not specific. Correlations of false-positive MRI and specific pathological results are worthy of study. Methods From March 2008 to September 2011, 217 cases received biopsy after dedicated breast MRI in our department. Biopsies were recommended for suspected malignancies based on the overall analysis of early subtracted phase images, postenhanced curve patterns, color mapping, and tumor morphology. Results Twenty-nine percent of cases were false positive for malignancy, according to MRI. These lesions included radial scar, apocrine metaplasia, atypical ductal hyperplasia, sclerosing adenosis, intraductal papilloma, fibrocystic change, and mastitis. Conclusion The ability of tumor cells to induce vascularization occurs early in the cell transformation process; therefore, premalignant breast lesions may also induce vascularization to facilitate malignant transformation. As a noninvasive method, contrast-enhanced MRI has a potential role in estimating the degree of angiogenesis and tumor microvascular permeability of breast neoplasms.

Background/purpose The tobacco-specific mitogen nicotine was reported to correlate with cancer progression and tumorigenesis in breast cancer. Metastasis is a major cause of cancer death, so the influence of nicotine on breast cancer cell migration is also of interest. Our aim is to elucidate the mechanisms of nicotine-enhanced migration of breast cancer cells and thereby achieve better control of metastasis. Methods The influence of nicotine on breast cancer cell migration was evaluated by trans-well and wound-healing migration assays. Receptor-mediated migration was studied with both a small molecule inhibitor and small interfering RNA (siRNA). Results The alpha9 nicotinic acetylcholine receptor, α9nAChR, was identified in breast cancer cell lines MCF-7 and MDA-MB-231. Nicotine enhanced cell migration in both trans-well and wound-healing migration assays. We used a specific inhibitor and siRNA to demonstrate that α9nAChR is the key modulator in mediating nicotine-enhanced breast cancer cell migration through up-regulation of fibronectin and vimentin. Conclusion Nicotine treatment enhanced breast cancer metastasis through α9nAChR signaling via enhanced fibronectin and vimentin expression.

Background/Purpose Neoadjuvant chemoradiation is considered to be the treatment of choice for locally advanced rectal cancer. However, patient-oriented outcomes and postoperative quality of life are unsatisfactory. In this study, we analyze histopathologic changes in the sphincter apparatus in patients who received abdominoperineal resection with or without preoperative chemoradiation. Methods Patients with low rectal cancer who underwent abdominoperineal resection from January 2009 to October 2009 were retrospectively enrolled and reviewed. The specimens obtained from the patients were stained using hematoxylin and eosin, Masson’s trichrome and S-100 immunoperoxidase. Semi-quantitative assessment of the fibrous replacement and nerve bundle densities were analyzed. Results Eleven patients were retrospectively chart reviewed [one female, 10 males; mean age 63 years (range, 48–77 years)]. Six patients with locally advanced disease staged by pelvic magnetic resonance imaging were treated with preoperative chemoradiation followed by surgical resection. The other five patients underwent surgery without chemoradiation (control group). There was a trend toward increased fibrosis in the patients receiving chemoradiation. Fibrous replacement was also detected in the area surrounding the tumor. In Meissner’s plexus (submucosal plexus), there was no difference in nerve density between the two groups; however, in Auerbach’s plexus (myenteric plexus), there was an increased density of nerve bundles in the chemoradiation group. Conclusion Neoadjuvant chemoradiation causes histopathologic changes in the anorectal region by increasing fibrous replacement and altering nerve bundle arrangement. These alterations may interfere with bowel function including a decrease in anorectal resting pressure, soiling and an incomplete defecation sensation. Further studies with larger patient samples are necessary for clarification.

Background The intersphincteric resection technique has been used to extend the opportunity for sphincter preservation in patients with very low rectal cancer. The aim of this study is to assess the long-term oncological and functional outcomes of intersphincteric resection. Methods Patients with extraperitoneal rectal cancer were treated and retrospectively chart reviewed. The oncological and functional outcomes were evaluated. Comparisons of the overall disease-free survival and recurrence were analyzed for the different surgical procedures. Results From July 2002 to August 2009, 162 patients with extraperitoneal rectal cancer were retrospectively chart reviewed. One-hundred one patients (62.3%) underwent low anterior resection, 26 patients (16%) received radical proctectomy and intersphincteric resection with coloanal anastomosis, and 23 (14.2%) had abdominoperineal resection. The sphincter preservation rate was 80%. In the intersphincteric resection group, overall survival rates at 3 and 5 y were 83% and 83%, and disease-free survival at 3 and 5 y were 82% and 76%, respectively. The mean stool frequency was 4.7 per 24 h. There were 38.1% of patients suffering from stool fragmentation, and 23.8% had nocturnal defecation. About one-third of the patients required antidiarrheal medications. Overall, 90.8% of patients were satisfied with the functional results of surgery. Conclusions Our data show intersphincteric resection for low rectal cancer is feasible and safe. Preoperative radiotherapy may negatively affect symptom-specific quality of life.

Accumulated evidence indicates that the incidence of early-onset breast cancer has rapidly increased in Taiwan and other Asian compared to Western countries. The mismatch repair (MMR) pathway might be one of the crucial mechanisms of predisposition to early breast cancer. In this study, we explored whether MMR gene polymorphisms contribute to the risk of breast cancer in young women. This was a 2-stage case–control study including 737 cases and 719 controls. After eight single nucleotide polymorphisms (SNPs) were genotyped in MMR pathway genes in the stage I study, a promising SNP, MSH2 rs2303425, was selected for validation in the stage II study. A luciferase reporter assay was used to evaluate the transcriptional activity of MSH2. Logistic regression analysis showed that individuals with the MSH2 rs2303425 C/C genotype had a significantly increased risk of breast cancer compared to those with the T/T genotype (adjusted odds ratio 2.0; 95 % confidence interval 1.1–3.8), particularly in early-onset breast cancer patients with the luminal A subtype. The luciferase assay in three cell lines indicated that the MSH2 rs2303425 T/C substitution decreased MSH2 expression, which is consistent with the finding of an association study. A common variant SNP in MSH2 may contribute to the susceptibility to early-onset breast cancer functionally, particularly for the luminal A subtype.