Purpose: Very few studies examined the issue of regret on choosing colorectal cancer (CRC) screening tests. We evaluated the determinants of regret and tested the hypothesis that regret over screening choices was associated with poorer screening compliance. Methods: A bowel cancer screening centre invited all Hong Kong citizens aged 50-70 years who were asymptomatic of CRC to participate in free-of-charge screening programmes. Upon attendance they attended health seminars on CRC and its screening, and were offered an option to choose yearly faecal immunochemical test (FIT) for up to four years vs. one direct colonoscopy. They were not allowed to switch the screening option after decision. A self-administered, four-item validated survey was used to assess whether they regretted over their choice (> 2 = regretful from a scale of 0 [no regret]-5 [extreme regret]). A binary logistic regression model evaluated if initial regret over their choice was associated with poorer programme compliance. Results: From 4,341 screening participants who have chosen FIT or colonoscopy, 120 (2.8%) regretted over their decision and 1,029 (23.7%) were non-compliant with the screening programme. Younger subjects and people who felt pressure when making their decision were associated with regret. People who regretted their decision were 2.189 (95% C.I. 1.361-3.521, p = 0.001) times more likely to be non-compliant with the programme. Conclusions: This study is the first to show that regret over the initial CRC screening choice was associated with later non-compliance. Screening participants who expressed regret over their choice should receive additional reminders to improve their programmatic compliance.

黄至生    Jessica Ching    Chan Victor C.W.    Bruggemann Renee    Lam Thomas Y.T.    Luk Arthur K.C.    Wu Justin C.Y.    Francis Chan    沈祖堯    

PLoS ONE

2015

Ding    沈祖堯     Henry lik yuen Chan    Luan Ju   

Hong Kong Medical Journal

2015

Colorectal cancer had a low incidence several decades ago. However, it has become a predominant cancer and now accounts for approximately 10% of cancer-related mortality in western countries. The 'rise' of colorectal cancer in developed countries can be attributed to the increasingly ageing population, unfavourable modern dietary habits and an increase in risk factors, such as smoking, low physical exercise and obesity. New treatments for primary and metastatic colorectal cancer have emerged, providing additional options for patients; these treatments include laparoscopic surgery for primary disease, more-aggressive resection of metastatic disease (such as liver and pulmonary metastases), radiotherapy for rectal cancer, and neoadjuvant and palliative chemotherapies. However, these new treatment options have had limited impact on cure rates and long-term survival. For these reasons, and the recognition that colorectal cancer is long preceded by a polypoid precursor, screening programmes have gained momentum. This Primer provides an overview of the current state of the art of knowledge on the epidemiology and mechanisms of colorectal cancer, as well as on diagnosis and treatment.

Kuipers Ernst J.    Grady William M.    Lieberman David A.    Thomas Seufferlein    沈祖堯     Petra Boelens    Van De Velde Cornelis J.H.    Toshiaki Watanabe   

Nature Reviews Disease Primers

2015

Helicobacter pylori is the primary cause of gastric cancer. However, monoclonal Epstein-Barr virus (EBV) nucleic acid is also present in up to 10% of these tumors worldwide. EBV prevalence is increased with male sex, nonantral localization and surgically disrupted anatomy. To further examine associations between EBV and gastric cancer, we organized an international consortium of 11 studies with tumor EBV status assessed by in situ hybridization. We pooled individual-level data on 2,648 gastric cancer patients, including 184 (7%) with EBV-positive cancers; all studies had information on cigarette use (64% smokers) and nine had data on alcohol (57% drinkers). We compared patients with EBV-positive and EBV-negative tumors to evaluate smoking and alcohol interactions with EBV status. To account for within-population clustering, multilevel logistic regression models were used to estimate interaction odds ratios (OR) adjusted for distributions of sex (72% male), age (mean 59 years), tumor histology (56% Lauren intestinal-type), anatomic subsite (61% noncardia) and year of diagnosis (1983-2012). In unadjusted analyses, the OR of EBV positivity with smoking was 2.2 [95% confidence interval (CI) 1.6-3.2]. The OR was attenuated to 1.5 (95% CI 1.01-2.3) by adjustment for the possible confounders. There was no significant interaction of EBV status with alcohol drinking (crude OR 1.4; adjusted OR 1.0). Our data indicate the smoking association with gastric cancer is stronger for EBV-positive than EBV-negative tumors. Conversely, the null association with alcohol does not vary by EBV status. Distinct epidemiologic characteristics of EBV-positive cancer further implicate the virus as a cofactor in gastric carcinogenesis. What's new? Although the H.pylori bacteria is the primary cause of gastric cancer, in some cases the Epstein-Barr virus also appears to be involved. In this study, the authors compared smoking and alcohol use between patients with EBV-positive and EBV-negative gastric cancers. No association was found with alcohol use, but smokers were more likely to have EBV-positive cancer. © 2013 UICC.

Camargo M. Constanza    Koriyama Chihaya    Keitaro Matsuo    Wooho Kim    Herrera-Goepfert Roberto    Linda Liao    Jun Yu    Carrasquilla Gabriel    沈祖堯     Alvarado-Cabrero Isabel    Lissowska    Meneses-Gonzalez Fernando    Yatabe Yashushi    Ti Ding    Hu Nan    Philip Taylor    Morgan Douglas R.    Margaret Gulley    Torres Javier    Akiba Suminori    Charles Rabkin   

International Journal of Cancer

2014

Background: Androgen receptor (AR) signalling contributes to male predominance in hepatocellular carcinoma (HCC), which is more pronounced in HBV-endemic areas. Cell cycle-related kinase (CCRK) is essential for AR-induced hepatocarcinogenesis but its molecular function in HBV-associated HCC remains obscure. Objective: To determine the molecular function of CCRK in HBV-associated HCC. Design: Transcriptional regulation was assessed by chromatin immunoprecipitation, promoter mutation and luciferase reporter assays. Hepatocellular proliferation and tumourigenesis were examined by colony formation, soft agar assays and using HBV X protein (HBx) transgenic mice with low-dose exposure to diethylnitrosamine. Protein expressions were examined in clinical samples and correlated with patient survival by log-rank Mantel-Cox test. Results: Overexpression of CCRK, but not its kinase-defective mutant, activated ß-catenin/T cell factor signalling through phosphorylation of glycogen synthase kinase-3ß (GSK-3ß) at Ser9, led to upregulation of AR transcriptional activity and, subsequently, expression of HBx. The viral transactivator in turn induced CCRK expression through enhanced AR signalling, thus forming a positive regulatory loop. RNA interference silencing of CCRK, which suppressed the CCRK/GSK-3ß/ß-catenin/AR regulatory loop, significantly suppressed HBx-induced hepatocellular proliferation (p=0.001) and transformation (p<0.001) and remarkably reduced >80% diethylnitrosamine-mediated hepatocarcinogenesis in HBx transgenic mice. Finally, patients with HBV-associated HCC with concordant overexpression of CCRK, GSK-3ß phosphorylation at Ser9, active dephosphorylated ß-catenin and AR phosphorylation at Ser81 had poorer overall (HR=31.26, p<0.0001) and disease-free (HR=3.60, p<0.01) survival rates. Conclusions: Our findings highlight the critical role of CCRK in a self-reinforcing circuitry that regulates HBV-associated hepatocarcinogenesis. Further characterisation of this intricate viral-host signalling may provide new prognostic biomarkers and therapeutic targets for HCC treatment. © 2014 BMJ Publishing Group Ltd & British Society of Gastroenterology.

Zhuo Yu    高月求    Feng Hai    Lee Ying-Ying    Li May S.    Tian Yuan    Minnieyy Go    Dae yeul Yu    Yuesun Cheung    Paul Lai    Jun Yu    Vincent Wong    沈祖堯     Henry lik yuen Chan    Alfred Cheng   

Gut

2014

Hepatocellular carcinoma (HCC) is one of the most common fatal malignancies but the molecular genetic basis of this disease remains unclear. By using genome-wide methylation profiling analysis, we identified CLDN3 as an epigenetically regulated gene in cancer. Here, we investigated its function and clinical relevance in human HCC. CLDN3 downregulation occurred in 87/114 (76.3%) of primary HCCs, where it was correlated significantly with shorter survival of HCC patients (P=0.021). Moreover, multivariate cyclooxygenase regression analysis showed that CLDN3 was an independent prognostic factor for overall survival (P=0.014). Absent expression of CLDN3 was also detected in 67% of HCC cell lines, which was significantly associated with its promoter hypermethylation. Ectopic expression of CLDN3 in HCC cells could inhibit cell motility, cell invasiveness, and tumor formation in nude mice. Mechanistic investigations suggested through downregulation of GSK3B, CTNNB1, SNAI2, and CDH2, CLDN3 could significantly suppress metastasis by inactivating the Wnt/β-catenin-epithelial mesenchymal transition (EMT) axis in HCC cells. Collectively, our findings demonstrated that CLDN3 is an epigenetically silenced metastasis suppressor gene in HCC. A better understanding of the molecular mechanism of CLDN3 in inhibiting liver cancer cell metastasis may lead to a more effective management of HCC patients with the inactivation of CLDN3.

Lei Jiang    Yang Yi-Dong    Fu Li    Xu Weiqi    Liu Dabin    Liang Qiaoyi    Xiang Zhang    Xu Lixia    关新元    Bin Wu    沈祖堯     Jun Yu   

Oncotarget

2014

B cell CLL/lymphoma 6 member B (BCL6B) is a novel tumor suppressor silenced in human cancer. In this study, we investigated the functional role and underlying mechanisms of BCL6B in hepatocellular carcinoma (HCC). BCL6B was expressed in normal HCC tissues, but its expression was suppressed in 6 out of 9 HCC cell lines. Loss of BCL6B expression was associated with promoter hypermethylation. Ectopic expression of BCL6B in HepG2 and Huh7 cell lines inhibited colony formation (. P <. 0.05), cell viability (. P <. 0.01), and tumorigenicity in nude mice (. P <. 0.05). BCL6B expression also induced apoptosis (. P <. 0.05), an effect associated with activation of the caspase cascade and cleavage of PARP. Stable expression of BCL6B in MHCC97L cells suppressed cell migration (. P <. 0.05) and invasion (. P <. 0.05), and significantly reduced the incidence and severity of lung metastasis in an orthotopic HCC mouse model. The anti-metastatic effect of BCL6B was mediated by up-regulation of cell adhesion gene E-cadherin, OB-cadherin, HIV-1 Tat interactive protein 2, and transient receptor potential cation channel, subfamily M, member 1; and down-regulation of angiogenesis gene VEGFA. BCL6B functions as a tumor suppressor that inhibits HCC metastases in vitro and in vivo.

Wang Jia    Dong Ling    Xu Lixia    Eagle sh Chu    Yangchao Chen    Jiayun Shen    Xiaoxing Li    Chichun Wong    沈祖堯     Jun Yu   

Cancer Letters

2014

Background:The detection of microRNA (miRNA) dysregulation in stool is a novel approach for the diagnosis of colorectal carcinoma (CRC). The aim of this study is to investigate the use of miR-221 and miR-18a in stool samples as non-invasive biomarkers for CRC diagnosis.Methods:A miRNA expression array containing 667 miRNAs was performed to identify miRNA dysregulation in CRC tissues. We focused on miR-221 and miR-18a, two significantly upregulated miRNAs which were subsequently verified in 40 pairs of CRC tissues and 595 stool samples (198 CRCs, 199 polyps and 198 normal controls).Results:miR-221 and miR-18a were upregulated in the miRNA expression array. miR-221 and miR-18a levels were also significantly higher in 40 CRC tumours compared with their respective adjacent normal tissues. In stool samples, miR-221 and miR-18a showed a significant increasing trend from normal controls to late stages of CRC (P<0.0001). The levels of stool miR-221 and miR-18a were both significantly higher in subjects with stages I+II (miR-221: P<0.0001, miR-18a: P<0.0001) and stages III+IV of CRC (miR-221: P=0.0004, miR-18a: P<0.0001) compared with normal controls. The AUC of stool miR-221 and miR-18a were 0.73 and 0.67 for CRC patients as compared with normal controls, respectively. No significant differences in stool miR-221 and miR-18a levels were found between patients with proximal and distal CRCs. The use of antibiotics did not influence stool miRNA-221 and miRNA-18a levels.Conclusions:Stool-based miR-221 can be used as a non-invasive biomarker for the detection of CRC.

Yau Tung On    Wu    Yujuan Dong    Ceenming Tang    吴兆文    Chan    沈祖堯     Jun Yu   

British Journal of Cancer

2014

Small molecules that restore the expression of growth-inhibitory microRNAs (miRNA) downregulated in tumors may have potential as anticancer agents. miR34a functions as a tumor suppressor and is downregulated or silenced commonly in a variety of human cancers, including hepatocellular carcinoma (HCC). In this study, we used an HCC cell-based miR34a luciferase reporter system to screen for miR34a modulators that could exert anticancer activity. One compound identified as a lead candidate, termed Rubone, was identified through its ability to specifically upregulate miR34a inHCC cells. Rubone activated miR34a expression inHCC cells with wildtype or mutated p53 but not in cells with p53 deletions. Notably, Rubone lacked growth-inhibitory effects on nontumorigenic human hepatocytes. In a mouse xenograft model of HCC, Rubone dramatically inhibited tumor growth, exhibiting stronger anti-HCC activity than sorafenib both in vitro and in vivo. Mechanistic investigations showed that Rubone decreased expression of cyclin D1, Bcl-2, and other miR34a target genes and that it enhanced the occupancy of p53 on the miR34a promoter. Taken together, our results offer a preclinical proof of concept for Rubone as a lead candidate for further investigation as a new class of HCC therapeutic based on restoration of miR34a tumor-suppressor function.

Xiao Zhangang    Han Li Chi    Stephenlam Chan    Xu Feiyue    Feng Lu    Wang Yan    Jiandong Jiang    沈祖堯     Christopher hon ki Cheng    Yangchao Chen   

Cancer Research

2014

CONCLUSIONS: By using genomic, transcriptome, and epigenomic comparisons of EBV infected vs noninfected gastric cancer cells and tumor samples, we identified alterations in genes, gene expression, and methylation that affect different signaling networks. These might be involved in EBV-associated gastric carcinogenesis.METHODS: We performed whole-genome, transcriptome, and epigenome sequence analyses of a gastric adenocarcinoma cell line (AGS cells), before and after EBV infection. We then looked for alterations in gastric tumor samples, with (n = 34) or without (n = 100) EBV infection, collected from patients at the Prince of Wales Hospital, Chinese University of Hong Kong (from 1998 through 2004), or the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China (from 1999 through 2006).BACKGROUND & AIMS: The mechanisms by which Epstein-Barr virus (EBV) contributes to the development of gastric cancer are unclear. We investigated EBV-associated genomic and epigenomic variations in gastric cancer cells and tumors.RESULTS: Transcriptome analysis showed that infected cells expressed 9 EBV genes previously detected in EBV-associated gastric tumors and 71 EBV genes not previously reported in gastric tumors. Ten viral genes that had not been reported previously in gastric cancer but were expressed most highly in EBV-infected cells also were expressed in primary EBV-positive gastric tumors. Whole-genome sequence analysis identified 45 EBV-associated nonsynonymous mutations. These mutations, in genes such as AKT2, CCNA1, MAP3K4, and TGFBR1, were associated significantly with EBV-positive gastric tumors, compared with EBV-negative tumors. An activating mutation in AKT2 was associated with reduced survival times of patients with EBV-positive gastric cancer (P =.006); this mutation was found to dysregulate mitogen-activated protein kinase signaling. Integrated epigenome and transcriptome analyses identified 216 genes transcriptionally down-regulated by EBV-associated hypermethylation; methylation of ACSS1, FAM3B, IHH, and TRABD increased significantly in EBV-positive tumors. Overexpression of Indian hedgehog (IHH) and TraB domain containing (TRABD) increased proliferation and colony formation of gastric cancer cells, whereas knockdown of these genes reduced these activities. We found 5 signaling pathways (axon guidance, focal adhesion formation, interactions among cytokines and receptors, mitogen-activated protein kinase signaling, and actin cytoskeleton regulation) to be affected commonly by EBV-associated genomic and epigenomic alterations.

Qiaoyi Liang    Yao Xiaotian    Tang Senwei    Zhang Jingwan    Yau Tung On    Xiaoxing Li    Ceenming Tang    Wei Kang    Lung Raymond W.M.    Jingwoei Li    陈子蔚    Rui Xing    Youyong Lü    Lo Kwok Wai    Wong Nathalie    Kafai To    Yu Chang    Francis Chan    沈祖堯     Jun Yu   

Gastroenterology

2014