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1.  MicroRNA-29a promotes colorectal cancer metastasis by regulating matrix metalloproteinase 2 and E-cadherin via KLF4 
Tang, W | Zhu, Y | Gao, J | Fu, J | Liu, C | Liu, Y | Song, C | Zhu, S | Leng, Y | Wang, G | Chen, W | Du, P | Huang, S | Zhou, X | Kang, J | Cui, L
British Journal of Cancer  2013;110(2):450-458.
Background:
Growing evidence suggests that miR-29a has an important role in regulating tumourigenesis and development of various types of cancer. However, the role and the underlying mechanism of miR-29a in colorectal cancer (CRC) remain largely unknown.
Methods:
MiR-29a targeted gene was identified by the luciferase assay and western blot. MiR-29a function was analysed by invasion assays and the orthotopic transplantation mouse model. The miR-29a pathway was assayed by real-time PCR, western blot and chip analysis.
Results:
KLF4 was identified as a direct target gene of miR-29a. MiR-29a promoted CRC cell invasion, which was blocked by re-expression of KLF4. In addition, MMP2 was identified as a novel direct target of KLF4. Both miR-29a overexpression and KLF4 knockdown promoted MMP2 expression but inhibited E-cadherin expression. Furthermore, clinical data indicated that both miR-29a high expression and KLF4 mRNA low expression were associated with metastasis and poor prognosis in CRC patients, and KLF4 protein expression was inversely correlated with MMP2 but positively correlated with E-cad protein expression.
Conclusion:
Increased expression of miR-29a promoted CRC metastasis by regulating MMP2/E-cad through direct targeting KLF4, which highlights the potential of the miR-29a inhibitor as a novel agent against CRC metastasis.
doi:10.1038/bjc.2013.724
PMCID: PMC3899762  PMID: 24281002
miR-29a; colorectal cancer; metastasis; KLF4
2.  PA28gamma emerges as a novel functional target of tumour suppressor microRNA-7 in non-small-cell lung cancer 
Xiong, S | Zheng, Y | Jiang, P | Liu, R | Liu, X | Qian, J | Gu, J | Chang, L | Ge, D | Chu, Y
British Journal of Cancer  2013;110(2):353-362.
Background:
MicroRNA-7 (miR-7) has been reported to be a tumour suppressor gene. However, whether it has a role in the growth of non-small-cell lung cancer (NSCLC) and what is its target involved in the tumour growth is still under investigation.
Methods:
NSCLC tissue sample, NSCLC cell lines and tissue microarray were investigated in this study. Total RNA, miRNA and protein were used for RT-PCR and western blot analysis. Immunohistochemistry was performed in tissues microarray. Cell culture and intervention experiments were performed in vitro and in vivo. Bioinformatics prediction, western blot and luciferase assay were identified the target of miR-7.
Results:
In this study, we found that the expression of miR-7 was significantly downregulated not only in NSCLC cell lines, but also in human NSCLC tissues compared with the matched adjacent tissues. Restoration of its expression through miR-7 mimics in A549 and H1299 NSCLC cells inhibited cell proliferation, colony formation, and cell-cycle progression in vitro. More importantly, the tumorigenicity in nude mice was reduced after administration of miR-7 in vivo. In advance, through bioinformatic analysis, luciferase assay and western blot, we identified a novel target of miR-7, PA28gamma (a proteasome activator) to be enrolled in the regulation with tumour. PA28gamma mRNA and protein levels are markedly upregulated in NSCLC cell lines and tumour samples, exhibiting a strong inverse relation with that of miR-7. In addition, knockdown of PA28gamma induced similar effects as overexpression of miR-7 in NSCLC cells. Furthermore, miR-7 overexpression or silencing of PA28gamma reduced the cyclinD1 expression at mRNA and protein level in NSCLC cell lines.
Conclusion:
All these findings strongly imply that the overexpression of PA28gamma resulted from miR-7 downexpression in NSCLC has an important role in promoting cancer cell progress and consequently results in NSCLC growth. Thus, strategies targeting PA28gamma and/or miR-7 may become promising molecular therapies in NSCLC treatment.
doi:10.1038/bjc.2013.728
PMCID: PMC3899764  PMID: 24281003
NSCLC; microRNA; miR-7; PA28gamma; tumour suppressor
4.  Statin use in primary inflammatory breast cancer: a cohort study 
British Journal of Cancer  2013;109(2):318-324.
Background:
Some studies have suggested that statins, which have cholesterol-lowering and anti-inflammatory properties, may have antitumor effects. Effects of statins on inflammatory breast cancer (IBC) have never been studied.
Methods:
We reviewed 723 patients diagnosed with primary IBC in 1995–2011 and treated at The University of Texas MD Anderson Cancer Center. Statin users were defined as being on statins at the initial evaluation. Based on Ahern et al's statin classification (JNCI, 2011), clinical outcomes were compared by statin use and type (weakly lipophilic to hydrophilic (H-statin) vs lipophilic statins (L-statin)). We used the Kaplan–Meier method to estimate the median progression-free survival (PFS), overall survival (OS) and disease-specific survival (DSS), and a Cox proportional hazards regression model to test the statistical significance of potential prognostic factors.
Results:
In the multivariable Cox model, H-statins were associated with significantly improved PFS compared with no statin (hazard ratio=0.49; 95% confidence interval=0.28–0.84; P<0.01); OS and DSS P-values were 0.80 and 0.85, respectively. For L-statins vs no statin, P-values for PFS, DSS, and OS were 0.81, 0.4, and 0.74, respectively.
Conclusion:
H-statins were associated with significantly improved PFS. A prospective randomised study evaluating the survival benefits of statins in primary IBC is warranted.
doi:10.1038/bjc.2013.342
PMCID: PMC3721387  PMID: 23820253
inflammatory breast cancer; statin; hydrophilic; lipophilic; progression-free survival; overall survival
5.  A step-by-step guide to the systematic review and meta-analysis of diagnostic and prognostic test accuracy evaluations 
Liu, Z | Yao, Z | Li, C | Liu, X | Chen, H | Gao, C
British Journal of Cancer  2013;108(11):2299-2303.
In evidence-based medicine (EBM), systematic reviews and meta-analyses have been widely applied in biological and medical research. Moreover, the most popular application of meta-analyses in this field may be to examine diagnostic (sensitivity and specificity) and prognostic (hazard ratio (HR) and its variance, standard error (SE) or confidence interval (CI)) test accuracy. However, conducting such analyses requires not only a great deal of time but also an advanced professional knowledge of mathematics, statistics and computer science. Regarding the practical application of meta-analyses for diagnostic and prognostic markers, the majority of users are clinicians and biologists, most of whom are not skilled at mathematics and computer science in particular. Hence, it is necessary for these users to have a simplified version of a protocol to help them to quickly conduct meta-analyses of the accuracy of diagnostic and prognostic tests. The aim of this paper is to enable individuals who have never performed a meta-analysis to do so from scratch. The paper does not attempt to serve as a comprehensive theoretical guide but instead describes one rigorous way of conducting a meta-analysis for diagnostic and prognostic markers. Investigators who follow the outlined methods should be able to understand the basic ideas behind the steps taken, the meaning of the meta-analysis results obtained for diagnostic and prognostic markers and the scope of questions that can be answered with Systematic Reviews and Meta-Analyses (SRMA). The presented protocols have been successfully tested by clinicians without meta-analysis experience.
doi:10.1038/bjc.2013.185
PMCID: PMC3681011  PMID: 23695015
systematic review; meta-analysis; prognostic marker; diagnostic marker; sensitivity and specificity; hazard ratio
6.  Distinct association between aberrant methylation of Wnt inhibitors and genetic alterations in acute myeloid leukaemia 
British Journal of Cancer  2011;105(12):1927-1933.
Background:
Aberrant activation of Wnt signalling through hypermethylation of Wnt inhibitor genes is involved in several human malignancies, including acute myeloid leukaemia (AML). It remains unclear whether hypermethylation of Wnt inhibitors is associated with molecular gene mutations in the development of AML.
Methods:
We investigated the association of the promoter hypermethylation of six Wnt inhibitors (Wif-1, SFRP1, SFRR2, SFRP4, SFRP5, and DKK1) with gene aberrations in the leukaemogenesis of 269 AML patients.
Results:
In total, 166 patients (61.7%) had hypermethylation of at least one Wnt inhibitor. The majority (68.5%) of patients with Wnt inhibitor hypermethylation had concurrent Class II gene mutations that affect transcription factors or cofactors. There was a close association of Wif-1 hypermethylation with t(15;17) (P=0.0005) and CEBPA mutation (P<0.0001), DKK1 hypermethylation with t(8;21) (P<0.0001) and ASXL1 mutation (P=0.0078), SFRP-1 hypermethylation with t(8;21) (P<0.0001), SFRP-2 hypermethylation with AML1/RUNX1 mutation (P=0.0012), and SFRP-5 hypermethylation with MLL/PTD (P=0.0505). On the other side, hypermethylation of Wnt inhibitors was always negatively associated with NPM1 mutation and FLT3/ITD.
Conclusion:
There was distinct association between hypermethylation of individual Wnt inhibitors and specific gene aberrations, especially Class II mutations. The Wnt inhibitor hypermethylation might interact with genetic alterations in the leukaemogenesis.
doi:10.1038/bjc.2011.471
PMCID: PMC3251886  PMID: 22095226
Wnt pathway inhibitors; methylation; genetic alteration; acute myeloid leukaemia
7.  Prevalence and risk factors for esophageal squamous cell cancer and precursor lesions in Anyang, China: a population-based endoscopic survey 
He, Z | Zhao, Y | Guo, C | Liu, Y | Sun, M | Liu, F | Wang, X | Guo, F | Chen, K | Gao, L | Ning, T | Pan, Y | Li, Y | Zhang, S | Lu, C | Wang, Z | Cai, H | Ke, Y
British Journal of Cancer  2010;103(7):1085-1088.
Background:
The etiology of esophageal squamous cell cancer (ESCC) in high prevalence regions of China remains unclear.
Methods:
Endoscopic biopsies were conducted among 7381 inhabitants aged from 25 to 65 of Anyang, China.
Results:
In this study, 2.57, 0.20 and 0.16% of the participants had mild, moderate and severe squamous dysplasia, respectively; 0.19 and 0.08% showed squamous carcinoma in situ and invasive ESCC. Using deep well (depth >100 meters) as water source (odds ratio=0.72, 95% confidence interval: 0.54–0.96) was negatively associated with ESCC and its precursors, whereas tobacco and alcohol use were not significantly associated with ESCC.
Conclusions:
Water source and other factors in this region need further evaluation by longitudinal studies.
doi:10.1038/sj.bjc.6605843
PMCID: PMC2965859  PMID: 20700119
prevalence; risk factor; esophageal cancer; precursor lesion; China
8.  Common genetic variability in ESR1 and EGF in relation to endometrial cancer risk and survival 
British Journal of Cancer  2009;100(8):1358-1364.
We investigated common genetic variation in the entire ESR1 and EGF genes in relation to endometrial cancer risk, myometrial invasion and endometrial cancer survival. We genotyped a dense set of single-nucleotide polymorphisms (SNPs) in both genes and selected haplotype tagging SNPs (tagSNPs). The tagSNPs were genotyped in 713 Swedish endometrial cancer cases and 1567 population controls and the results incorporated into logistic regression and Cox proportional hazards models. We found five adjacent tagSNPs covering a region of 15 kb at the 5′ end of ESR1 that decreased the endometrial cancer risk. The ESR1 variants did not, however, seem to affect myometrial invasion or endometrial cancer survival. For the EGF gene, no association emerged between common genetic variants and endometrial cancer risk or myometrial invasion, but we found a five-tagSNP region that covered 51 kb at the 5′ end of the gene where all five tagSNPs seemed to decrease the risk of dying from endometrial cancer. One of the five tagSNPs in this region was in strong linkage disequilibrium (LD) with the untranslated A61G (rs4444903) EGF variant, earlier shown to be associated with risk for other forms of cancer.
doi:10.1038/sj.bjc.6604984
PMCID: PMC2676544  PMID: 19319135
ESR1; EGF; polymorphism; endometrial cancer; survival
9.  ERCC1 mRNA levels and survival of advanced gastric cancer patients treated with a modified FOLFOX regimen 
Wei, J | Zou, Z | Qian, X | Ding, Y | Xie, L | Sanchez, J J | Zhao, Y | Feng, J | Ling, Y | Liu, Y | Yu, L | Rosell, R | Liu, B
British Journal of Cancer  2008;98(8):1398-1402.
Molecular markers involved in DNA repair can help to predict survival in gastric cancer patients treated with 5-FU plus platinum chemotherapy. Excision repair cross-complementing 1 (ERCC1) and thymidylate synthase (TS) mRNA expression levels were assessed in advanced gastric cancer tumour samples using real-time quantitative PCR in 76 patients treated with a modified FOLFOX (biweekly oxaliplatin plus 5-FU and folinic acid) regimen. Median survival time in patients with low ERCC1 levels was significantly longer than in those with high levels (15.8 vs 6.2 months; P<0.0001). Patients with high TS levels had longer survival than those with low levels (12.2 vs 10.1 months; P=0.01). Forty-eight patients with low ERCC1 and high TS levels had a median survival of 16.1 months (P<0.0001). The hazard ratio for patients with high ERCC1 expression was 9.4 (P<0.0001). In patients with high mRNA levels of ERCC1, alternative chemotherapy regimens should be considered.
doi:10.1038/sj.bjc.6604317
PMCID: PMC2361707  PMID: 18362936
ERCC1; TS; advanced gastric cancer; FOLFOX
10.  Risk of cervical cancer is not increased in Chinese carrying homozygous arginine at codon 72 of p53 
British Journal of Cancer  1999;80(11):1828-1829.
Homozygous arginine at codon 72 (HA72) of p53 was found in 22% of normal cervices and 30.0% of cervical cancers and no significant difference was detected between normal and cervical cancer with or without HPV 16/18. There was no correlation between HA72 and risk of cervical cancer in Chinese. © 1999 Cancer Research Campaign
doi:10.1038/sj.bjc.6690606
PMCID: PMC2374271  PMID: 10468305
p53 codon 72 polymorphism; cervical cancer; Chinese
11.  A prospective randomised controlled trial of laparoscopic vs open radical cystectomy for bladder cancer: perioperative and oncologic outcomes with 5-year follow-upT Lin et al 
Lin, T | Fan, X | Zhang, C | Xu, K | Liu, H | Zhang, J | Jiang, C | Huang, H | Han, J | Yao, Y | Xie, W | Dong, W | Bi, L | Huang, J
British Journal of Cancer  2014;110(4):842-849.
Background:
Laparoscopic radical cystectomy (LRC) is increasingly being used for muscle-invasive bladder cancer. However, high levels of clinical evidence comparing laparoscopic vs open radical cystectomy (ORC) are lacking.
Methods:
A prospective randomised controlled clinical trial comparing LRC vs ORC in patients undergoing radical cystectomy for bladder cancer. Thirty-five patients were eligible for final analysis in each group.
Results:
The median follow-up was 26 months (range, 4–59 months) for laparoscopic vs 32 months (range, 6–60 months) for ORC. Significant differences were noted in operative time, estimated blood loss (EBL), blood transfusion rate, analgesic requirement, and time to resumption of oral intake. No significant differences were noted in the length of hospital stay, complication rate, lymph node yield (14.1±6.3 for LRC and 15.2±5.9 for ORC), positive surgical margin rate, postoperative pathology, or recurrence rate (7 for LRC and 8 for ORC). The 5-year recurrence-free survival with laparoscopic vs ORC was 78.5% vs 70.9%, respectively (P=0.773). The overall survival with laparoscopic vs ORC was 73.8% vs 67.4%, respectively (P=0.511).
Conclusion:
Our study demonstrated that LRC is superior to ORC in perioperative outcomes, including EBL, blood transfusion rate, and analgesic requirement. We found no major difference in oncologic outcomes. The number of patients is too small to allow for a final conclusion.
doi:10.1038/bjc.2013.777
PMCID: PMC3929868  PMID: 24407192
bladder cancer; laparoscopic radical cystectomy; open radical cystectomy; orthotopic ileal neobladder; randomised controlled study
12.  HBx mutants differentially affect the activation of hypoxia-inducible factor-1α in hepatocellular carcinoma 
British Journal of Cancer  2013;110(4):1066-1073.
Background:
Mutations in HBx gene are frequently found in HBV-associated hepatocellular carcinoma (HCC). Activation of hypoxia-inducible factor-1α (HIF-1α) contributes to HCC development and progression. Wild-type HBx has been demonstrated to activate HIF-1α, but the effect of HBx mutations on HIF-1α has not been elucidated.
Methods:
HBx mutations were identified by gene sequencing in 101 HCC tissues. Representative HBx mutants were cloned and transfected into HCC cells. Expression and activation of HIF-1α were analysed by western blot and luciferase assays, respectively. The relationship between HBx mutants and HIF-1α expression in HCC tissues was also evaluated.
Results:
The dual mutations K130M/V131I enhanced the functionality of HBx as they upregulated the expression and transcriptional activity of HIF-1α. The C-terminal truncations and deletion mutations, however, weakened the ability of HBx to upregulate HIF-1α. Meanwhile, the C-terminus was further found to be essential for the stability and transactivation of HBx. In the HCC tissues, there was a positive association between the HBx mutants and HIF-1α expression.
Conclusion:
Different mutations of HBx exert differentiated effects on the functionality of HIF-1α, however, the overall activity of HBx mutants appears to increase the expression and transcriptional activity of HIF-1α.
doi:10.1038/bjc.2013.787
PMCID: PMC3929872  PMID: 24346287
HBx; HIF-1α; mutation; hepatocellular carcinoma
13.  Prognostic model for survival of local recurrent nasopharyngeal carcinoma with intensity-modulated radiotherapy 
British Journal of Cancer  2013;110(2):297-303.
Background:
Intensity-modulated radiotherapy (IMRT) is the main salvage treatment for advanced locally recurrent nasopharyngeal carcinoma (NPC); however, survival outcomes vary. We aimed to construct a prognostic-score model to identify patients who could benefit from salvage IMRT.
Methods:
This retrospective study involved 251 patients with locally recurrent NPC. The following parameters were analysed following IMRT: patient performance status, age, gender, late complications, T-stage of recurrence, synchronous nodal recurrence, primary gross tumour volume (GTV-nx), disease-free interval, re-irradiation dose and chemotherapy. The model was based on the hazard ratio coefficients of six significantly negative prognostic factors for survival.
Results:
Significantly negative prognostic factors included Karnofsky Performance Status ⩽70, age >50 years, late complications, recurrent T3–4 stage, synchronous nodal recurrence and GTV-nx >30 cm3. Three subgroups were defined according to model scores: low risk (0–4), intermediate risk (5–8) and high risk (9–15). The 5-year overall survival rates were 64.3%, 32.2% and 7.7%, respectively. The main cause of death was radiation-induced complications.
Conclusion:
The prognostic-score model demonstrated that re-irradiation with IMRT is suitable for low-risk and intermediate-risk patients but may be unsuitable for high-risk patients. Further research into the protection of critical adjacent organs to reduce late complications in these patients is warranted.
doi:10.1038/bjc.2013.715
PMCID: PMC3899759  PMID: 24335924
nasopharyngeal carcinoma; local recurrence; prognostic-score model; intensity-modulated radiotherapy (IMRT); late complications
14.  Predictive value of miR-9 as a potential biomarker for nasopharyngeal carcinoma metastasis 
Lu, J | Xu, X | Liu, X | Peng, Y | Zhang, B | Wang, L | Luo, H | Peng, X | Li, G | Tian, W | He, M | Li, X
British Journal of Cancer  2013;110(2):392-398.
Background:
Nasopharyngeal carcinoma (NPC) has a distinctive geographic distribution and is characterised by its strong tendency of metastasis. We aimed to examine the microRNA (miRNA) expression profiles in plasma samples of NPC patients to explore their clinical significance in disease development and progression.
Methods:
This study was divided into four steps: (1) confirmation of differentially expressed miRNAs using microarray analysis and quantitative PCR validation; (2) comparison of plasma miR-9 levels during NPC progression; (3) evaluation of the predictive performance of plasma miR-9 as a biomarker for NPC metastasis; and (4) comparison of plasma miR-9 levels between pre- and post-treatment samples.
Results:
Plasma microarray profiling identified 33 differentially expressed miRNAs between NPC patients and healthy volunteers. The significantly declined level of miR-9 in NPC patients was confirmed through two-stage validation. The low level of plasma miR-9 was significantly correlated with worse lymphatic invasion and advanced TNM stage. The plasma miR-9 could distinguish locoregional from metastatic NPC cases with a high sensitivity and specificity. Furthermore, the plasma miR-9 level was significantly elevated in post-treatment plasma compared with those pre-treatment samples.
Conclusion:
Our study reports that plasma miR-9 may serve as a useful biomarker to predict NPC metastasis and to monitor tumour dynamics.
doi:10.1038/bjc.2013.751
PMCID: PMC3899774  PMID: 24327016
nasopharyngeal carcinoma; miR-9; plasma; metastasis
15.  Comparison of TNM staging systems for nasopharyngeal carcinoma, and proposal of a new staging system 
British Journal of Cancer  2013;109(12):2987-2997.
Background:
There are few systematic evaluations regarding the sixth and seventh editions of the UICC/AJCC TNM Staging System (TNM6th, TNM7th) and Chinese 2008 Staging System (TNMc2008) for nasopharyngeal carcinoma (NPC).
Methods:
We classified 2333 patients into intensity-modulated radiotherapy (IMRT) cohort (n=941) and conventional radiotherapy (CRT) cohort (n=1392). Tumour staging defined by TNM6th, TNM7th and TNMc2008 was compared based on Akaike information criterion (AIC) and Harrell's concordance index (c-index).
Results:
For T-classification, TNM6th (AIC=2585.367; c-index=0.6390385) had superior prognostic value to TNM7th (AIC=2593.242; c-index=0.6226889) and TNMc2008 (AIC=2593.998; c-index=0.6237146) in the IMRT cohort, whereas TNMc2008 was superior (AIC=5999.054; c-index=0.623547) in the CRT cohort. For N-classification, TNMc2008 had the highest prognostic value in both cohorts (AIC=2577.726, c-index=0.6297874; AIC=5956.339, c-index=0.6533576). Similar results were obtained when patients were stratified by chemotherapy types, age and gender. Using staging models in the IMRT cohort, we failed to identify better stage migrations than TNM6th T-classification and TNMc2008 N-classification. We therefore proposed to combine these categories; resultantly, stage groups of the proposed staging system showed superior prognostic value over TNM6th, TNM7th and TNMc2008.
Conclusion:
TNM6th T-classification and TNMc2008 N-classification have superior prognostic value in the IMRT era. By combining them with slight modifications, TNM criteria can be unified and its prognostic value be improved.
doi:10.1038/bjc.2013.659
PMCID: PMC3859943  PMID: 24149175
comparison; evaluation; magnetic resonance imaging; nasopharyngeal carcinoma; staging system
16.  The impact of body mass index on complication and survival in resected oesophageal cancer: a clinical-based cohort and meta-analysis 
British Journal of Cancer  2013;109(11):2894-2903.
Background:
Body mass index (BMI) has been associated with the risk of oesophageal cancer. But the influence of BMI on postoperative complication and prognosis has always been controversial.
Methods:
In total, 2031 consecutive patients who underwent oesophagectomy between 1998 and 2008 were classified according to Asian-specific BMI (kg m−2) cutoff values. The impact of BMI on overall survival (OS) was estimated using the Kaplan–Meier method and Cox proportional hazard models. We performed a meta-analysis to examine the association of BMI with OS and postoperative complication.
Results:
Patients with higher BMI had more postoperative complication (P=0.002), such as anastomotic leakage (P=0.016) and cardiovascular diseases (P<0.001), but less incidence of chylous leakage (P=0.010). Logistic regression analysis showed that BMI (P=0.005) was a confounding factor associated with postoperative complication. Multivariate analysis showed that overweight and obese patients had a more favourable survival than normal weight patients (HR (hazard ratio) = 0.80, 95% CI (confidence interval): 0.70–0.92, P=0.001). Subgroup analysis showed that the association with higher BMI and increased OS was observed in patients with oesophageal squamous cell carcinoma (ESCC) (P<0.001), oesophageal adenocarcinoma (EA) (P=0.034), never-smoking (P=0.035), ever-smoking (P=0.035), never alcohol consumption (P=0.005), weight loss (P=0.003) and advanced pathological stage (P<0.001). The meta-analysis further corroborated that higher BMI was associated with increased complication of anastomotic leakage (RR (risk ratio)=1.04, 95% CI: 1.02–1.06, P=0.001), wound infection (RR=1.03, 95% CI: 1.00–1.05, P=0.031) and cardiovascular diseases (RR=1.02, 95% CI: 1.00–1.05, P=0.039), but decreased incidence of chylous leakage (RR=0.98, 95% CI: 0.96–0.99, P<0.001). In addition, high BMI could significantly improved OS (HR=0.78, 95% CI: 0.71–0.85, P<0.001).
Conclusion:
Preoperative BMI was an independent prognostic factor for survival, and strongly associated with postoperative complications in oesophageal cancer.
doi:10.1038/bjc.2013.666
PMCID: PMC3844915  PMID: 24201750
body mass index; oesophageal cancer; meta-analysis; postoperative complication; survival
17.  Comparisons of vaginal and abdominal radical trachelectomy for early-stage cervical cancer: preliminary results of a multi-center research in China 
British Journal of Cancer  2013;109(11):2778-2782.
Background:
There are limited data comparing the prognosis and fertility outcomes of the patients with early cervical cancer treated by trans-vaginal radical trachelectomy (VRT) or abdominal radical trachelectomy (ART).The objective of this study was to compare the surgical and pathologic characteristics, the prognosis and fertility outcomes of the patients treated by VRT or ART.
Methods:
Matched-case study based on a prospectively maintained database of patients underwent radical trachelectomy in 10 centres of China was designed to compare the prognosis and fertility outcomes of the patients treated by VRT or ART.
Results:
Totally 150 cases, 77 in the VRT and 73 in the ART group, were included. VRT and ART provide similar surgical and pathological outcomes except larger specimens obtained by ART. In the ART group, no patient developed recurrent diseases, but, in the VRT group, 7 (9.8%) patients developed recurrent diseases and 2 (1.6%) patients died of the tumours (P=0.035). The rate of pregnancy in the VRT group was significantly higher than those of ART (39.5% vs 8.8% P=0.003). The patients with tumour size >2 cm showed significant higher recurrent rate (11.6% vs 2.4%, P<0.05) and lower pregnant rate (12.5% vs 32.1%, P=0.094) compared with the patients with tumour size <2 cm.
Conclusion:
Patients treated by ART obtained better oncology results, but their fertility outcomes were unfavourable compared with VRT. Tumour size <2 cm should be emphasised as an indication for radical trachelectomy for improving the outcome of fertility and prognosis.
doi:10.1038/bjc.2013.656
PMCID: PMC3844910  PMID: 24169350
radical trachelectomy; cervical cancer; fertility; prognosis
18.  MiR-125b acts as an oncogene in glioblastoma cells and inhibits cell apoptosis through p53 and p38MAPK-independent pathways 
Wu, N | Lin, X | Zhao, X | Zheng, L | Xiao, L | Liu, J | Ge, L | Cao, S
British Journal of Cancer  2013;109(11):2853-2863.
Background:
We have recently identified miR-125b upregulation in glioblastoma (GMB). The aim of this study is to determine the correlation between miR-125b expression and malignant grades of glioma and the genes targeted by miR-125b.
Methods:
Real-time PCR was employed to measure the expression level of miR-125b. Cell viability was evaluated by cell growth and colony formation in soft-agar assays. Cell apoptosis was determined by Hoechst 33342 staining and AnnexinV-FITC assay. The Luciferase assay was used to confirm the actual binding sites of p38MAPK mRNA. Western blot was used to detect the gene expression level.
Results:
The expression level of miR-125b is positively correlated with the malignant grade of glioma. Ectopic expression of miR-125b promotes the proliferation of GMB cells. Knockdown of endogenous miR-125b inhibits cell proliferation and promotes cell apoptosis. Further studies reveal that p53 is regulated by miR-125b. However, downregulation of the endogenous miR-125b also results in p53-independent apoptotic pathway leading to apoptosis in p53 mutated U251 cells and p53 knockdown U87 cells. Moreover, p38MAPK is also regulated by miR-125b and downregulation of miR-125b activates the p38MAPK-induced mitochondria apoptotic pathway.
Conclusion:
High-level expression of miR-125b is associated with poor outcomes of GMB. MiR-125b may have an oncogenic role in GMB cells by promoting cell proliferation and inhibiting apoptosis.
doi:10.1038/bjc.2013.672
PMCID: PMC3844918  PMID: 24169356
microRNA; miR-125b; glioblastoma; cell apoptosis; p53; p38MAPK
19.  Prognostic value of ABO blood group in southern Chinese patients with established nasopharyngeal carcinoma 
British Journal of Cancer  2013;109(9):2462-2466.
Background:
ABO blood group is associated with aetiology of nasopharyngeal carcinoma (NPC); however, the effect of it on survival of patients diagnosed with NPC has not been explored.
Methods:
We retrospectively analysed two cohorts of southern Chinese patients with WHO histological type III: intensity-modulated radiotherapy (IMRT) cohort, 924 patients; and conventional radiotherapy (CRT) cohort, 1193 patients. Associations of ABO blood group with survival were estimated using Cox regression.
Results:
In IMRT cohort, we observed significant associations of blood type A with overall survival (OS) and distant metastasis-free survival (DMFS), compared with type O, after adjusting for prognostic factors. Compared with non-A blood types (B, AB, and O), type A patients had significantly lower OS and DMFS (adjusted hazard ratio (HR)=1.49, 95% CI 1.03–2.17, P=0.036; HR=1.68, 95% CI 1.13–2.51, P=0.011, respectively); similar results were obtained in CRT cohort. Subgroup analyses of the entire population showed that lower OS conferred by blood type A was not significantly modified by age, smoking status, drinking status, immunoglobulin A against Epstein–Barr virus viral capsid antigen (VCA-IgA) titre, or chemotherapy; however, lower OS was not observed in female patients or patients with early clinical stage disease.
Conclusion:
ABO blood group is associated with survival in NPC; patients with blood type A had significantly lower OS and DMFS than patients with non-A blood types.
doi:10.1038/bjc.2013.559
PMCID: PMC3817319  PMID: 24022193
ABO blood group; nasopharyngeal carcinoma; prognosis; survival
20.  CXCR3/CCR5 pathways in metastatic melanoma patients treated with adoptive therapy and interleukin-2 
British Journal of Cancer  2013;109(9):2412-2423.
Background:
Adoptive therapy with tumour-infiltrating lymphocytes (TILs) induces durable complete responses (CR) in ∼20% of patients with metastatic melanoma. The recruitment of T cells through CXCR3/CCR5 chemokine ligands is critical for immune-mediated rejection. We postulated that polymorphisms and/or expression of CXCR3/CCR5 in TILs and the expression of their ligands in tumour influence the migration of TILs to tumours and tumour regression.
Methods:
Tumour-infiltrating lymphocytes from 142 metastatic melanoma patients enrolled in adoptive therapy trials were genotyped for CXCR3 rs2280964 and CCR5-Δ32 deletion, which encodes a protein not expressed on the cell surface. Expression of CXCR3/CCR5 in TILs and CXCR3/CCR5 and ligand genes in 113 available parental tumours was also assessed. Tumour-infiltrating lymphocyte data were validated by flow cytometry (N=50).
Results:
The full gene expression/polymorphism model, which includes CXCR3 and CCR5 expression data, CCR5-Δ32 polymorphism data and their interaction, was significantly associated with both CR and overall response (OR; P=0.0009, and P=0.007, respectively). More in detail, the predicted underexpression of both CXCR3 and CCR5 according to gene expression and polymorphism data (protein prediction model, PPM) was associated with response to therapy (odds ratio=6.16 and 2.32, for CR and OR, respectively). Flow cytometric analysis confirmed the PPM. Coordinate upregulation of CXCL9, CXCL10, CXCL11, and CCL5 in pretreatment tumour biopsies was associated with OR.
Conclusion:
Coordinate overexpression of CXCL9, CXCL10, CXCL11, and CCL5 in pretreatment tumours was associated with responsiveness to treatment. Conversely, CCR5-Δ32 polymorphism and CXCR3/CCR5 underexpression influence downregulation of the corresponding receptors in TILs and were associated with likelihood and degree of response.
doi:10.1038/bjc.2013.557
PMCID: PMC3817317  PMID: 24129241
immunotherapy; interlukin-2; chemokines; melanoma; tumour microenvironment
21.  Predicting response and survival in chemotherapy-treated triple-negative breast cancer 
British Journal of Cancer  2014;111(8):1532-1541.
Background:
In this study, we evaluated the ability of gene expression profiles to predict chemotherapy response and survival in triple-negative breast cancer (TNBC).
Methods:
Gene expression and clinical–pathological data were evaluated in five independent cohorts, including three randomised clinical trials for a total of 1055 patients with TNBC, basal-like disease (BLBC) or both. Previously defined intrinsic molecular subtype and a proliferation signature were determined and tested. Each signature was tested using multivariable logistic regression models (for pCR (pathological complete response)) and Cox models (for survival). Within TNBC, interactions between each signature and the basal-like subtype (vs other subtypes) for predicting either pCR or survival were investigated.
Results:
Within TNBC, all intrinsic subtypes were identified but BLBC predominated (55–81%). Significant associations between genomic signatures and response and survival after chemotherapy were only identified within BLBC and not within TNBC as a whole. In particular, high expression of a previously identified proliferation signature, or low expression of the luminal A signature, was found independently associated with pCR and improved survival following chemotherapy across different cohorts. Significant interaction tests were only obtained between each signature and the BLBC subtype for prediction of chemotherapy response or survival.
Conclusions:
The proliferation signature predicts response and improved survival after chemotherapy, but only within BLBC. This highlights the clinical implications of TNBC heterogeneity, and suggests that future clinical trials focused on this phenotypic subtype should consider stratifying patients as having BLBC or not.
doi:10.1038/bjc.2014.444
PMCID: PMC4200088  PMID: 25101563
breast cancer; genomics; subtypes; intrinsic; basal like; chemotherapy; neoadjuvant
22.  Disulfiram targets cancer stem-like cells and reverses resistance and cross-resistance in acquired paclitaxel-resistant triple-negative breast cancer cells 
British Journal of Cancer  2013;109(7):1876-1885.
Background:
Triple-negative breast cancer (TNBC) has significantly worse prognosis. Acquired chemoresistance remains the major cause of therapeutic failure of TNBC. In clinic, the relapsed TNBC is commonly pan-resistant to various drugs with completely different resistant mechanisms. Investigation of the mechanisms and development of new drugs to target pan-chemoresistance will potentially improve the therapeutic outcomes of TNBC patients.
Methods:
In this study, 1-(4,5-Dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT), combination index (CI)–isobologram, western blot, ALDEFLUOR analysis, clonogenic assay and immunocytochemistry were used.
Results:
The chemoresistant MDA-MB-231PAC10 cells are highly cross-resistant to paclitaxel (PAC), cisplatin (CDDP), docetaxel and doxorubicin. The MDA-MB-231PAC10 cells are quiescent with significantly longer doubling time (64.9 vs 31.7 h). This may be caused by high expression of p21Waf1. The MDA-MB-231PAC10 cells express high aldehyde dehydrogenase (ALDH) activity and a panel of embryonic stem cell-related proteins, for example, Oct4, Sox2, Nanog and nuclealisation of HIF2α and NF-κBp65. We have previously reported that disulfiram (DS), an antialcoholism drug, targets cancer stem cells (CSCs) and enhances cytotoxicity of anticancer drugs. Disulfiram abolished CSC characters and completely reversed PAC and CDDP resistance in MDA-MB-231PAC10 cells.
Conclusion:
Cancer stem cells may be responsible for acquired pan-chemoresistance. As a drug used in clinic, DS may be repurposed as a CSC inhibitor to reverse the acquired pan-chemoresistance.
doi:10.1038/bjc.2013.534
PMCID: PMC3790184  PMID: 24008666
disulfiram; CSCs; paclitaxel; acquired resistance; breast cancer
23.  Prognostic value of peritumoral heat-shock factor-1 in patients receiving resection of hepatocellular carcinoma 
British Journal of Cancer  2013;109(6):1648-1656.
Background:
The cross-talk of hepatocellular carcinoma (HCC) cells and abnormal metabolic signals in peritumoral microenvironment modifies our knowledge of hepatocarcinogenesis. As an indispensable modulator of various stresses, the clinical significance of heat-shock transcription factor-1 (HSF1) in HCC microenvironment has never been defined.
Methods:
Hepatocellular carcinoma and matched peritumoral liver tissues (n=332) were semiquantitatively analysed for HSF1 expression, followed by correlation with clinicopathological parameters (patient outcomes). Moreover, the effects of HSF1 deficiency in L02 on monocarboxylate transporter-4 (MCT4) and HCC cells' colonisation and proliferation were investigated.
Results:
High expression of HSF1 in peritumoral tissue but not in HCC tissue was associated with poorer overall survival (OS) and time to recurrence (TTR), especially early recurrence (ER), which was further reconfirmed in validation cohort. Multivariate analysis showed that prognostic performance of peritumoral HSF1 was independent of other clinicopathological factors (hazard ratio for OS=2.60, P=0.002, for TTR=2.52, P<0.001). Notably, downregulation of HSF1 in L02 decreased MCT4 expression significantly. The supernatant from L02-shRNA-HSF1 in hypoxia, NOT normoxia condition, inhibited HCC cell colonisation and proliferation. Moreover, the combination of peritumoral HSF1 and MCT4 was the best predictor for ER and OS.
Conclusion:
High peritumoral HSF1 expression can serve as a sensitive ‘readout' for high-risk HCC ER, and could be a potential metabolic intervention target following curative resection.
doi:10.1038/bjc.2013.488
PMCID: PMC3776997  PMID: 24002609
hepatocellular carcinoma; microenvironment; heat-shock transcription factor-1; monocarboxylate transporter-4; early recurrence
24.  TNFAIP8 as a predictor of metastasis and a novel prognostic biomarker in patients with epithelial ovarian cancer 
Liu, T | Gao, H | Chen, X | Lou, G | Gu, L | Yang, M | Xia, B | Yin, H
British Journal of Cancer  2013;109(6):1685-1692.
Background:
Tumour necrosis factor-α-induced protein 8 (TNFAIP8) has been recently documented in various malignancies, but its role in epithelial ovarian cancer (EOC) remains unknown.
Methods:
Tumour necrosis factor-α-induced protein 8 expression was determined by real-time reverse transcription PCR and western blot analysis. Tumour tissues, consisting of serous, mucinous, endometrioid and clear cell histotypes, from 202 EOC patients (International Federation of Gynecologists and Obstetricians I–IV) who underwent primary cytoreduction were collected. Then, we examined the immunohistochemical expression of TNFAIP8 and evaluated its clinical significances.
Results:
Tumour necrosis factor-α-induced protein 8 overexpression was significantly associated with high histologic grade (P=0.005), large residual tumour size (P=0.014), recurrence (P=0.024) and response to chemotherapy (P<0.001). Multivariate analysis showed that TNFAIP8 overexpression was independently correlated with the presence of lymph node (odds ratio (OR): 4.129; 95% confidence interval (CI): 1.491–11.435; P=0.006) and intraperitoneal metastasis (OR: 2.209; 95% CI: 1.174–4.156; P=0.014). Moreover, results revealed that the status of TNFAIP8 expression was an independently prognostic factor for both cancer-specific survival (hazard ratio (HR): 1.852; 95% CI: 1.322–2.594; P<0.001) and disease-free survival (HR: 1.724; 95% CI: 1.235–2.407; P=0.001) in patients with EOC.
Conclusion:
The present data provide evidence that TNFAIP8 predicts EOC metastasis and poor survival, highlighting its potential function as a therapeutic target for EOCs.
doi:10.1038/bjc.2013.501
PMCID: PMC3777007  PMID: 23982604
TNFAIP8; epithelial ovarian cancer; prognosis; metastasis; peritoneum; lymph node
25.  Gene-expression data integration to squamous cell lung cancer subtypes reveals drug sensitivity 
British Journal of Cancer  2013;109(6):1599-1608.
Background:
Squamous cell lung cancer (SqCC) is the second most common type of lung cancer in the United States. Previous studies have used gene-expression data to classify SqCC samples into four subtypes, including the primitive, classical, secretory and basal subtypes. These subtypes have different survival outcomes, although it is unknown whether these molecular subtypes predict response to therapy.
Methods:
Here, we analysed RNAseq data of 178 SqCC tumour samples and characterised the features of the different SqCC subtypes to define signature genes and pathway alterations specific to each subtype. Further, we compared the gene-expression features of each molecular subtype to specific time points in models of airway development. We also classified SqCC-derived cell lines and their reported therapeutic vulnerabilities.
Results:
We found that the primitive subtype may come from a later stage of differentiation, whereas the basal subtype may be from an early time. Most SqCC cell lines responded to one of five anticancer drugs (Panobinostat, 17-AAG, Irinotecan, Topotecan and Paclitaxel), whereas the basal-type cell line EBC-1 was sensitive to three other drugs (PF2341066, AZD6244 and PD-0325901).
Conclusion:
Compared with the other three subtypes of cell lines, the secretory-type cell lines were significantly less sensitive to the five most effective drugs, possibly because of their low proliferation activity. We provide a bioinformatics framework to explore drug repurposing for cancer subtypes based on the available genomic profiles of tumour samples, normal cell types, cancer cell lines and data of drug sensitivity in cell lines.
doi:10.1038/bjc.2013.452
PMCID: PMC3776976  PMID: 24002593
squamous cell lung cancer subtypes; gene expression; RNAseq; microarray; signature genes; cells of origin; representative cell line; drug sensitivity; classification

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