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1.  DJ-1 upregulates breast cancer cell invasion by repressing KLF17 expression 
British Journal of Cancer  2014;110(5):1298-1306.
DJ-1 (PARK7) was reported as an oncogene in a Ras-dependent manner. Recent studies have shown that DJ-1 stimulates cell proliferation, cell invasion, and cancer metastasis. However, the molecular mehchanism by which DJ-1 induces cancer cell invasion and metastasis remains unclear.
Breast cancer cells were transfected with DJ-1 siRNA or DJ-1 overexpression to investigate the effect of DJ-1 on KLF17 expression. ID-1 luciferase promoter assay was performed to evaluate DJ-1-dependent KLF17 expression changes. In addition, Epistasis analysis of DJ-1 and KLF17 was performed to evaluate their regulatory interactions. Ras inhibitors were pretreated to determine whether DJ-1 regulates cell invasion in a Ras-dependent manner.
In the present study, we found increased DJ-1 expression in highly invasive breast cancer cells as compared with non-metastatic cells. Furthermore, DJ-1 promoted breast cancer cell invasion by downregulating E-cadherin and increasing Snail expression. Interestingly, exogenous DJ-1 overexpression markedly decreased mRNA and protein expression of KLF17, the EMT negative regulator. These data were confirmed by ID-1 promoter activity, which is directly regulated by DJ-1-dependent KLF17 transcription factor. Epistasis analysis showed that KLF17 overexpression overcomes increased cell invasion by DJ-1, suggesting that KLF17 might be one of the downstream signalling molecules of DJ-1. Acceleration of cell invasion by DJ-1 was alleviated by Ras inhibitors, suggesting that DJ-1 cooperates with Ras to increase cell invasion.
Altogether, these data suggest for the first time that DJ-1 acts as an EMT-positive regulator in breast cancer cells via regulation of the KLF17/ID-1 pathway.
PMCID: PMC3950878  PMID: 24504364
DJ-1 (PARK7); breast cancer cells; invasion; epithelial–mesenchymal transition (EMT); KLF17; ID-1; Ras
2.  Assessing the value of matrix metalloproteinase 9 (MMP9) in improving the appropriateness of referrals for colorectal cancer 
British Journal of Cancer  2013;108(5):1149-1156.
A blood test may be an effective means of improving the appropriateness of referrals for symptomatic patients referred to specialist colorectal clinics. We evaluated the accuracy of a serum matrix metalloproteinase (MMP9) test in indicating colorectal cancer or its precursor conditions in a symptomatic population.
Patients aged over 18, referred urgently or routinely to secondary care following primary care presentation with colorectal symptoms completed a questionnaire and provided a blood sample for serum MMP9 estimation. Univariate analysis and logistic regression modelling investigated the association between presenting symptoms, MMP9 measurements and the diagnostic outcome of patient investigations, in order to derive the combination of factors which best predicted a high risk of malignancy.
Data were analysed for 1002 patients. Forty-seven cases of neoplasia were identified. Age, male gender, absence of anal pain, diabetes, blood in stools, urgent referral, previous bowel polyps and previous bowel cancer were significantly associated with neoplasia. Matrix metalloproteinase 9 measurements were not found to be associated with significant colorectal pathology.
This study, despite robust sampling protocols, showed no clear association between MMP9 and colorectal neoplasia. Matrix metalloproteinase 9 therefore appears to have little value as a tool to aid referral decisions in the symptomatic population.
PMCID: PMC3619067  PMID: 23392084
colorectal cancer; matrix metalloproteinase; diagnosis; referral; serum; risk
3.  Serum matrix metalloproteinase 9 and colorectal neoplasia: a community-based evaluation of a potential diagnostic test 
British Journal of Cancer  2012;106(8):1431-1438.
A blood test may be a more acceptable routine colorectal cancer (CRC) screening test than faecal occult blood test, flexible sigmoidoscopy or colonoscopy, and could be safer and cheaper. We evaluated the accuracy of a serum matrix metalloproteinase (MMP9) test for CRC in a non-presenting symptomatic population.
A cohort, aged 50–69 with lower gastrointestinal symptoms, was identified by community-based survey. Accuracy of serum MMP9 was assessed by comparison with colonoscopy. Logistic regression identified predictors of neoplasia and receiver operating characteristic curve analyses determined the cutoff to maximise the sensitivity.
Data were available for 748 patients. Overall, 46 cases of neoplasia were identified. Univariate analysis demonstrated that demographic characteristics, behavioural factors, clinical symptoms and raised serum MMP9 concentration were all significantly associated with the presence of neoplasia. Our final logistic regression model had a sensitivity of 79% and specificity of 70%.
We demonstrated a significant association between serum MMP9 concentration and the presence of neoplasia. Serum MMP9 levels are raised in those with cancer and high-risk adenomas, although MMP9 estimation is likely to have the greatest predictive utility when used as part of a panel of biomarkers. Further work is required to identify biomarkers that are sufficiently accurate for implementing into routine practice.
PMCID: PMC3326675  PMID: 22433968
colorectal cancer; matrix metalloproteinase; diagnosis; serum; screening; risk
4.  A phase II study of the histone deacetylase inhibitor vorinostat combined with tamoxifen for the treatment of patients with hormone therapy-resistant breast cancer 
British Journal of Cancer  2011;104(12):1828-1835.
Histone deacetylases (HDACs) are crucial components of the oestrogen receptor (ER) transcriptional complex. Preclinically, HDAC inhibitors can reverse tamoxifen/aromatase inhibitor resistance in hormone receptor-positive breast cancer. This concept was examined in a phase II combination trial with correlative end points.
Patients with ER-positive metastatic breast cancer progressing on endocrine therapy were treated with 400 mg of vorinostat daily for 3 of 4 weeks and 20 mg tamoxifen daily, continuously. Histone acetylation and HDAC2 expression in peripheral blood mononuclear cells were also evaluated.
In all, 43 patients (median age 56 years (31–71)) were treated, 25 (58%) received prior adjuvant tamoxifen, 29 (67%) failed one prior chemotherapy regimen, 42 (98%) progressed after one, and 23 (54%) after two aromatase inhibitors. The objective response rate by Response Evaluation Criteria in Solid Tumours criteria was 19% and the clinical benefit rate (response or stable disease >24 weeks) was 40%. The median response duration was 10.3 months (confidence interval: 8.1–12.4). Histone hyperacetylation and higher baseline HDAC2 levels correlated with response.
The combination of vorinostat and tamoxifen is well tolerated and exhibits encouraging activity in reversing hormone resistance. Correlative studies suggest that HDAC2 expression is a predictive marker and histone hyperacetylation is a useful pharmacodynamic marker for the efficacy of this combination.
PMCID: PMC3111195  PMID: 21559012
histone deacetylase; HDAC; HDAC inhibitors; breast cancer; oestrogen receptor; anti-oestrogen therapy
6.  Factors affecting attitudes toward colorectal cancer screening in the primary care population 
British Journal of Cancer  2009;101(2):250-255.
Colorectal cancer (CRC) is a major cause of death in the United Kingdom. Regular screening could significantly reduce CRC-related morbidity and mortality. However, screening programmes in the United Kingdom have to date seen uptake rates of less than 60%. Attitudes towards screening are the primary factors determining patient uptake.
A questionnaire was sent to people aged 50–69 years who were registered with general practices in the West Midlands. A total of 11 355 people (53%) completed the questionnaire. Multivariable logistic regression analyses were performed to identify those factors (gender, age, ethnicity, deprivation, number of symptoms, and their duration) that most strongly contributed to negative/positive attitudes in the primary care population.
Fourteen percent of respondents had a negative attitude towards screening. Men, older people, and those with Indian ethnic backgrounds were more likely to have negative attitudes toward screening, whereas people with Black-Caribbean ethnic background, people with multiple symptoms and those reporting abdominal pain, bleeding, and tiredness were more likely to have a positive attitude.
Culturally relevant screening strategies should aim to increase knowledge of the symptoms and signs related to bowel cancer among South Asian ethnic groups in the United Kingdom. It is also important to find ways to increase the acceptability of screening among asymptomatic patients.
PMCID: PMC2720207  PMID: 19550423
colorectal cancer; screening; attitude; ethnic minority; symptom
7.  Inhibition of the aquaporin 3 water channel increases the sensitivity of prostate cancer cells to cryotherapy 
British Journal of Cancer  2009;100(12):1889-1895.
Aquaporins (AQPs) are intrinsic membrane proteins that facilitate selective water and small solute movement across the plasma membrane. In this study, we investigate the role of inhibiting AQPs in sensitising prostate cancer cells to cryotherapy. PC-3 and DU145 prostate cancer cells were cooled to 0, −5 and −10°C. The expression of AQP3 in response to freezing was determined using real-time quantitative polymerase chain reaction (RT–qPCR) and western blot analysis. Aquaporins were inhibited using mercuric chloride (HgCl2) and small interfering RNA (siRNA) duplex, and cell survival was assessed using a colorimetric assay. There was a significant increase in AQP3 expression in response to freezing. Cells treated with AQP3 siRNA were more sensitive to cryoinjury compared with control cells (P<0.001). Inhibition of the AQPs by HgCl2 also increased the sensitivity of both cell lines to cryoinjury and there was a complete loss of cell viability at −10°C (P<0.01). In conclusion, we have shown that AQP3 is involved directly in cryoinjury. Inhibition of AQP3 increases the sensitivity of prostate cancer cells to freezing. This strategy may be exploited in the clinic to improve the efficacy of prostate cryotherapy.
PMCID: PMC2714232  PMID: 19513079
AQP3; cryotherapy; prostate cancer
8.  The transforming mutation E17K/AKT1 is not a major event in B-cell-derived lymphoid leukaemias 
British Journal of Cancer  2008;99(3):488-490.
Despite the major role of the AKT/PKB family of proteins in the regulation of many growth and survival mechanisms in the cell, and the increasing evidence suggesting that AKT disruption could play a key role in many human malignancies, no major mutations of AKT genes had been reported, until very recently when Carpten et al reported a novel transforming mutation (E17K) in the pleckstrin homology domain of the AKT1 gene in solid tumours. Several laboratories are now screening for this mutation in different malignancies, and, recently, the mutation was described by Malanga et al in 1.9% of lung cancer patients. Considering the importance of the PI3K/AKT pathway in mediating survival and antiapoptotic signals in the B-cell types of chronic lymphocytic leukaemia (CLL) and acute lymphoblastic leukaemia (ALL), we sequenced the AKT1 exon 3 for the above mentioned mutation in 87 specimens, representing 45 CLLs, 38 ALLs and 4 prolymphocytic leukaemia (PLL) cases, which are all of B-cell origin. Our results show that the mutation E17K/AKT1 was not detected in the pleckstrin homology domain of AKT1 of the investigated cases. We conclude that this mutation is not a major event in B-cell-derived lymphoid leukaemias.
PMCID: PMC2527790  PMID: 18665177
AKT1; lymphoid leukaemia; mutation
10.  Elevated serum matrix metalloproteinase 9 (MMP-9) concentration predicts the presence of colorectal neoplasia in symptomatic patients 
British Journal of Cancer  2007;97(7):971-977.
Early detection of polyps or colorectal carcinoma can reduce colorectal carcinoma-associated deaths. Previous studies have demonstrated raised serum levels of matrix metalloproteinase 9 (sMMP-9) in a range of cancers. The aim of this study was to investigate the role of sMMP-9 levels in identifying colorectal neoplasia. Consenting patients donated a blood sample and were assessed by proforma-led history and physical examination. Samples were analysed for sMMP-9 concentration (enzyme-linked immuno-sorbant assay) and compared to final diagnoses. Logistic regression modelling determined independent factors associated with neoplasia. A total of 365 patients were recruited of whom 300 were analysed, including 46 normal controls. A total of 27 significant adenomas and 63 malignancies were identified. The median sMMP-9 concentration was 443ng ml−1 (IQR: 219–782; mean: 546). Patients with neoplasia had significantly elevated sMMP-9 levels (P<0.001). Logistic regression modelling identified elevated log(sMMP-9) as the most significant predictor of neoplasia (χ2=38.33, P<0.001). Other significant factors were age, sex, smoking history, abdominal pain and weight loss. The model accurately predicted neoplasia in 77.3% of cases. Sensitivity and specificity were 77.9 and 77.1%. sMMP-9 estimation can accurately stratify patient to low- or high-risk cohorts. Serum sampling is a potential means of avoiding unnecessary colonoscopy and reducing patient anxiety, iatrogenic morbidity and mortality, and cost.
PMCID: PMC2360395  PMID: 17912241
colorectal; matrix metalloproteinase; screening; risk
11.  Identification of serum biomarkers for colon cancer by proteomic analysis 
British Journal of Cancer  2006;94(12):1898-1905.
Colorectal cancer (CRC) is often diagnosed at a late stage with concomitant poor prognosis. Early detection greatly improves prognosis; however, the invasive, unpleasant and inconvenient nature of current diagnostic procedures limits their applicability. No serum-based test is currently of sufficient sensitivity or specificity for widespread use. In the best currently available blood test, carcinoembryonic antigen exhibits low sensitivity and specificity particularly in the setting of early disease. Hence, there is great need for new biomarkers for early detection of CRC. We have used surface-enhanced laser desorbtion/ionisation (SELDI) to investigate the serum proteome of 62 CRC patients and 31 noncancer subjects. We have identified proteins (complement C3a des-arg, α1-antitrypsin and transferrin) with diagnostic potential. Artificial neural networks trained using only the intensities of the SELDI peaks corresponding to identified proteins were able to classify the patients used in this study with 95% sensitivity and 91% specificity.
PMCID: PMC2361335  PMID: 16755300
colorectal cancer; SELDI; serum proteome; biomarker; proteomic; mass spectrometry
12.  Oestrogen receptor protein and mRNA in adenocarcinoma of the uterine cervix. 
British Journal of Cancer  1992;66(6):1150-1154.
We have investigated the oestrogen receptor (ER) status of 20 cervical adenocarcinomas by immunocytochemistry for ER protein and non-isotopic in situ hybridisation for ER mRNA. Both methods, which are applicable to paraffin sections, were developed and validated in breast carcinomas with known ER content. Six cervical adenocarcinomas contained immunocytochemically demonstrable ER protein; all contained ER mRNA, but staining was less intense in poorly differentiated areas of four tumours. This disparity between protein and mRNA detection needs further investigation as does the possibility that oestrogens may play a role in the pathogenesis of cervical adenocarcinoma.
PMCID: PMC1978005  PMID: 1457356
13.  Erythropoiesis and iron metabolism in Hodgkin's disease. 
British Journal of Cancer  1979;40(3):365-370.
Recently developed techniques for the investigation of iron kinetics were used to study the disturbance of iron metabolism in 19 untreated patients with Hodgkin's diseases (HD). The erythroid abnormality in newly diagnosed HD appears to be confined to those patients with systemic symptoms of weight loss, night sweats and fever, and consists of depression of marrow erythroid activity. These patients had a significnatly lower haemoglobin and serum iron concentration and a higher serum ferritin concentration, both when compared to normal subjects and to those patients with HD who lacked systemic symptoms. Ineffective erythropoiesis and red-cell destruction were not significantly increased. The present findings, confirm that HD patients with systemic symptoms have a depression of erythropoiesis, and that in these patients the marrow fails to respond to the stimulus of mild anaemia.
PMCID: PMC2010035  PMID: 508565

Results 1-13 (13)