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Ruan S.-Q.,Cancer Institute Key Laboratory of Cancer Prevention and Intervention | Ruan S.-Q.,Zhejiang University | Wang Z.-H.,Cancer Institute Key Laboratory of Cancer Prevention and Intervention | Wang Z.-H.,Zhejiang University | And 7 more authors.
Biochemical and Biophysical Research Communications | Year: 2012

Estrogen receptor (ER)-negative breast cancer cells are probably more aggressive with larger metastatic potential than ER-positive cells. Loss of ER in recurrent breast cancer is associated with poor response to endocrine therapy. G protein-coupled receptor 30 (GPR30) is expressed in half of ER-negative breast cancers. Tumor cell-derived heregulin-β1 (HRG-β1) is also found mainly in ER-negative cancer. In SkBr3 breast cancer cells that lack ER but express GPR30, HRG-β1 upregulates mRNA and protein levels of GPR30 by promoting ErbB2-ErbB3 heterodimerization and activating the downstream MAPK-ERK signaling pathway. Moreover, GPR30 boosts HRG-β1-induced migration and invasion of SkBr3 cells after combinative treatment with E2, 4-hydroxy-tamoxifen or the specific GPR30 agonist G-1, which are blocked by the specific GPR30 antagonist G-15 or the transfection with the small interfering RNA for GPR30. The ErbB2 inhibitor AG825 and the MEK1/2 inhibitor U0126 also partly inhibit the enhanced migration and invasion. Therefore, HRG-β1-induced migration and invasion partly depend on the upregulation of GPR30 expression through activation of the ErbB2-ERK pathway in SkBr3 cells. The results of this study indicate that the crosstalk between GPR30 and HRGs signaling is important for endocrine therapy resistance and may provide a new therapeutic way to treat breast cancer. © 2012 Elsevier Inc.


Huang Y.,Cancer Institute Key Laboratory of Cancer Prevention and Intervention | Huang Y.,Zhejiang University | Ge W.,Cancer Institute Key Laboratory of Cancer Prevention and Intervention | Ge W.,Zhejiang University | And 7 more authors.
Clinical Chemistry and Laboratory Medicine | Year: 2013

Background: There is currently very little data available on the consistency of quantitative and qualitative faecal immunochemical test (FIT) for colorectal cancer screening. Methods: A representative random population (n=1889, 40-74 year olds) in Jiashan, China was invited for FIT screening in 2012. Faecal samples were collected by a single specimen collection device and simultaneously tested by a quantitative FIT (OC-SENSOR, OC) and two qualitative FITs (FIT A and FIT B with intrinsic positive haemoglobin cut-off concentrations of 20 μg Hb/g faeces and 40 μg Hb/g faeces, respectively). The observational criteria for a positive result of the qualitative FIT were set according to the density of the colour appearing in the test strip. The results produced by the quantitative and qualitative FIT for each sample were compared. κ coefficient was used to measure consistency. Results: A total of 1368 (72.4%) individuals returned faecal samples. Both FIT A and FIT B precisely identified all faecal samples with haemoglobin concentration above 100 μg Hb/g faeces, but the overall consistency was poor for OC & FIT A (κ=0.32, 95% CI 0.20-0.44) and was moderate for OC & FIT B (κ=0.74, 95% CI 0.64-0.85). A more favourable consistency (κ=0.64, 95% CI 0.57-0.72) was achieved when a different positive criterion was employed for FIT A. Conclusions: The diagnostic inconsistency between quantitative and qualitative FITs mainly exists in the faecal samples with low haemoglobin concentrations. Refining the criterion for a positive result may be a feasible way to improve the accuracy of qualitative FIT. © 2013 by Walter de Gruyter Berlin Boston.


Huang Y.Q.,Cancer Institute Key Laboratory of Cancer Prevention and Intervention
Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine] | Year: 2013

To compare the performances of fecal occult blood quantitive testing instrument and colloidal gold strip method in colorectal cancer screening. A representative random population of 9000 subjects aging between 40 and 74 years old were selected from Xuxiang, Haining city, Zhejiang province, by random cluster sampling method in year 2011. The fecal samples from each subject were separately detected by the two methods, namely fecal occult blood quantitive testing instrument and colloidal gold strip method. The positive result was standardized by hemoglobin concentration (HGB) ≥ 100 ng/ml under the application of quantitive testing instrument, or color-developing by colloidal gold strip method. The positive subjects from either method would be provided a further colonoscopy examination for pathological diagnosis. The positive rate and consistency of the two methods were compared, as well as the positive predictive value and population detecting rate of the colorectal cancer and adenoma. A total of 6475 (71.9%) subjects submitted their two fecal samples according to our requirement in 9000 subjects. There were separately 319 positive cases (4.9%) and 146 positive cases (2.3%) by the performances of fecal occult blood quantitive testing instrument and colloidal gold strip method, including 45 positive in both tests (Kappa = 0.168, 95%CI:0.119-0.217).184 out of the 319 positive cases (57.7%) in the test by quantitive testing instrument and 89 out of 146 positive cases (61.0%) in the test by colloidal gold strip method received the colonoscopy examination. There were no significant statistical differences between the two methods in the positive predictive value of colorectal cancer (P > 0.05) , developing adenoma and non-developing adenoma.However, the population detecting rate of the colorectal cancer and developing adenoma were higher in the test by quantitive testing instrument (26 cases, 0.402%) than it in the test by colloidal gold strip method (10 cases, 0.154%). The difference showed statistical significance (χ(2) = 7.131, P < 0.01). The performances of fecal occult blood quantitive testing instrument might be better than colloidal gold strip method in colorectal cancer screening. However, the results need to be further verified.


Wang K.,Cancer Institute Key Laboratory of Cancer Prevention and Intervention
International journal of nanomedicine | Year: 2011

The failure of cancer treatments is partly due to the enrichment of cancer stem-like cells (CSLCs) that are resistant to conventional chemotherapy. A novel micelle formulation of oxaliplatin (OXA) encapsulated in chitosan vesicle was developed. The authors postulate that micelle encapsulation of OXA would eliminate both CSLCs and bulk cancer cells in colorectal cancer (CRC). In this study, using stearic acid-g-chitosan oligosaccharide (CSO-SA) polymeric micelles as a drug-delivery system, OXA-loaded CSO-SA micelles (CSO-SA/OXA) were prepared. Intracellular uptake of CSO-SA/OXA micelles was assessed by confocal microscope. The effects of free OXA, the empty carrier, and CSO-SA/OXA micelles were tested using human CRC cell lines in vitro and in vivo. The micelles showed excellent internalization ability that increased OXA accumulation both in CRC cells and tissues. Furthermore, CSO-SA/OXA micelles could either increase the cytotoxicity of OXA against the bulk cancer cells or reverse chemoresistance of CSLC subpopulations in vitro. Intravenous administration of CSO-SA/OXA micelles effectively suppressed the tumor growth and reduced CD133+/CD24+ cell (putative CRC CSLC markers) compared with free OXA treatment, which caused CSLC enrichment in xenograft tumors (P < 0.05). The results of this study indicate that CSO-SA micelle as a drug-delivery carrier is effective for eradicating CSLCs and may act as a new option for CRC therapy.


Huang W.,Harbin Medical University | Liu G.,Harbin Medical University | Zhang X.,Harbin Medical University | Fu W.,Harbin Medical University | And 6 more authors.
PloS one | Year: 2014

Colorectal cancer (CRC) takes a second and fourth position in the incidence and mortality lists respectively among all malignant tumors in urban populations in China. This study was designed to evaluate the cost-effectiveness of two different CRC screening protocols: faecal occult blood test (FOBT) alone, and FOBT plus a high-risk factor questionnaire (HRFQ) as the respective initial screens, followed by colonoscopy. We developed a Markov model to simulate the progression of a cohort of 100,000 average risk asymptomatic individuals moving through a defined series of states between the ages of 40 to 74 years. The parameters used for the modeling came from the CESP (Comparison and Evaluation of Screening Programs for Colorectal Cancer in Urban Communities in China) study and published literature. Eight CRC screening scenarios were tested in the Markov model. The cost-effectiveness of CRC screening under each scenario was measured by an incremental cost-effectiveness ratio (ICER) compared with a scenario without CRC screening. The study revealed that a combined use of FOBT and HRFQ is preferable in CRC screening programs as an initial screening instrument. Annual FOBT+HRFQ screening is recommended for those who have a negative initial result and those who have a positive result but have failed to continue to colonoscopic examination. Repeated colonoscopy (for those with a positive result in initial screening but a negative colonoscopy result) should be performed at a ten-year interval instead of one-year. Such a protocol would cost 7732 Yuan per life year saved, which is the most cost-effective option. In conclusion, the current Chinese Trial Version for CRC Screening Strategy should be revised in line with the most cost-effective protocol identified in this study.


Wang Y.K.,Cancer Institute Key Laboratory of Cancer Prevention and Intervention | Zhu Y.L.,Zhejiang University | Qiu F.M.,Zhejiang University | Zhang T.,Cancer Institute Key Laboratory of Cancer Prevention and Intervention | And 4 more authors.
Carcinogenesis | Year: 2010

Cancer stem cells (CSCs) play an important role in carcinogenesis, resistance to treatment and may lead to cancer recurrence and metastasis. However, the molecular mechanism of CSC involved in these events needs to be further elucidated. In this study, CD133+ colon cancer cells were cultured, which showed CSC properties both in vitro and in vivo from metastatic tissue. Upstream molecules in Akt and mitogen-activated protein kinase (MAPK) pathways were preferentially expressed in these CD133+ cells, as revealed by a global gene chip. The kinase activities of Akt and extracellular signal-regulated kinase (Erk)1/2 were also significantly upregulated in CD133+ cells. In addition, the clonogenic growth of CD133+ cell was reduced greatly by inhibiting the activity of Akt and Erk1/2. The results revealed the Akt and MAPK pathways were involved in the tumorigenesis of CD133+ colon cancer cells, suggesting that molecules in these two pathways might be potential targets in the future therapy. © The Author 2010. Published by Oxford University Press. All rights reserved.


Wang K.,Cancer Institute Key Laboratory of Cancer Prevention and Intervention | Xu J.,Zhejiang University of Finance and Economics | Zhang J.,Cancer Institute Key Laboratory of Cancer Prevention and Intervention | Huang J.,Cancer Institute Key Laboratory of Cancer Prevention and Intervention
BMC Cancer | Year: 2012

Background: CD133 has been identified as a putative cancer stem cell marker in colorectal cancer (CRC). However, the clinical and prognostic significance of CD133 in CRC remains controversial.Methods: Publications were identified which assessed the clinical or prognostic significance of CD133 in CRC up to October 2012. A meta-analysis was performed to clarify the association between CD133 expression and clinical outcomes.Results: A total of 12 studies met the inclusion criteria, and comprised 3652 cases. Analysis of these data showed that CD133 was not significantly associated with the depth of CRC invasion (odds ratio [OR] = 1.44, 95% confidence interval [CI]: 0.77-2.68, Z = 1.15, P = 0.252) or tumor differentiation (OR = 0.63, 95% CI: 0.28-1.46, Z = -1.06, P = 0.286). Also, there was no statistically significant association of CD133 with lymph node metastasis (OR = 1.16, 95% CI: 0.87-1.54, Z = 1.05, P = 0.315) or lymphatic invasion (OR = 1.08, 95% CI: 0.81-1.43, Z = 0.53, P = 0.594). However, in identified studies, overexpression of CD133 was highly correlated with reduced overall survival (relative risk [RR] = 2.14, 95% CI: 1.45-3.17, Z = 3.81, P = 0.0001).Conclusions: CD133 may play an important role in the progression of CRC, and overexpression of CD133 is closely related with poorer patient survival. If these findings are confirmed by well-designed prospective studies, CD133 may be a useful maker for clinical applications. © 2012 Wang et al.; licensee BioMed Central Ltd.


Yin X.-F.,Chinese Academy of Sciences | Wu S.,Chinese Academy of Sciences | Yang Y.-Q.,Zhejiang Sci-Tech University | Fang X.-L.,Chinese Academy of Sciences | And 7 more authors.
Progress in Biochemistry and Biophysics | Year: 2016

Colorectal cancer (CRC) is the third leading cause of cancer-related death worldwide. Many microRNAs (miRNAs) have been reported to be abnormally expressed in CRC. Recent studies have identified miR-92b as a potential oncogene in several types of cancer. However, the role of miR-92b in CRC has not been clarified. This study aimed to elucidate the role of miR-92b in CRC progression. Relative quantitative PCR revealed that miR-92b expression was significantly increased in human CRC tissues compared to the adjacent tissues. Overexpression of miR-92b in the colorectal cancer cell line SW620 substantially increased cell viability in vitro and xenograft tumor growth in vivo. Also, miR-92b was identified as a secreted miRNA, which can be detected in both cultured medium and the peripheral blood of xenograft mice. Furthermore, we demonstrated that c-MYC, which was also elevated in CRC tissues, promoted the transcription of miR-92b by regulating its promoter activity. Luciferase assay and Western blot analysis revealed that FBXW7 was a novel target of miR-92b and can be negatively regulated by c-MYC. As FBXW7 is a major E3 ligase of c-MYC, our data suggested a potential positive regulatory feedback loop among c-MYC, miR-92b and FBXW7 in CRC. Collectively, we partly provided evidence on how miR-92b is regulated and the potential implications of miR-92b in CRC diagnosis.


Wang Z.-H.,Cancer Institute Key Laboratory of Cancer Prevention and Intervention | Wang Z.-H.,Zhejiang University | Ding K.-F.,Zhejiang University | Yu J.-K.,Cancer Institute Key Laboratory of Cancer Prevention and Intervention | And 12 more authors.
Journal of Zhejiang University: Science B | Year: 2012

Objective: Cancer-associated fibroblasts (CAFs) are one of the hallmarks of the cancer microenvironment. Recent evidence has indicated that CAFs are more competent in enhancing cancer cell growth and migration than normal fibroblasts. However, the unique protein expression of CAFs has not been fully elucidated. This study aims to investigate the characterizations of colon CAFs by comparing the differential protein expression between CAFs and normal fibroblasts. Methods: Primary fibroblasts were isolated from surgical specimen of human colon cancer and matched normal colonic tissue. Purity of the cell population was verified through immunostain analysis. Total cell lysates and conditioned media from each group of cells were extracted, and protein expression analysis was conducted using the surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) ProteinChip platform. Results: Most primary cells showed typical fibroblast-like features after two weeks. Increased proportion of α-smooth muscle actin-positive myofibroblasts was detected within the CAFs in four of the six pairs of primary cells. Fibroblast activation protein was weakly expressed in most cells without differences. Using SELDI-TOF-MS ProteinChip platform, four protein peaks mass over charge ratio (m/z) 1142, 3011, 4035, and 4945 were detected in the total cell lysates, and two protein peaks m/z 1368 and 1389 were detected in the conditioned media. The potential candidate proteins found in the Swiss-Prot database include morphogenetic neuropeptides, FMRFamide-related peptides, insulin-like growth factor II, thymosin β-4-like protein 3, and tight junction-associated protein 1. Conclusions: Using the SELDI-ProteinChip platform, differential protein expressions were identified in colon CAFs compared with normal colonic stromal fibroblasts. The complex proteomic alternations in colon CAFs may play important roles related to the colon cancer microenvironment. © Zhejiang University and Springer-Verlag Berlin Heidelberg 2012.


PubMed | Cancer Institute Key Laboratory of Cancer Prevention and Intervention
Type: Comparative Study | Journal: Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine] | Year: 2013

To compare the performances of fecal occult blood quantitive testing instrument and colloidal gold strip method in colorectal cancer screening.A representative random population of 9000 subjects aging between 40 and 74 years old were selected from Xuxiang, Haining city, Zhejiang province, by random cluster sampling method in year 2011. The fecal samples from each subject were separately detected by the two methods, namely fecal occult blood quantitive testing instrument and colloidal gold strip method. The positive result was standardized by hemoglobin concentration (HGB) 100 ng/ml under the application of quantitive testing instrument, or color-developing by colloidal gold strip method. The positive subjects from either method would be provided a further colonoscopy examination for pathological diagnosis. The positive rate and consistency of the two methods were compared, as well as the positive predictive value and population detecting rate of the colorectal cancer and adenoma.A total of 6475 (71.9%) subjects submitted their two fecal samples according to our requirement in 9000 subjects. There were separately 319 positive cases (4.9%) and 146 positive cases (2.3%) by the performances of fecal occult blood quantitive testing instrument and colloidal gold strip method, including 45 positive in both tests (Kappa = 0.168, 95%CI:0.119-0.217).184 out of the 319 positive cases (57.7%) in the test by quantitive testing instrument and 89 out of 146 positive cases (61.0%) in the test by colloidal gold strip method received the colonoscopy examination. There were no significant statistical differences between the two methods in the positive predictive value of colorectal cancer (P > 0.05) , developing adenoma and non-developing adenoma.However, the population detecting rate of the colorectal cancer and developing adenoma were higher in the test by quantitive testing instrument (26 cases, 0.402%) than it in the test by colloidal gold strip method (10 cases, 0.154%). The difference showed statistical significance ((2) = 7.131, P < 0.01).The performances of fecal occult blood quantitive testing instrument might be better than colloidal gold strip method in colorectal cancer screening. However, the results need to be further verified.

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