Key Laboratory of Cancer Prevention and Intervention
Key Laboratory of Cancer Prevention and Intervention
PubMed | Key Surgical, Key Laboratory of Cancer Prevention and Intervention and Zhejiang University
Type: Journal Article | Journal: Oncology letters | Year: 2016
-fetoprotein (AFP)-producing colorectal adenocarcinoma is rare and typically not well recognized. In the present study, 3 cases of AFP-producing colorectal cancer are described. All 3 of these cases demonstrated increased levels of blood AFP associated with disease progression. Only case 2 exhibited classical histological hepatoid features. Following immunohistochemical tissue staining, all 3 cases were observed to be positive for AFP expression. In addition, the expression of hepatocyte growth factor (HGF), c-Met receptor and the transcription factor c-Myc were identified to be associated with the expression of AFP. The 3 cases demonstrated resistance to multiple drugs, including epidermal growth factor receptor inhibitors, despite the presence of wild-type Kirsten rat sarcoma viral oncogene homolog (K-RAS; codons 12 and 13), neuroblastoma-RAS (codons 12 and 13) and B-Raf proto-oncogene, serine/threonine kinase (V600E). We propose that hepatoid histological features or a positive AFP finding by immunohistochemistry are sufficient for a diagnosis of AFP-producing colorectal adenocarcinoma. Furthermore, we speculates that autocrine HGF/c-Met activation may be capable of inducing the dedifferentiation of common adenocarcinoma cells, reverting them to a cancer stem cell state and producing AFP or hepatoid differentiation. Consequently, therapy targeted to the HGF/c-Met signaling pathway may potentially be effective for the treatment of AFP-producing colorectal adenocarcinoma.
Bai R.,Zhejiang University |
Bai R.,Key Laboratory of Cancer Prevention and Intervention |
Bai R.,Hangzhou First Peoples Hospital |
Li D.,Zhejiang University |
And 9 more authors.
Journal of Experimental and Clinical Cancer Research | Year: 2013
Background: Ankyrin repeat domain 12 (ANKRD12), is encoding a 224 kDa nuclear protein and most conserved at its N-terminal ankyrin repeats region and the C-terminal co-activator interacting domain. The aim of this study was to investigate the ANKRD12 mRNA expression in colorectal cancer (CRC) tumor tissues and the normal adjacent mucosa and its potential relevance to clinicopathological characteristics and prognosis. Methods. Surgical specimens of tumor tissues (n = 68) and adjacent normal mucosa (n = 51) were obtained from CRC patients. The ANKRD12 mRNA expression was measured by quantitative real time reverse transcriptase polymerase chain reaction. The relationship between ANKRD12 mRNA expression and clinicopathological features was analyzed by appropriate statistics. Kaplan-Meier analysis and Cox proportional hazards regression models were used to investigate the correlation between ANKRD12 expression and prognosis of CRC patients. Results: The relative mRNA expression of ANKRD12 were significantly lower in CRC tumor tissues than in the normal adjacent mucosa (P < 0.001), and the cases with low ANKRD12 expression showed a higher frequency of liver metastasis (P = 0.015). Kaplan-Meier analysis indicated that patients (CRC without liver metastasis) with low ANKRD12 expression had poor overall survival (P = 0.041). Multivariate analysis showed that low ANKRD12 expression was an independent predictor of overall survival. Conclusion: This study revealed that ANKRD12 mRNA were down regulated in CRC tumor tissues and low ANKRD12 expression was correlated with liver metastasis and poor survival of CRC patients. © 2013 Bai et al.; licensee BioMed Central Ltd.
Hong Y.,Zhejiang Provincial Peoples Hospital |
Zhang Q.,Zhejiang University |
Zhang Q.,Key Laboratory of Cancer Prevention and Intervention
Tumor Biology | Year: 2016
Most patients with cancers died of distant metastasis. It is always difficult to find cancer metastasis in early time, let alone to prevent or cure it. Currently, oncologists place high hopes on circulating tumor cell (CTC), which, compared to current imaging methods, is found more sensitive for early metastasis. Recently, techniques for CTC enrichment and identification are developing quickly. However, there are great challenges in the clinical interpretation of CTC assessments. Increasing studies have shown the heterogeneity of CTCs, which may play different roles in cancer metastasis. Epithelial-mesenchymal transition is not only the main mechanism of the cancer cells invading the circulation system but also a distinguished characteristic of CTCs. Investigators are trying to differentiate specific subgroups of CTCs that are truly responsible for cancer metastasis. Here, we reviewed the current evidences on epithelial-mesenchymal transition of CTCs from perspectives of enrichment methods, biology, and its subgroups. © 2016 International Society of Oncology and BioMarkers (ISOBM)
Wang G.,Zhejiang University |
Zhang J.,Zhejiang University |
Liu L.,Zhejiang Cancer Hospital |
Sharma S.,University of California at Los Angeles |
And 2 more authors.
PLoS ONE | Year: 2012
Background: The dose-dependent toxicities of doxorubicin (DOX) limit its clinical applications, particularly in drug-resistant cancers, such as liver cancer. In this study, we investigated the role of quercetin on the antitumor effects of DOX on liver cancer cells and its ability to provide protection against DOX-mediated liver damage in mice. Methodology and Results: The MTT and Annexin V/PI staining assay demonstrated that quercetin selectively sensitized DOX-induced cytotoxicity against liver cancer cells while protecting normal liver cells. The increase in DOX-mediated apoptosis in hepatoma cells by quercetin was p53-dependent and occurred by downregulating Bcl-xl expression. Z-VAD-fmk (caspase inhibitor), pifithrin-α (p53 inhibitor), or overexpressed Bcl-xl decreased the effects of quercetin on DOX-mediated apoptosis. The combined treatment of quercetin and DOX significantly reduced the growth of liver cancer xenografts in mice. Moreover, quercetin decreased the serum levels of alanine aminotransferase and aspartate aminotransferase that were increased in DOX-treated mice. Quercetin also reversed the DOX-induced pathological changes in mice livers. Conclusion and Significance: These results indicate that quercetin potentiated the antitumor effects of DOX on liver cancer cells while protecting normal liver cells. Therefore, the development of quercetin may be beneficial in a combined treatment with DOX for increased therapeutic efficacy against liver cancer. © 2012 Wang et al.
Gu Y.,Key Laboratory of Cancer Prevention and Intervention |
Gu Y.,Zhejiang University |
Gu Y.,Beckman Research Institute |
Chen T.,Key Laboratory of Cancer Prevention and Intervention |
And 17 more authors.
Blood | Year: 2012
Bcr-Abl tyrosine kinase inhibitors (TKIs) have been a remarkable success for the treatment of Ph+ chronic myeloid leukemia (CML). However, a significant proportion of patients treated with TKIs develop resistance because of leukemia stem cells (LSCs) and T315I mutant Bcr-Abl. Here we describe the unknown activity of the natural product berbamine that efficiently eradicates LSCs and T315I mutant Bcr- Abl clones. Unexpectedly, we identify CaMKII γ as a specific and critical target of berbamine for its antileukemia activity. Berbamine specifically binds to the ATP-binding pocket of CaMKII γ, inhibits its phosphorylation and triggers apoptosis of leukemia cells. More importantly, CaMKII γ is highly activated in LSCs but not in normal hematopoietic stem cells and coactivates LSC-related β-catenin and Stat3 signaling networks. The identification of CaMKII γ as a specific target of berbamine and as a critical molecular switch regulating multiple LSC-related signaling pathways can explain the unique antileukemia activity of berbamine. These findings also suggest that berbamine may be the first ATP-competitive inhibitor of CaMKII γ, and potentially, can serve as a new type of molecular targeted agent through inhibition of the CaMKII γ activity for treatment of leukemia. © 2012 by The American Society of Hematology.
Meng Z.,Beckman Research Institute |
Li T.,Beckman Research Institute |
Ma X.,Beckman Research Institute |
Wang X.,Beckman Research Institute |
And 16 more authors.
Molecular Cancer Therapeutics | Year: 2013
Liver cancer is the third leading cause of cancer deaths worldwide but no effective treatment toward liver cancer is available so far. Therefore, there is an unmet medical need to identify novel therapies to efficiently treat liver cancer and improve the prognosis of this disease. Here, we report that berbamine and one of its derivatives, bbd24, potently suppressed liver cancer cell proliferation and induced cancer cell death by targeting Ca2+ /calmodulin-dependent protein kinase II (CAMKII). Furthermore, berbamine inhibited the in vivo tumorigenicity of liver cancer cells in NOD/SCID mice and downregulated the self-renewal abilities of liver cancer-initiating cells. Chemical inhibition or short hairpin RNA-mediated knockdown of CAMKII recapitulated the effects of berbamine, whereas overexpression of CAMKII promoted cancer cell proliferation and increased the resistance of liver cancer cells to berbamine treatments. Western blot analyses of human liver cancer specimens showed that CAMKII was hyperphosphorylated in liver tumors compared with the paired peritumor tissues, which supports a role of CAMKII in promoting human liver cancer progression and the potential clinical use of berbamine for liver cancer therapies. Our data suggest that berbamine and its derivatives are promising agents to suppress liver cancer growth by targeting CAMKII. © 2013 AACR.
Wu D.,Zhejiang University |
Wu D.,Key Laboratory of Cancer Prevention and Intervention |
Wu P.,Zhejiang University |
Wu P.,Key Laboratory of Cancer Prevention and Intervention |
And 8 more authors.
Medicine (United States) | Year: 2015
Nuclear factor-kappaB (NF-κB) is a key inflammatory transcription factor expressed frequently in tumors. Numerous studies have investigated the correlation between NF-κB expression and prognosis in solid tumors, but the conclusions are still in contradiction. Here, we conduct a meta-analysis to explore the overall association of NF-κB overexpression and survival in human solid tumors. Pubmed and EBSCO databases were searched for studies evaluating expression of NF-κB (as measured by immunohistochemistry) and overall survival (OS) and disease-free survival (DFS) in solid tumors. Published data were extracted and computed into odds ratios (ORs) for death at 3, 5, and 10 years. Data were pooled using the Mantel-Haenszel random-effect model. All statistical tests were two-sided. Forty-four studies with a total of 4418 patients were included in this meta-analysis. NF-κB overexpression was associated with worse OS at 3 years (OR=3.40, 95% confidence interval [CI]=2.41-4.79, P<0.00001), 5 years (OR=2.72, 95% CI=1.92-3.85, P<0.00001), and 10 years (OR=2.63, 95% CI=1.34-5.16, P=0.005) of solid tumors. Results for 3-and 5-year DFS were similar. NF-κB expression was associated with poor 3-year OS in both Tumor, Lymph Node, Metastasis stage I-II (OR=9.11, 95% CI=2.90-28.68, P=0.0002) and III-IV (OR=2.59, 95% CI=1.61-4.15, P<0.0001). There is no correlation between cellular localization of NF-κB overexpression and OS of solid tumors. Among the tumor types, NF-κB was associated with worse 3 year-OS of colorectal cancer (OR=2.70, 95% CI=1.64-4.46, P<0.0001), esophageal carcinoma (OR=6.00, 95% CI=3.29-10.94, P<0.0001) and worse 5 year-OS of colorectal cancer (OR=2.72, 95% CI=1.92-3.85, P<0.00001), esophageal carcinoma (OR=5.96, 95% CI=3.48-10.18, P=0.03), and nonsmall cell lung cancer (OR=1.69, 95% CI=1.20-2.38, P=0.002). Expression of NF-κB is associated with worse survival in most solid tumors irrespective of NF-κB localization. © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Fu J.,Key Laboratory of Cancer Prevention and Intervention |
Fu J.,Zhejiang University |
Yang J.,Key Laboratory of Cancer Prevention and Intervention |
Yang J.,Zhejiang University |
And 10 more authors.
Medicine (United States) | Year: 2014
An appropriate cutoff of age and the impact of age on colorectal cancer outcomes remain unclear and need to be explored, particularly in China. In total, 2460 colorectal cancer patients were studied retrospectively. All patients were divided into 6 groups according to their ages at the time of diagnosis: ≤30, 31 to 35, 36 to 40, 41 to 45, 46 to 50, and ≥50 years. A suitable cutoff age for defining young adult colorectal cancer was explored according to the distribution of survival in each group. Clinical characteristics and prognosis between the young adult group and the older group were then compared. According to the survival curves for each group, 35 years old was considered a suitable cutoff age for defining young adult colorectal cancer. There were 140 (5.7%) and 2320 (94.3%) cases in the young adult and older groups, respectively. The proportion of stage III-IV tumors was significantly higher in the young adult group (69.3%) than in the older group (46.4%) (P=0.000). The univariate analysis showed that the 5-year overall survival (OS) rate and the 10-year OS rate in the young adult group were 48.9% and 38.6%, respectively, whereas in the older group, they were 63.6% and 56.9%, respectively. The young adult group had a worse prognosis (P=0.000). The multivariate analysis showed that age was not an independent prognostic factor (relative risk 0.787, P=0.062). After adjusting for tumor stage, the hazard proportion of death in the young adult group increased by 27.6%, but this difference was not significant (P=0.053). Stratified analyses showed that the young adults with stage IV tumors had a worse survival rate (P=0.046). Patients≤35 years who were diagnosed with colorectal cancer had a worse prognosis because of a higher proportion of advanced stage tumors. When stage-to-stage analysis was performed, it was found that young adult colorectal cancer patients had a worse outcome only if they had stage IV tumors. © 2014 Wolters Kluwer Health.
PubMed | Key Laboratory of Cancer Prevention and Intervention
Type: Journal Article | Journal: Blood | Year: 2012
Bcr-Abl tyrosine kinase inhibitors (TKIs) have been a remarkable success for the treatment of Ph(+) chronic myeloid leukemia (CML). However, a significant proportion of patients treated with TKIs develop resistance because of leukemia stem cells (LSCs) and T315I mutant Bcr-Abl. Here we describe the unknown activity of the natural product berbamine that efficiently eradicates LSCs and T315I mutant Bcr-Abl clones. Unexpectedly, we identify CaMKII as a specific and critical target of berbamine for its antileukemia activity. Berbamine specifically binds to the ATP-binding pocket of CaMKII , inhibits its phosphorylation and triggers apoptosis of leukemia cells. More importantly, CaMKII is highly activated in LSCs but not in normal hematopoietic stem cells and coactivates LSC-related -catenin and Stat3 signaling networks. The identification of CaMKII as a specific target of berbamine and as a critical molecular switch regulating multiple LSC-related signaling pathways can explain the unique antileukemia activity of berbamine. These findings also suggest that berbamine may be the first ATP-competitive inhibitor of CaMKII , and potentially, can serve as a new type of molecular targeted agent through inhibition of the CaMKII activity for treatment of leukemia.