|
1
|
Kang N, Fan Z, Yang L, Shen J, Shen Y, Fang Z, Li B, Yang B, Wang J. Camel Milk Protein Ameliorates Ulcerative Colitis by Modulating Gut Microbiota and Amino Acid Metabolism. Nutrients 2025; 17:780. [PMID: 40077650 PMCID: PMC11902107 DOI: 10.3390/nu17050780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 02/09/2025] [Accepted: 02/18/2025] [Indexed: 03/14/2025] Open
Abstract
The protective effects of the milk fat globule membrane (MFGM) in alleviating inflammation have been reported. However, limited attention has been paid to the key fraction of milk fat globule membrane protein (MFGMP). This study investigated the protective effects of camel MFGMP against dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice. The results revealed that administering 50 mg/kg MFGMP significantly alleviated colonic inflammation, as evidenced by a marked decrease in IL-6, IL-1β, and TNF-α levels, along with pathological damage in DSS-induced mice with UC. MFGMP supplementation partially regulated gut microbiota dysbiosis in mice with UC by increasing α-diversity and the relative abundance of beneficial gut bacteria, such as Lactobacillus, while decreasing the abundance of Akkermansia. Additionally, MFGMP treatment exhibited significant regulatory effects on metabolites, particularly amino acid metabolism, in the feces. Specifically, this treatment restored L-valine to normal physiological levels and increased the concentrations of L-leucine, L-lysine, and L-tyrosine to nearly twice their baseline levels, whereas the concentration of L-tryptophan increased threefold. These upregulated amino acids were negatively correlated with pro-inflammatory cytokines and positively correlated with the anti-inflammatory cytokine IL-10, as indicated by Spearman's correlation analysis. Furthermore, the significant reduction in the mRNA expression levels of WNT-1, β-catenin, and Cyclin D1 suggests that MFGMP exerts a positive effect on UC via the Wnt/β-catenin pathway. These findings indicate that MFGMP exerts a protective effect against UC by modulating intestinal microbiota and amino acid metabolism in mice, with potential implications for treating intestinal inflammatory diseases.
Collapse
Affiliation(s)
- Ning Kang
- Key Laboratory of Agricultural Product Processing and Quality Control of Specialty (Co-Construction by Ministry and Province), School of Food Science and Technology, Shihezi University, Shihezi 832000, China; (N.K.); (Z.F.); (J.S.); (Y.S.); (Z.F.); (B.L.)
- Key Laboratory for Food Nutrition and Safety Control of Xinjiang Production and Construction Corps, School of Food Science and Technology, Shihezi 832000, China
- Engineering Research Center of Storage and Processing of Xinjiang Characteristic Fruits and Vegetables, Ministry of Education, School of Food Science and Technology, Shihezi University, Shihezi 832000, China
| | - Zhexin Fan
- Key Laboratory of Agricultural Product Processing and Quality Control of Specialty (Co-Construction by Ministry and Province), School of Food Science and Technology, Shihezi University, Shihezi 832000, China; (N.K.); (Z.F.); (J.S.); (Y.S.); (Z.F.); (B.L.)
- Key Laboratory for Food Nutrition and Safety Control of Xinjiang Production and Construction Corps, School of Food Science and Technology, Shihezi 832000, China
- Engineering Research Center of Storage and Processing of Xinjiang Characteristic Fruits and Vegetables, Ministry of Education, School of Food Science and Technology, Shihezi University, Shihezi 832000, China
- Functional Food Center, Key Laboratory of Xinjiang Medicinal Plant Resources Utilization, Ministry of Education, Shihezi University, Shihezi 832000, China
| | - Li Yang
- Alashankou Customs Technology Center, Alashankou 833418, China;
| | - Jie Shen
- Key Laboratory of Agricultural Product Processing and Quality Control of Specialty (Co-Construction by Ministry and Province), School of Food Science and Technology, Shihezi University, Shihezi 832000, China; (N.K.); (Z.F.); (J.S.); (Y.S.); (Z.F.); (B.L.)
- Key Laboratory for Food Nutrition and Safety Control of Xinjiang Production and Construction Corps, School of Food Science and Technology, Shihezi 832000, China
- Engineering Research Center of Storage and Processing of Xinjiang Characteristic Fruits and Vegetables, Ministry of Education, School of Food Science and Technology, Shihezi University, Shihezi 832000, China
| | - Yuechenfei Shen
- Key Laboratory of Agricultural Product Processing and Quality Control of Specialty (Co-Construction by Ministry and Province), School of Food Science and Technology, Shihezi University, Shihezi 832000, China; (N.K.); (Z.F.); (J.S.); (Y.S.); (Z.F.); (B.L.)
- Key Laboratory for Food Nutrition and Safety Control of Xinjiang Production and Construction Corps, School of Food Science and Technology, Shihezi 832000, China
- Engineering Research Center of Storage and Processing of Xinjiang Characteristic Fruits and Vegetables, Ministry of Education, School of Food Science and Technology, Shihezi University, Shihezi 832000, China
| | - Zhifeng Fang
- Key Laboratory of Agricultural Product Processing and Quality Control of Specialty (Co-Construction by Ministry and Province), School of Food Science and Technology, Shihezi University, Shihezi 832000, China; (N.K.); (Z.F.); (J.S.); (Y.S.); (Z.F.); (B.L.)
- Key Laboratory for Food Nutrition and Safety Control of Xinjiang Production and Construction Corps, School of Food Science and Technology, Shihezi 832000, China
- Engineering Research Center of Storage and Processing of Xinjiang Characteristic Fruits and Vegetables, Ministry of Education, School of Food Science and Technology, Shihezi University, Shihezi 832000, China
- Functional Food Center, Key Laboratory of Xinjiang Medicinal Plant Resources Utilization, Ministry of Education, Shihezi University, Shihezi 832000, China
| | - Baokun Li
- Key Laboratory of Agricultural Product Processing and Quality Control of Specialty (Co-Construction by Ministry and Province), School of Food Science and Technology, Shihezi University, Shihezi 832000, China; (N.K.); (Z.F.); (J.S.); (Y.S.); (Z.F.); (B.L.)
- Key Laboratory for Food Nutrition and Safety Control of Xinjiang Production and Construction Corps, School of Food Science and Technology, Shihezi 832000, China
- Engineering Research Center of Storage and Processing of Xinjiang Characteristic Fruits and Vegetables, Ministry of Education, School of Food Science and Technology, Shihezi University, Shihezi 832000, China
- Functional Food Center, Key Laboratory of Xinjiang Medicinal Plant Resources Utilization, Ministry of Education, Shihezi University, Shihezi 832000, China
| | - Bo Yang
- State Key Laboratory of Food Science and Resources, School of Food Science and Technology, Jiangnan University, Wuxi 214122, China;
- International Joint Research Laboratory for Maternal-Infant Microbiota and Health, Jiangnan University, Wuxi 214122, China
| | - Jiancheng Wang
- Key Laboratory of Agricultural Product Processing and Quality Control of Specialty (Co-Construction by Ministry and Province), School of Food Science and Technology, Shihezi University, Shihezi 832000, China; (N.K.); (Z.F.); (J.S.); (Y.S.); (Z.F.); (B.L.)
- Key Laboratory for Food Nutrition and Safety Control of Xinjiang Production and Construction Corps, School of Food Science and Technology, Shihezi 832000, China
- Engineering Research Center of Storage and Processing of Xinjiang Characteristic Fruits and Vegetables, Ministry of Education, School of Food Science and Technology, Shihezi University, Shihezi 832000, China
- Functional Food Center, Key Laboratory of Xinjiang Medicinal Plant Resources Utilization, Ministry of Education, Shihezi University, Shihezi 832000, China
| |
Collapse
|
|
2
|
Kolawole OR, Kashfi K. NSAIDs and Cancer Resolution: New Paradigms beyond Cyclooxygenase. Int J Mol Sci 2022; 23:1432. [PMID: 35163356 PMCID: PMC8836048 DOI: 10.3390/ijms23031432] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 01/19/2022] [Accepted: 01/20/2022] [Indexed: 12/12/2022] Open
Abstract
Acute inflammation or resolved inflammation is an adaptive host defense mechanism and is self-limiting, which returns the body to a state of homeostasis. However, unresolved, uncontrolled, or chronic inflammation may lead to various maladies, including cancer. Important evidence that links inflammation and cancer is that nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, reduce the risk and mortality from many cancers. The fact that NSAIDs inhibit the eicosanoid pathway prompted mechanistic drug developmental work focusing on cyclooxygenase (COX) and its products. The increased prostaglandin E2 levels and the overexpression of COX-2 in the colon and many other cancers provided the rationale for clinical trials with COX-2 inhibitors for cancer prevention or treatment. However, NSAIDs do not require the presence of COX-2 to prevent cancer. In this review, we highlight the effects of NSAIDs and selective COX-2 inhibitors (COXIBs) on targets beyond COX-2 that have shown to be important against many cancers. Finally, we hone in on specialized pro-resolving mediators (SPMs) that are biosynthesized locally and, in a time, -dependent manner to promote the resolution of inflammation and subsequent tissue healing. Different classes of SPMs are reviewed, highlighting aspirin's potential in triggering the production of these resolution-promoting mediators (resolvins, lipoxins, protectins, and maresins), which show promise in inhibiting cancer growth and metastasis.
Collapse
Affiliation(s)
- Oluwafunke R. Kolawole
- Department of Molecular, Cellular and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY 10031, USA;
| | - Khosrow Kashfi
- Department of Molecular, Cellular and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY 10031, USA;
- Graduate Program in Biology, City University of New York Graduate Center, New York, NY 10091, USA
| |
Collapse
|
|
3
|
Li Q, Wang G, Tao J, Chen W. RNF6 promotes colorectal cancer invasion and migration via the Wnt/β-catenin pathway by inhibiting GSK3β activity. Pathol Res Pract 2021; 225:153545. [PMID: 34352441 DOI: 10.1016/j.prp.2021.153545] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 07/04/2021] [Accepted: 07/07/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND The purpose of this study was to explore the molecular mechanism underlying the interaction between ring finger protein 6 (RNF6) and glycogen synthase kinase 3β (GSK3β) in colorectal cancer (CRC). METHODS In this study, cell models of overexpressed or silenced RNF6 were established by liposome transfection, and IM-12 was used as the inhibitor of GSK3β. Real-time quantitative PCR and western blots were used to detect the expression of RNF6, p-GSK3β, GSK3β, and β-catenin, and MTT assays were used to quantify cell proliferation. The tumorigenicity of cells was observed by plate clonal formation assay; the invasiveness of cells was examined in Transwell Boyden chambers, and the migratory capacity of cells was tested by scratch wound assays. The rat CRC model was induced by AOM/DSS, in which we verified activity in the Wnt/β-catenin pathway by examining GSK3β phosphorylation. RESULTS RNF6 was upregulated in CRC samples and cell lines. Silencing or overexpressing RNF6 in colorectal cancer cells inhibited or promoted, respectively, the proliferation, tumorigenicity, invasion and migration of CRC cells, as well as expression of p-GSK3β, GSK3β and β-catenin. IM-12 reversed the Wnt/β-catenin-activated state change induced by RNF6 silencing and the inhibition of cell proliferation, tumorigenicity, invasion and migration. The same results were observed in vivo in the rat CRC model. CONCLUSIONS Overexpression of RNF6 in CRC increased the GSK3β phosphorylation level, which led to activation of the Wnt/β-catenin pathway and promoted the invasion and migration of CRC cells, suggesting that RNF6 may be a novel target for the treatment of CRC.
Collapse
Affiliation(s)
- Qiken Li
- Department of Colorectal Cancer Surgery, Cancer Hospital of The University of Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China.
| | - Gang Wang
- Department of Colorectal Cancer Surgery, Cancer Hospital of The University of Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
| | - Jinhua Tao
- Department of Colorectal Cancer Surgery, Cancer Hospital of The University of Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
| | - Weiping Chen
- Department of Colorectal Cancer Surgery, Cancer Hospital of The University of Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China.
| |
Collapse
|
|
4
|
Ouban A. SALL4 stemness agent expression in oral squamous cell cancer and its clinical significance. BIOTECHNOL BIOTEC EQ 2021. [DOI: 10.1080/13102818.2021.1914165] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
Affiliation(s)
- Abderrahman Ouban
- Department of Pathology, College of Medicine, Alfaisal University, Riyadh, Kingdom of Saudi Arabia
| |
Collapse
|
|
5
|
Wang P, Ding S, Sun L, Feng Y, Guo K, Zhu Y, Huang D, Ruan S. Characteristics and differences of gut microbiota in patients with different Traditional Chinese Medicine Syndromes of Colorectal Cancer and normal population. J Cancer 2020; 11:7357-7367. [PMID: 33193900 PMCID: PMC7646174 DOI: 10.7150/jca.50318] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Accepted: 10/12/2020] [Indexed: 12/14/2022] Open
Abstract
Colorectal cancer (CRC) is considered to be closely associated with alteration of intestinal microorganisms. The purpose of present study was to investigate the distribution of gut microbiota in the distinction of microbiota dysbiosis between two disease syndromes called Zheng-Qi-Kui-Xu(ZQKX) and Xie-Du-Yong-Sheng (XDYS). First, From February 2019 to June 2019, CRC patients presenting to the oncology department of Zhejiang Province Hospital of TCM who met the established inclusion and exclusion criteria were enrolled in this prospective study. After fresh stool specimens of healthy volunteers and CRC patients with ZQKX or XDYS syndorme were collected, 16S rRNA gene amplification and sequencing could be used to identify the diversity and abundance of gut microbiota among groups. The results demonstrated that the composition of the microbiota in general control group was superior to those in experimental groups. At the phylum level, a significantly increased abundance of Bacteroides was observed in healthy volunteers. At the class level, Erysipelothrix decreased while Lactobacillaceae showed increased abundance in the ZQKX group compared to healthy controls. At the family level, Prevotella Shan and Collins decreased while Streptococcus significantly increased in patients with XDYS syndrome compared to healthy subjects. Five differential taxa were identified between ZQKX and XDYS syndromes. We suggest that the gut microbiota contributes to the distinction between the two TCM syndromes of CRC, which can be used as a biological basis of TCM syndrome differentiation treatment in CRC.
Collapse
Affiliation(s)
- Peipei Wang
- The First Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou 310053, Z.J. China
| | - Shuning Ding
- The First Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou 310053, Z.J. China
| | - Leitao Sun
- Department of Medical Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, Z.J. China
| | - Yuqian Feng
- The First Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou 310053, Z.J. China
| | - Kaibo Guo
- The First Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou 310053, Z.J. China
| | - Ying Zhu
- The First Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou 310053, Z.J. China
| | - Dawei Huang
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, Z.J. China
| | - Shanming Ruan
- Department of Medical Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, Z.J. China
| |
Collapse
|
|
6
|
Bao B, Prasad AS. Targeting CSC in a Most Aggressive Subtype of Breast Cancer TNBC. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1152:311-334. [DOI: 10.1007/978-3-030-20301-6_17] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
|
|
7
|
Long non-coding RNAs: crucial regulators of gastrointestinal cancer cell proliferation. Cell Death Discov 2018; 4:50. [PMID: 29736267 PMCID: PMC5919979 DOI: 10.1038/s41420-018-0051-8] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2018] [Revised: 03/14/2018] [Accepted: 03/19/2018] [Indexed: 12/13/2022] Open
Abstract
Studies of long non-coding RNAs (lncRNAs) have been prevalent in the field of non-coding RNA regulation in recent years. LncRNAs exert crucial effects on malignant cell processes in the gastrointestinal system, including proliferation. Aberrant lncRNA expression, through both oncogenes and tumor suppressor genes, is instrumental to tumor cell proliferation. Here, we summarize the different molecular mechanisms and relevant signaling pathways through which multifarious lncRNAs regulate cell proliferation and we show that lncRNAs are potential biomarkers for gastrointestinal cancers.
Collapse
|
|
8
|
Zhuang K, Yan Y, Zhang X, Zhang J, Zhang L, Han K. Gastrin promotes the metastasis of gastric carcinoma through the β-catenin/TCF-4 pathway. Oncol Rep 2016; 36:1369-76. [PMID: 27430592 DOI: 10.3892/or.2016.4943] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Accepted: 03/26/2016] [Indexed: 11/06/2022] Open
Abstract
Gastric cancer is the most common epithelial malignancy and the second leading cause of cancer-related death worldwide; metastasis is a crucial factor in the progression of gastric cancer. The present study applied gastrin-17 amide (G-17) in SGC7901 cells. The results showed that G-17 promoted the cell cycle by accelerating the G0/G1 phase and by increasing the cell proliferation rate by binding to the gastrin receptor. The migratory and invasive abilities of the SGC7901 cells were increased by G-17. The expression levels of matrix metalloproteinase (MMP)-7, MMP-9 and vascular endothelial growth factor (VEGF) were enhanced by G-17 as well. Moreover, G-17 caused the overexpression of β-catenin and TCF-4. G-17 also caused a preferential cytoplasmic and nuclear localization of β-catenin with a high TOP-FLASH activity. Finally, axin reduced the migratory and invasive abilities of the SGC7901 cells, and inhibited the expression of β-catenin, TCF-4, MMP-7, MMP-9 and VEGF; these effects were counteracted by adding G-17. In summary, the present study confirmed the proliferation and metastasis-promoting role of G-17 via binding to the gastrin receptor, and the β-catenin/TCF-4 pathway was found to be essential for mediating G-17-induced metastasis in gastric cancer. These results may provide a novel gene target for the treatment of gastric cancer.
Collapse
Affiliation(s)
- Kun Zhuang
- Division of Gastroenterology, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710003, P.R. China
| | - Yuan Yan
- Division of Gastroenterology, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710003, P.R. China
| | - Xin Zhang
- Division of Gastroenterology, Xi'an Central Hospital, Xi'an, Shaanxi 710003, P.R. China
| | - Jun Zhang
- Division of Gastroenterology, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710003, P.R. China
| | - Lingxia Zhang
- Division of Gastroenterology, Xi'an Central Hospital, Xi'an, Shaanxi 710003, P.R. China
| | - Kun Han
- Division of Gastroenterology, Xi'an Central Hospital, Xi'an, Shaanxi 710003, P.R. China
| |
Collapse
|
|
9
|
Jung YG, Lee HW, Kim MG, Dhong HJ, Cho KS, Roh HJ. Role of Wnt signaling pathway in progression of sinonasal inverted papilloma to squamous cell carcinoma. Am J Rhinol Allergy 2016; 29:e81-6. [PMID: 25975243 DOI: 10.2500/ajra.2015.29.4193] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND Sinonasal inverted papilloma (IP) is one of the most common benign tumors of the sinonasal area and malignant transformation has frequently been reported. However, the exact mechanism of the transition from benign lesion to malignancy is not known. The Wnt signaling pathway involves a network of multiple signaling glycoproteins that are known to play an important role in embryogenesis and carcinogenesis. OBJECTIVE The purpose of this study was to evaluate the role of the Wnt pathway and signaling proteins in malignant transformation of IP to dysplasia and squamous cell carcinoma. METHODS Expression of the Wnt signaling pathway proteins, including Wnt-1, beta-catenin, cyclin D1, and Dishevelled-1 (Dvl-1), were detected by immunohistochemistry by using 3-mm tissue core microarrays that consisted of 115 cores of IP tissue. Each of the IP cores was graded as I (prominent squamous metaplasia), II (inverted pattern), III (dysplasia), or IV (squamous cell carcinoma). The expression pattern of each protein and the correlation between the expression of each target protein and IP grade were evaluated. RESULTS Membranous staining of beta-catenin showed a significant positive correlation with IP grade (ρ = 0.247, p < 0.001), as did staining of cyclin D1 (ρ = 0.365, p < 0.001), which showed a nuclear pattern and staining of Dvl-1 (ρ = 0.380, p < 0.001), which showed a membranous, cytoplasmic, and nuclear pattern. For Dvl-1, a nuclear expression pattern was more frequently observed in grade III and IV IP (p = 0.036). In the case of Wnt-1, cytoplasmic expression was observed; however, it did not show a significant correlation with IP grade (ρ = 0.141, p = 0.130). CONCLUSIONS Wnt signaling proteins, including beta-catenin, cyclin D1, and Dvl-1, may play crucial roles in the malignant transformation of IP.
Collapse
Affiliation(s)
- Yong Gi Jung
- Department of Otorhinolaryngology-Head and Neck Surgery, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon-Si, Republic of Korea
| | | | | | | | | | | |
Collapse
|
|
10
|
The value of preoperative screening colonoscopies in patients with biliary tract cancer. J Gastroenterol 2016; 51:138-43. [PMID: 26026308 DOI: 10.1007/s00535-015-1092-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2015] [Accepted: 05/10/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND The purpose of this study was to evaluate the value of preoperative screening colonoscopies in patients with biliary tract cancer. METHODS A total of 544 patients with biliary tract cancer who underwent preoperative screening colonoscopies between January 2005 and December 2012 were retrospectively analyzed. RESULTS Synchronous colorectal neoplasia was detected in 199 patients (36.7 %), with adenocarcinomas detected in 21 (3.9 %) patients, carcinoids in two (0.4 %) patients, and adenomas in 176 (32.4 %) patients. Of those with adenomas, 32 patients were diagnosed with advanced adenomas, defined as adenomas with a maximum diameter of >1 cm, villous histology, or high-grade dysplasia because these characteristics implied the risk of malignant transformation. Fifty-five (10.1 %) of the patients with colorectal neoplasia required resection (11 surgical and 44 endoscopic resections). There were no major adverse events related to the resection. Univariate and multivariate analyses revealed that smoking status [ex-smoker + current smoker vs. non-smoker: odds ratio (OR) 2.32; 95 % confidence interval (CI) 1.30-4.21] and advanced age (≥70 vs. ≤69 years: OR 2.22; 95 % CI 1.24-3.91) were independent risk factors of having a colorectal neoplasia that required resection. CONCLUSIONS In patients with biliary tract cancer, preoperative screening colonoscopy was feasible and provided valuable clinical information. Synchronous colorectal neoplasia was detected in a substantial number of patients. Preoperative screening colonoscopies should be considered especially in high-risk patients such as smokers and elderly patients.
Collapse
|
|
11
|
Hao L, Zhao Y, Wang Z, Yin H, Zhang X, He T, Song S, Sun S, Wang B, Li Z, Su Q. Expression and clinical significance of SALL4 and β-catenin in colorectal cancer. J Mol Histol 2016; 47:117-28. [DOI: 10.1007/s10735-016-9656-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2015] [Accepted: 01/08/2016] [Indexed: 12/20/2022]
|
|
12
|
Zhao S, Wang J, Qin C. Blockade of CXCL12/CXCR4 signaling inhibits intrahepatic cholangiocarcinoma progression and metastasis via inactivation of canonical Wnt pathway. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2014; 33:103. [PMID: 25471741 PMCID: PMC4265318 DOI: 10.1186/s13046-014-0103-8] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/16/2014] [Accepted: 11/21/2014] [Indexed: 12/25/2022]
Abstract
Background Intrahepatic cholangiocarcinoma (IHCC) is the second most frequent primary malignant liver tumor following hepatocellular carcinoma. It is a highly fatal disease and has few therapeutics. The CXC chemokine ligand-12 (CXCL12)/CXC chemokine receptor type 4 (CXCR4) axis has been shown to be involved in tumorgenesis, proliferation, and angiogenesis in a variety of cancers including IHCC. However, its prognostic significance in IHCC is unclear. The purpose of this study was to examine the functional role of CXCR4 in the progression and metastasis of IHCC and explore the underlying mechanism. Methods The CXCR4 expression, overall survival, and the clinical characteristics including age, sex, differentiation degree, tumor size, vascular invasion, lymph node metastasis, TNM stage, and T stage were analyzed for 122 IHCC patients. Short hairpin RNA (shRNA) against CXCR4 was used to disrupt the CXCL12/CXCR4 signal transduction pathways in IHCC cell lines. In vitro assays, including CCK-8 assay, flow cytometry, and colony formation assay, and in vivo tumor formation assay were utilized to detect the cell phenotype of CXCR4 knockdown cells. Transwell and wound healing assays were used to examine the IHCC cell invasion and migration ability. The Wnt pathway was assessed by Western blot and β-Catenin/Tcf transcription reporter assay. Results We demonstrated that CXCR4 expression was closely correlated with IHCC progression and metastasis characteristics. The overall survival of patients with high CXCR4 expression was significantly lower than that of patients with low CXCR4 expression. Furthermore, we showed that the abrogation of CXCR4 had significantly negative influence on the IHCC cell phenotype, including in vitro cell proliferation, cell cycle, colony formation, cell invasion, and in vivo tumorigenicity. In addition, CXCR4 knockdown downregulated Wnt target genes and mesenchymal markers such as Vimentin and Slug. Conclusions In conclusion, our result shows that high CXCR4 expression is associated with IHCC progression and metastasis via the canonical Wnt pathway, suggesting that CXCR4 may serve as a promising therapeutic target for IHCC.
Collapse
Affiliation(s)
- Shengqiang Zhao
- Department of Gastroenterology, Shandong Provincial Hospital, Shandong University, Jinan, China.
| | - Jing Wang
- Department of Gastroenterology, Shandong Provincial Hospital, Shandong University, Jinan, China.
| | - Chengyong Qin
- Department of Gastroenterology, Shandong Provincial Hospital, Shandong University, Jinan, China.
| |
Collapse
|
|
13
|
Nakabeppu Y. Cellular levels of 8-oxoguanine in either DNA or the nucleotide pool play pivotal roles in carcinogenesis and survival of cancer cells. Int J Mol Sci 2014; 15:12543-57. [PMID: 25029543 PMCID: PMC4139859 DOI: 10.3390/ijms150712543] [Citation(s) in RCA: 145] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2014] [Revised: 06/23/2014] [Accepted: 07/08/2014] [Indexed: 01/06/2023] Open
Abstract
8-Oxoguanine, a major oxidized base lesion formed by reactive oxygen species, causes G to T transversion mutations or leads to cell death in mammals if it accumulates in DNA. 8-Oxoguanine can originate as 8-oxo-dGTP, formed in the nucleotide pool, or by direct oxidation of the DNA guanine base. MTH1, also known as NUDT1, with 8-oxo-dGTP hydrolyzing activity, 8-oxoguanine DNA glycosylase (OGG1) an 8-oxoG DNA glycosylase, and MutY homolog (MUTYH) with adenine DNA glycosylase activity, minimize the accumulation of 8-oxoG in DNA; deficiencies in these enzymes increase spontaneous and induced tumorigenesis susceptibility. However, different tissue types have different tumorigenesis susceptibilities. These can be reversed by combined deficiencies in the defense systems, because cell death induced by accumulation of 8-oxoG in DNA is dependent on MUTYH, which can be suppressed by MTH1 and OGG1. In cancer cells encountering high oxidative stress levels, a high level of 8-oxo-dGTP accumulates in the nucleotide pool, and cells therefore express increased levels of MTH1 in order to eliminate 8-oxo-dGTP. Suppression of MTH1 may be an efficient strategy for killing cancer cells; however, because MTH1 and OGG1 protect normal tissues from oxidative-stress-induced cell death, it is important that MTH1 inhibition does not increase the risk of healthy tissue degeneration.
Collapse
Affiliation(s)
- Yusaku Nakabeppu
- Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, and Research Center for Nucleotide Pool, Kyushu University, 3-1-1 Maidashi, Fukuoka 812-8582, Japan.
| |
Collapse
|
|
14
|
Wang C, Wang J, Liu H, Fu Z. Tumor suppressor DLC-1 induces apoptosis and inhibits the growth and invasion of colon cancer cells through the Wnt/β-catenin signaling pathway. Oncol Rep 2014; 31:2270-8. [PMID: 24604602 DOI: 10.3892/or.2014.3057] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2014] [Accepted: 02/10/2014] [Indexed: 11/06/2022] Open
Abstract
The aim of the present study was to investigate the biological role and molecular mechanism of the deleted in liver cancer-1 (DLC-1) gene in human colon cancer growth and invasion. Recombinant lentiviral vectors encoding the DLC-1 gene were constructed for transfection into the human colon cancer cell line SW480. Real-time quantitative polymerase chain reaction (real-time qPCR) and western blot analysis were employed to evaluate the expression of DLC-1, β-catenin, GSK-3β and c-myc in DLC-1-transfected cells. Moreover, cell proliferation assay, cell colony formation assay, cell cycle analysis, apoptosis analysis and cell migration and invasion assays were performed in order to elucidate the role of DLC-1 in colorectal cancer development and progression. Both real-time qPCR and western blot analyses showed that the DLC-1 gene and protein were overexpressed in the DLC-1-transfected SW480 cells. In addition, the expression of β-catenin and GSK-3β was upregulated and the expression of the c-myc gene was downregulated in the DLC-1-transfected SW480 cells. Furthermore, DLC-1 overexpression inhibited cell proliferation, colony formation, migration and invasion, and induced cell cycle arrest at the G1 phase with subsequent apoptosis. DLC-1 inhibits cell growth and invasion in human colon cancer, functioning as a tumor-suppressor gene, possibly through the regulation of the Wnt/β-catenin signaling pathway.
Collapse
Affiliation(s)
- Chunyi Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Jialin Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Hong Liu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Zhongxue Fu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| |
Collapse
|
|
15
|
WNT signaling in neoplasia. Mol Oncol 2013. [DOI: 10.1017/cbo9781139046947.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
|
|
16
|
Huang MY, Yen LC, Liu HC, Liu PP, Chung FY, Wang TN, Wang JY, Lin SR. Significant overexpression of DVL1 in Taiwanese colorectal cancer patients with liver metastasis. Int J Mol Sci 2013; 14:20492-20507. [PMID: 24129181 PMCID: PMC3821627 DOI: 10.3390/ijms141020492] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2013] [Revised: 09/24/2013] [Accepted: 09/29/2013] [Indexed: 01/06/2023] Open
Abstract
Undetected micrometastasis plays a key role in the metastasis of cancer in colorectal cancer (CRC) patients. The aim of this study is to identify a biomarker of CRC patients with liver metastasis through the detection of circulating tumor cells (CTCs). Microarray and bioinformatics analysis of 10 CRC cancer tissue specimens compared with normal adjacent tissues revealed that 31 genes were up-regulated (gene expression ratio of cancer tissue to paired normal tissue > 2) in the cancer patients. We used a weighted enzymatic chip array (WEnCA) including 31 prognosis-related genes to investigate CTCs in 214 postoperative stage I-III CRC patients and to analyze the correlation between gene expression and clinico-pathological parameters. We employed the immunohistochemistry (IHC) method with polyclonal mouse antibody against DVL1 to detect DVL1 expression in 60 CRC patients. CRC liver metastasis occurred in 19.16% (41/214) of the patients. Using univariate analysis and multivariate proportional hazards regression analysis, we found that DVL1 mRNA overexpression had a significant, independent predictive value for liver metastasis in CRC patients (OR: 5.764; 95% CI: 2.588-12.837; p < 0.0001 on univariate analysis; OR: 3.768; 95% CI: 1.469-9.665; p = 0.006 on multivariate analysis). IHC staining of the immunoreactivity of DVL1 showed that DVL1 was localized in the cytoplasm of CRC cells. High expression of DVL1 was observed in 55% (33/60) of CRC tumor specimens and was associated significantly with tumor depth, perineural invasion and liver metastasis status (all p < 0.05). Our experimental results demonstrated that DVL1 is significantly overexpressed in CRC patients with liver metastasis, leading us to conclude that DVL1 could be a potential prognostic and predictive marker for CRC patients.
Collapse
Affiliation(s)
- Ming-Yii Huang
- Department of Radiation Oncology, Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; E-Mail:
- Department of Radiation Oncology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Li-Chen Yen
- Division of Medical Research, Fooyin University Hospital, Pingtung 928, Taiwan; E-Mails: (L.-C.Y.); (F.-Y.C.)
| | - Hsueh-Chiao Liu
- Personalized Medical Service Center, Division of Laboratory Medicine, Fooyin University Hospital, Pingtung 928, Taiwan; E-Mail:
| | - Po-Ping Liu
- Department of Surgery, Fooyin University Hospital, Pingtung 928, Taiwan; E-Mail:
| | - Fu-Yen Chung
- Division of Medical Research, Fooyin University Hospital, Pingtung 928, Taiwan; E-Mails: (L.-C.Y.); (F.-Y.C.)
| | - Tsu-Nai Wang
- Department of Public Health, College of Health Science, Kaohsiung Medical University, Kaohsiung 807, Taiwan; E-Mail:
| | - Jaw-Yuan Wang
- Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Division of Gastrointestinal and General Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Shiu-Ru Lin
- Division of Medical Research, Fooyin University Hospital, Pingtung 928, Taiwan; E-Mails: (L.-C.Y.); (F.-Y.C.)
- School of Medical and Health Sciences, Fooyin University, Kaohsiung 831, Taiwan
| |
Collapse
|
|
17
|
WANG YONGXIANG, GU JIAXIANG, FENG XINMIN, WANG HUA, TAO YUPING, WANG JINGCHENG. Effects of Nogo-A receptor antagonist on the regulation of the Wnt signaling pathway and neural cell proliferation in newborn rats with hypoxic ischemic encephalopathy. Mol Med Rep 2013; 8:883-6. [DOI: 10.3892/mmr.2013.1579] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2013] [Accepted: 07/03/2013] [Indexed: 11/05/2022] Open
|
|
18
|
Lin CH, Liu CH, Tsai HL, Wang JY, Tsai HP, Chai CY. Expression of OV-6 in primary colorectal cancer and rectal cancer with preoperative chemoradiotherapy: a clinicopathological study. Histopathology 2013; 62:742-751. [PMID: 23445514 DOI: 10.1111/his.12075] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2012] [Accepted: 11/27/2012] [Indexed: 01/06/2023]
Abstract
AIMS OV-6 is among the best available markers of liver stem cells. The aim of this study was to investigate OV-6 expression and its clinical implications in colorectal cancer. METHODS AND RESULTS Expression of OV-6 and its clinical implications were investigated in 94 patients with American Joint Committee on Cancer (AJCC) stage I-III primary colorectal cancer and in 37 rectal cancer patients who had received preoperative chemoradiotherapy. The two main expression patterns of OV-6 were cytoplasmic and membranous. Overexpression of OV-6, which was identified on the basis of overall staining intensity, was associated with perineural invasion, lymphovascular invasion, and early relapses. Membranous OV-6 overexpression was also significantly associated with depth of tumour invasion, AJCC stage, lymphovascular and perineural invasion, and postoperative early relapse. Disease-free survival and overall survival were significantly poorer in patients with high overall OV-6 expression than in those with low overall OV-6 expression (P = 0.015 and P = 0.029, respectively), and significantly poorer in patients with high membranous OV-6 expression than in those with low membranous OV-6 expression (P < 0.001 and P < 0.001, respectively). Membranous OV-6 expression was a more reliable prognostic marker than overall expression. CONCLUSIONS OV-6 is not unique to the hepatobiliary system, and may be a novel prognostic marker in colorectal cancer.
Collapse
Affiliation(s)
- Chih-Hung Lin
- Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | | | | | | | | | | |
Collapse
|
|
19
|
Bao B, Azmi AS, Ali S, Ahmad A, Li Y, Banerjee S, Kong D, Sarkar FH. The biological kinship of hypoxia with CSC and EMT and their relationship with deregulated expression of miRNAs and tumor aggressiveness. BIOCHIMICA ET BIOPHYSICA ACTA 2012; 1826:272-96. [PMID: 22579961 PMCID: PMC3788359 DOI: 10.1016/j.bbcan.2012.04.008] [Citation(s) in RCA: 103] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/20/2012] [Revised: 04/25/2012] [Accepted: 04/28/2012] [Indexed: 12/13/2022]
Abstract
Hypoxia is one of the fundamental biological phenomena that are intricately associated with the development and aggressiveness of a variety of solid tumors. Hypoxia-inducible factors (HIF) function as a master transcription factor, which regulates hypoxia responsive genes and has been recognized to play critical roles in tumor invasion, metastasis, and chemo-radiation resistance, and contributes to increased cell proliferation, survival, angiogenesis and metastasis. Therefore, tumor hypoxia with deregulated expression of HIF and its biological consequence lead to poor prognosis of patients diagnosed with solid tumors, resulting in higher mortality, suggesting that understanding of the molecular relationship of hypoxia with other cellular features of tumor aggressiveness would be invaluable for developing newer targeted therapy for solid tumors. It has been well recognized that cancer stem cells (CSCs) and epithelial-to-mesenchymal transition (EMT) phenotypic cells are associated with therapeutic resistance and contribute to aggressive tumor growth, invasion, metastasis and believed to be the cause of tumor recurrence. Interestingly, hypoxia and HIF signaling pathway are known to play an important role in the regulation and sustenance of CSCs and EMT phenotype. However, the molecular relationship between HIF signaling pathway with the biology of CSCs and EMT remains unclear although NF-κB, PI3K/Akt/mTOR, Notch, Wnt/β-catenin, and Hedgehog signaling pathways have been recognized as important regulators of CSCs and EMT. In this article, we will discuss the state of our knowledge on the role of HIF-hypoxia signaling pathway and its kinship with CSCs and EMT within the tumor microenvironment. We will also discuss the potential role of hypoxia-induced microRNAs (miRNAs) in tumor development and aggressiveness, and finally discuss the potential effects of nutraceuticals on the biology of CSCs and EMT in the context of tumor hypoxia.
Collapse
Affiliation(s)
- Bin Bao
- Department of Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
| | - Asfar S. Azmi
- Department of Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
| | - Shadan Ali
- Department of Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
| | - Aamir Ahmad
- Department of Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
| | - Yiwei Li
- Department of Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
| | - Sanjeev Banerjee
- Department of Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
| | - Dejuan Kong
- Department of Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
| | - Fazlul H. Sarkar
- Department of Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
| |
Collapse
|
|
20
|
Shao X, Miao M, Qi X, Chen Z. Ras-proximate-1 GTPase-activating protein and Rac2 may play pivotal roles in the initial development of myelodysplastic syndrome. Oncol Lett 2012; 4:289-298. [PMID: 22844372 DOI: 10.3892/ol.2012.736] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2012] [Accepted: 05/09/2012] [Indexed: 11/06/2022] Open
Abstract
Myelodysplastic syndrome (MDS) is a stem cell disease that has a characteristic morphological dysplasia. Adhesion molecules and the Wnt signaling pathway are mostly involved with the self-renewal, proliferation and differentiation of hematopoietic stem cells (HSCs) while Rho GTPases are closely correlated with the cytoskeleton and therefore cell morphology. To gain insight into the poorly understood pathophysiology of MDS, the present study focused on analyzing the gene expression profiles of these molecules with whole genomic array using CD34(+) cells from MDS patients. These profiles showed that N-cadherin, E-cadherin and c-myc binding protein tended to be downregulated, whereas β-catenin, Ras-proximate-1 GTPase-activating protein (Rap1GAP), c-myc promoter binding protein, Rac1, Rac2 and CDC42 tended to be upregulated. However, no change in the expression of genes involved in the canonical Wnt signaling pathway, with the exception of β-catenin, was observed. The array results were confirmed by real-time quantitative polymerase chain reaction (RQ-PCR) using CD34(+) cells from a cohort of patients with MDS-refractory anemia (RA) [WHO (2008) RCUD, RCMD and MDS-U] who had normal karyotypes. Only Rap1GAP and Rac2 showed higher expression levels when mononuclear cells were used from another group of patients with MDS-RA [WHO (2008) RCUD, RCMD and MDS-U] who also had normal karyotypes. We believe that the cadherin-β-catenin-c-myc signaling axis is crucial in the hematopoiesis of HSCs in the early stages of MDS. In addition, Ras-proximate-1 (Rap1), which is negatively regulated by Rap1GAP, may serve as an initiator of this axis through interplay with cadherin. This pathway is strengthened by the upregulation of Rac2, which may allow the nuclear translocation of β-catenin. The aberrant expression of Rho GTPases may also be responsible for the dysplasia characteristics observed in MDS. This study provides vital and new insights into the pathophysiology of MDS. The two small G proteins, Rap1GAP and Rac2, may act as new molecular markers for the diagnosis of MDS.
Collapse
Affiliation(s)
- Xuejun Shao
- The First Affiliated Hospital, Soochow University, Jiangsu Institute of Hematology, Jiangsu, P.R. China
| | | | | | | |
Collapse
|
|
21
|
Liu W, Xing F, Iiizumi-Gairani M, Okuda H, Watabe M, Pai SK, Pandey PR, Hirota S, Kobayashi A, Mo YY, Fukuda K, Li Y, Watabe K. N-myc downstream regulated gene 1 modulates Wnt-β-catenin signalling and pleiotropically suppresses metastasis. EMBO Mol Med 2012; 4:93-108. [PMID: 22246988 PMCID: PMC3306556 DOI: 10.1002/emmm.201100190] [Citation(s) in RCA: 171] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2011] [Revised: 11/15/2011] [Accepted: 11/18/2011] [Indexed: 02/06/2023] Open
Abstract
Wnt signalling has pivotal roles in tumour progression and metastasis; however, the exact molecular mechanism of Wnt signalling in the metastatic process is as yet poorly defined. Here we demonstrate that the tumour metastasis suppressor gene, NDRG1, interacts with the Wnt receptor, LRP6, followed by blocking of the Wnt signalling, and therefore, orchestrates a cellular network that impairs the metastatic progression of tumour cells. Importantly, restoring NDRG1 expression by a small molecule compound significantly suppressed the capability of otherwise highly metastatic tumour cells to thrive in circulation and distant organs in animal models. In addition, our analysis of clinical cohorts data indicate that Wnt+/NDRG−/LRP+ signature has a strong predictable value for recurrence-free survival of cancer patients. Collectively, we have identified NDRG1 as a novel negative master regulator of Wnt signalling during the metastatic progression, which opens an opportunity to define a potential therapeutic target for metastatic disease.
Collapse
Affiliation(s)
- Wen Liu
- Department of Medical Microbiology, Southern Illinois University School of Medicine, Springfield, IL, USA
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
22
|
Wnt signaling and cardiac differentiation. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2012; 111:153-74. [PMID: 22917230 DOI: 10.1016/b978-0-12-398459-3.00007-1] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The Wnt family of secreted glycoproteins participates in a wide array of biological processes, including cellular differentiation, proliferation, survival, apoptosis, adhesion, angiogenesis, hypertrophy, and aging. The canonical Wnt signaling primarily utilizes β-catenin-mediated activation of transcription, while the noncanonical mechanisms involve a calcium-dependent protein kinase C-mediated Wnt/Ca(2+) pathway and a dishevelled-dependent c-Jun N-terminal kinase-mediated planar cell polarity pathway. Although both canonical and noncanonical Wnts have been implicated in cardiac specification, morphogenesis, and differentiation; the molecular events remain unclear and often depend on the cell type and biological context. In this regard, growing evidence indicates that Wnt11 is able to induce cardiogenesis not only during embryonic development but also in adult cells. The cardiogenic properties of Wnt11 may prove useful for preprogramming adult stem cells before myocardial transplantation. Further, elucidation of the molecular steps in Wnt11-induced cardiac differentiation will be necessary to enhance the outcomes of cardiac cell therapy.
Collapse
|
|
23
|
Goodman ZD, Terracciano LM, Wee A. Tumours and tumour-like lesions of the liver. MACSWEEN'S PATHOLOGY OF THE LIVER 2012:761-851. [DOI: 10.1016/b978-0-7020-3398-8.00014-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
24
|
Mikami T, Yoshida T, Numata Y, Kikuchi M, Araki K, Nakada N, Okayasu I. Invasive behavior of ulcerative colitis-associated carcinoma is related to reduced expression of CD44 extracellular domain: comparison with sporadic colon carcinoma. Diagn Pathol 2011; 6:30. [PMID: 21473743 PMCID: PMC3079596 DOI: 10.1186/1746-1596-6-30] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2010] [Accepted: 04/07/2011] [Indexed: 12/16/2022] Open
Abstract
Background To elucidate relations of invasion of ulcerative colitis (UC)-associated carcinoma with its prognosis, the characteristics of invasive fronts were analyzed in comparison with sporadic colonic carcinomas. Methods Prognoses of 15 cases of UC-associated colonic carcinoma were compared with those of sporadic colon carcinoma cases, after which 75 cases of sporadic invasive adenocarcinoma were collected. Tumor budding was examined histologically at invasive fronts using immunohistochemistry (IHC) of pancytokeratin. Expressions of beta-catenin with mutation analysis, CD44 extracellular domain, Zo-1, occludin, matrix matalloproteinase-7, laminin-5γ2, and sialyl Lewis X (LeX) were immunohistochemically evaluated. Results UC-associated carcinoma showed worse prognosis than sporadic colon carcinoma in all the cases, and exhibited a tendency to become more poorly differentiated when carcinoma invaded the submucosa or deeper layers than sporadic carcinoma. When the lesions were compared with sporadic carcinomas considering differentiation grade, reduced expression of CD44 extracellular domain in UC-associated carcinoma was apparent. Laminin-5γ2 and sialyl-LeX expression showed a lower tendency in UC-associated carcinomas than in their sporadic counterparts. There were no differences in the numbers of tumor budding foci between the two lesion types, with no apparent relation to nuclear beta-catenin levels in IHC. Conclusions UC-associated carcinoma showed poorer differentiation when the carcinoma invaded submucosa or deeper parts, which may influence the poorer prognosis. The invasive behavior of UC-associated carcinoma is more associated with CD44 cleavage than with basement membrane disruption or sialyl-Lewis-antigen alteration.
Collapse
Affiliation(s)
- Tetuo Mikami
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Japan.
| | | | | | | | | | | | | |
Collapse
|
|
25
|
Wang J, Barak LS, Mook RA, Chen W. Glucocorticoid hedgehog agonists in neurogenesis. VITAMINS AND HORMONES 2011; 87:207-15. [PMID: 22127244 DOI: 10.1016/b978-0-12-386015-6.00030-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
The process of neurogenesis in mammals, which is prolific and widespread at birth, gradually slows with aging and in humans becomes restricted to areas including the cerebellum and hippocampus. It has been reported that exposure to glucocorticoids can impair neurogenesis in both adults and children. Glucocorticoids are known to bind with high affinity to intracellular receptors. Glucocorticoid blood levels are normally regulated by environmental stresses, but because of their clinical utility, exogenous glucocorticoids are frequently administered in drug formulations. Consequently, concerns have arisen about the consequences of glucocorticoid use on neurogenesis and health, especially in the pediatric population. In this article, we will review recent findings that a select number of related glucocorticoids, halcinonide, fluticasone propionate, clobetasol propionate, and fluocinonide, also bind the hedgehog pathway receptor Smoothened. We will discuss their pharmacology and also a most surprising result; that this select group of compounds, which includes FDA approved drugs, unlike typical glucocorticoids such as dexamethasone, stimulate stem cell growth, and thus enhance neurogenesis.
Collapse
Affiliation(s)
- Jiangbo Wang
- Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA
| | | | | | | |
Collapse
|
|
26
|
A digest on the role of the tumor microenvironment in gastrointestinal cancers. CANCER MICROENVIRONMENT 2010; 3:167-76. [PMID: 21209782 DOI: 10.1007/s12307-010-0040-9] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/04/2009] [Accepted: 01/27/2010] [Indexed: 12/12/2022]
Abstract
Experimental studies and analyses of clinical material have convincingly demonstrated that tumor formation and progression occurs through a concerted action of malignant cells and the surrounding microenvironment of the tumor stroma. The tumor microenvironment is comprised of various cell types like fibroblasts, immune cells, vascular cells and bone-marrow-derived cells embedded in the extracellular matrix. This review, focusing on recent findings in the context of gastrointestinal tumors, introduces the different stromal cell types and delineates their contributions to cancer initiation, growth and metastasis. By selected examples we also present how the tumor microenvironment is emerging as a promising target for therapeutic intervention.
Collapse
|
|
27
|
Reduced beta-catenin expression is associated with good prognosis in Astrocytoma. Pathol Oncol Res 2009; 16:253-7. [PMID: 20182836 DOI: 10.1007/s12253-009-9219-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2009] [Accepted: 10/20/2009] [Indexed: 10/20/2022]
Abstract
The aim of this study was to evaluate the expression of beta-catenin in astrocytoma, and the clinical relevance and prognostic significance of the expression of beta-catenin was also analyzed. Immunohistochemistry was performed on 63 resected astrocytoma tumor specimens to detect the expression of beta-catenin. The correlation between the results of immuoexpression and the clinicopathologic parameters and patient survival was processed statistically. In 63 samples of astrocytoma, 36 cases were immunoreactive for beta-catenin at cytoplasm, ten cases of astrocytoma were immunoreactive at cytomembrane, and four cases of astrocytoma were stained for beta-catenin at nucleus. Spearman analysis showed that the distribution of beta-catenin was not correlated with the grades of astrocytoma. However, the expression profiles were correlated with the patient's 2-year survival, but not correlated with the grades, tumor size, sex, age, or tumor location. Patients with low beta-catenin expression levels tended to be associated with a better prognosis than those who with high levels (p = 0.042). Our results suggest that beta-catenin is useful for the prognosis evaluation of astrocytoma.
Collapse
|
|
28
|
Nakanuma Y, Zen Y, Harada K, Ikeda H, Sato Y, Uehara T, Sasaki M. Tumorigenesis and phenotypic characteristics of mucin-producing bile duct tumors: an immunohistochemical approach. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2009; 17:211-22. [PMID: 19680592 DOI: 10.1007/s00534-009-0158-7] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/01/2009] [Accepted: 04/30/2009] [Indexed: 12/13/2022]
Abstract
Intraductal papillary neoplasm of the bile duct (IPNB) is characterized by exophytic proliferation of neoplastic epithelial cells with fibrovascular stalks in bile duct lumen, mucin hypersecretion, and considerable dilatation or multilocular changes of the affected bile ducts. A mucin-producing bile duct tumor is an IPNB with excessive mucin production and clinical symptoms. Herein, the phenotypes as well as the tumorigenesis and progression of IPNB are reviewed with immunohistochemical assistance. The tumors are subdivided into three phenotypes: pancreatobiliary, intestinal, and gastric. About half of IPNB cases are of the pancreatobiliary type, and the remaining half are of the intestinal type. Aberrant expression of CDX2 with MUC2 and CK20 is related to the development of intestinal metaplasia. Inactivation of P16INK4a and nuclear expression of beta-catenin are related to the development of IPNB. Decreased expression of membranous beta-catenin and E-cadherin and aberrant expression of MMP-7 and -9 and of MUC1 are related to invasion of IPNB with tubular adenocarcinoma, whereas MUC2 is involved in the invasion of IPNB with mucinous carcinoma. IPNB can be regarded as a counterpart of intraductal papillary mucinous neoplasm (IPMN) of the pancreas, particularly the main duct type. More comparative studies between IPNB and pancreatic IPMN are recommended for further analysis of these papillary neoplasms.
Collapse
Affiliation(s)
- Yasuni Nakanuma
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, 920-8640, Japan.
| | | | | | | | | | | | | |
Collapse
|
|
29
|
Li AFY, Hsu PK, Tzao C, Wang YC, Hung IC, Huang MH, Hsu HS. Reduced axin protein expression is associated with a poor prognosis in patients with squamous cell carcinoma of esophagus. Ann Surg Oncol 2009; 16:2486-93. [PMID: 19582507 DOI: 10.1245/s10434-009-0593-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2008] [Revised: 04/22/2009] [Accepted: 05/19/2009] [Indexed: 12/20/2022]
Abstract
AIMS Our study investigates the significance of the expression of Wnt pathway proteins including beta-catenin, Axin, beta-transducin-repeat-containing protein (beta-TrCP), and adenomatous polyposis coli (APC) in squamous cell carcinoma of the esophagus (ESCC). METHODS Immunohistochemical analysis was performed on paraffin-embedded tissue specimens from 128 resected ESCC tumors to detect the expression of beta-catenin, Axin, beta-TrCP, and APC. Correlation between immunoexpression, clinicopathological parameters, and patient survival was analyzed. RESULTS Increased beta-catenin expression was noted in 22 (18.2%) of 121 tumor specimens. Reduced expression of Axin, beta-TrCP, and APC was observed in 57 (46.0%) of 124, 29 (24.4%) of 119, and 54 (48.2%) of 119 specimens, respectively. No correlation was found among these protein expressions. Axin protein expression was inversely correlated with tumor invasion depth (P = 0.033). Reduced Axin protein expression, lymph node involvement, and distant metastasis were significant negative predictors for overall survival and disease-free survival on univariate analysis. In multivariate analysis, reduced Axin expression remained a significant prognostic factor for patients with ESCC (P = 0.005). CONCLUSIONS Reduced Axin expression was observed in 46% of ESCC tumor specimens and was associated with poor prognosis in patients with ESCC. Further study is mandatory to elucidate the underlying mechanism responsible for loss of Axin expression and the role of Axin in ESCC tumorigenesis.
Collapse
Affiliation(s)
- Anna Fen-Yau Li
- Department of Pathology, Taipei Veterans General Hospital, Taipei, Taiwan
| | | | | | | | | | | | | |
Collapse
|
|
30
|
Darlavoix T, Seelentag W, Yan P, Bachmann A, Bosman FT. Altered expression of CD44 and DKK1 in the progression of Barrett's esophagus to esophageal adenocarcinoma. Virchows Arch 2009; 454:629-37. [PMID: 19396460 DOI: 10.1007/s00428-009-0769-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2008] [Revised: 03/26/2009] [Accepted: 03/30/2009] [Indexed: 12/24/2022]
Abstract
Barrett's esophagus (BE) is an acquired condition in which the normal lining of the esophagus is replaced by intestinal metaplastic epithelium. BE can evolve to esophageal adenocarcinoma (EAC) through low-grade dysplasia (LGD) and high-grade dysplasia (HGD). The only generally accepted marker for increased risk of EAC is the presence of HGD, diagnosed on endoscopic biopsies. More specific markers for the prediction of EAC risk are needed. A tissue microarray was constructed comprising tissue samples from BE, LGD, HGD, and EAC. Marker expression was studied by immunohistochemistry using antibodies against CD44, DKK1, CDX2, COX2, SOX9, OCT1, E-cadherin, and beta-catenin. Immunostaining was evaluated semi-quantitatively. CD44 expression decreased in HGD and EAC relative to BE and LGD. DKK1 expression increased in HGD and EAC relative to BE and LDG. CDX2 expression increased in HGD but decreased in EAC. COX2 expression decreased in EAC, and SOX9 expression increased only in the upper crypt epithelial cells in HGD. E-cadherin expression decreased in EAC. Nuclear beta-catenin was not significantly different between BE, LGD, and HGD. Loss of CD44 and gain of DKK1 expression characterizes progression from BE and LGD to HGD and EAC, and their altered expression might indicate an increased risk for developing an EAC. This observation warrants inclusion of these immunohistochemically detectable markers in a study with a long patient follow-up.
Collapse
Affiliation(s)
- T Darlavoix
- Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | | | | | | | | |
Collapse
|
|
31
|
Nakayama M, Hisatsune J, Yamasaki E, Isomoto H, Kurazono H, Hatakeyama M, Azuma T, Yamaoka Y, Yahiro K, Moss J, Hirayama T. Helicobacter pylori VacA-induced inhibition of GSK3 through the PI3K/Akt signaling pathway. J Biol Chem 2008; 284:1612-9. [PMID: 18996844 DOI: 10.1074/jbc.m806981200] [Citation(s) in RCA: 111] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Helicobacter pylori VacA toxin contributes to the pathogenesis and severity of gastric injury. We found that incubation of AZ-521 cells with VacA resulted in phosphorylation of protein kinase B (Akt) and glycogen synthase kinase-3beta (GSK3beta) through a PI3K-dependent pathway. Following phosphorylation and inhibition of GSK3beta,beta-catenin was released from a GSK3beta/beta-catenin complex, with subsequent nuclear translocation. Methyl-beta-cyclodextrin (MCD) and phosphatidylinositol-specific phospholipase C (PI-PLC), but not 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB) and bafilomycin A1, inhibited VacA-induced phosphorylation of Akt, indicating that it does not require VacA internalization and is independent of vacuolation. VacA treatment of AZ-521 cells transfected with TOPtkLuciferase reporter plasmid or control FOPtkLucifease reporter plasmid resulted in activation of TOPtkLuciferase, but not FOPtkLucifease. In addition, VacA transactivated the beta-catenin-dependent cyclin D1 promoter in a luciferase reporter assay. Infection of AZ-521 cells by a vacA mutant strain of H. pylori failed to induce phosphorylation of Akt and GSK3beta, or release of beta-catenin from a GSK3beta/beta-catenin complex. Taken together, these results support the conclusion that VacA activates the PI3K/Akt signaling pathway, resulting in phosphorylation and inhibition of GSK3beta, and subsequent translocation ofbeta-catenin to the nucleus, consistent with effects of VacA on beta-catenin-regulated transcriptional activity. These data introduce the possibility that Wnt-dependent signaling might play a role in the pathogenesis of H. pylori infection, including the development of gastric cancer.
Collapse
Affiliation(s)
- Masaaki Nakayama
- Department of Bacteriology, Institute of Tropical Medicine, Nagasaki University, Nagasaki 8528523, Japan
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
32
|
Ge X, Jin Q, Zhang F, Yan T, Zhai Q. PCAF acetylates {beta}-catenin and improves its stability. Mol Biol Cell 2008; 20:419-27. [PMID: 18987336 DOI: 10.1091/mbc.e08-08-0792] [Citation(s) in RCA: 96] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
beta-Catenin plays an important role in development and tumorigenesis. However, the effect of a key acetyltransferase p300/CBP-associated factor (PCAF) on beta-catenin signaling is largely unknown. In this study, we found PCAF could increase the beta-catenin transcriptional activity, induce its nuclear translocation, and up-regulate its protein level by inhibiting its ubiquitination and improving its stability. Further studies showed that PCAF directly binds to and acetylates beta-catenin. The key ubiquitination sites Lys-19 and Lys-49 of beta-catenin were shown as the critical residues for PCAF-induced acetylation and stabilization. Knockdown of PCAF in colon cancer cells markedly reduced the protein level, transcriptional activity, and acetylation level of beta-catenin; promoted cell differentiation; inhibited cell migration; and repressed xenografted tumorigenesis and tumor growth in nude mice. All these data demonstrate that PCAF acetylates beta-catenin and regulates its stability, and they raise the prospect that therapies targeting PCAF may be of clinical use in beta-catenin-driven diseases, such as colon cancer.
Collapse
Affiliation(s)
- Xinjian Ge
- Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and Graduate School of the Chinese Academy of Sciences, Shanghai, China
| | | | | | | | | |
Collapse
|
|
33
|
Dilek FH, Topak N, Aktepe F, Sahin O, Türel KS, Sahin DA, Dilek ON. E-cadherin, beta-catenin adhesion complex and relation to matrilysin expression in pT3 rectosigmoid cancers. Pathol Res Pract 2008; 204:809-815. [PMID: 18674869 DOI: 10.1016/j.prp.2008.05.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2008] [Revised: 04/29/2008] [Accepted: 05/19/2008] [Indexed: 01/27/2023]
Abstract
E-cadherin/beta-catenin complex has a critical role in cell-cell adhesion. beta-Catenin is a critical component of the highly conserved Wnt signaling pathway that regulates cell proliferation and differentiation. Wnt signaling leads to the stabilization of cytosolic beta-catenin and to translocation to the nucleus, where it binds with T-cell factor and promotes the transcription and changes in target gene expression, including matrix metalloproteinases. In this study, we analyzed paraffin-embedded specimens from 42 patients with pT3 rectosigmoid cancer for E-cadherin, beta-catenin, and matrix metalloproteinase-7(MMP-7, matrilysin) expression using immunohistochemistry. Seventy-four and 79% of tumors expressed beta-catenin and E-cadherin, respectively. Nuclear expression of beta-catenin was detected only in 26.1% of tumors. Forty-five percent of the rectosigmoid cancers showed strong expression of MMP-7. It was revealed that membranous or cytoplasmic beta-catenin expression was significantly related to E-cadherin and MMP-7 expression. No significant association was seen between E-cadherin, beta-catenin, or MMP-7 expression and some clinicopathologic features. Our results may contribute to the functional interaction between beta-catenin and MMP-7. Further studies on Wnt/beta-catenin and MMP-7 gene activity and protein expression are necessary to better understand the pathogenesis of colorectal carcinoma.
Collapse
Affiliation(s)
- Fatma Hüsniye Dilek
- Department of Pathology, School of Medicine, Kocatepe University, Afyonkarahisar, Turkey.
| | | | | | | | | | | | | |
Collapse
|
|
34
|
Hsu PK, Li AFY, Wang YC, Hsieh CC, Huang MH, Hsu WH, Hsu HS. Reduced membranous beta-catenin protein expression is associated with metastasis and poor prognosis in squamous cell carcinoma of the esophagus. J Thorac Cardiovasc Surg 2008; 135:1029-35. [PMID: 18455580 DOI: 10.1016/j.jtcvs.2007.11.007] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2007] [Revised: 08/29/2007] [Accepted: 11/09/2007] [Indexed: 11/24/2022]
Abstract
OBJECTIVES The aim of this study was to evaluate, by immunohistochemical analysis, the protein expression of beta-catenin and p53 in resected esophageal squamous cell carcinoma specimens. The clinical relevance and prognostic significance of the expression of these proteins were also analyzed. METHODS Immunohistochemistry was performed on paraffin-embedded tissue specimens from 68 resected esophageal squamous cell carcinoma tumor specimens to detect the expression of beta-catenin and p53. The correlation between the results of immunoexpression and the clinicopathologic parameters and patient survival was processed statistically. RESULTS Reduced membranous beta-catenin expression was noted in 43 (63.2%) of 68 tumor specimens. Increased expression of p53 was observed in 43 (63.2%) of 68 specimens. Reduced membranous beta-catenin protein expression was associated with the presence of distant metastasis (P = .006). Patients with reduced membranous beta-catenin expression had a worse prognosis than patients with normal membranous beta-catenin expression (P = .005). Patients with combined increased p53 and reduced membranous beta-catenin protein expression had the worst prognosis (P = .012). In a multivariate survival analysis, reduced membranous beta-catenin expression and nodal involvement were independent prognostic factors (P = .004 and .019, respectively). CONCLUSIONS Immunohistochemical analysis revealed that reduced membranous beta-catenin protein expression was associated with the presence of distant metastasis and a poor prognosis in patients with esophageal squamous cell carcinoma. Combined increased p53 and reduced membranous beta-catenin protein expression indicated a very poor prognosis in patients with esophageal squamous cell carcinoma. Further investigation is needed to understand the roles of beta-catenin and p53 in the tumorigenesis and metastasis of esophageal squamous cell carcinoma.
Collapse
Affiliation(s)
- Po-Kuei Hsu
- Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital, National Yang-Ming University, School of Medicine, Taipei, Taiwan
| | | | | | | | | | | | | |
Collapse
|
|
35
|
Loss of membrane localization and aberrant nuclear E-cadherin expression correlates with invasion in pancreatic endocrine tumors. Am J Surg Pathol 2008; 32:413-9. [PMID: 18300809 DOI: 10.1097/pas.0b013e31813547f8] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Decrease in E-cadherin is considered a molecular event in dysfunction of the cell-cell adhesion system, triggering invasion and metastasis in many malignancies, including those of endocrine origin. In addition, alterations in the cadherin-catenin system may also be involved in tumorigenesis. E-cadherin and beta-catenin, components of the Wnt signal transduction pathway, may serve as a common switch in central processes that regulate cellular differentiation and growth. The purpose of this study was to examine if abnormalities of the Wnt signaling pathway, specifically, E-cadherin and beta-catenin, occur in pancreatic endocrine tumors (PETs) and correlate these with clinicopathologic parameters. Tissue microarrays were constructed from 57 cases with 4 to 14 cores measuring 1.0 mm from each case. Size of tumor, presence or absences of necrosis, gross invasiveness/demarcation, lymphovascular invasion, and lymph node involvement and liver metastasis were recorded. The mitotic count, expressed per 50 high power fields (HPF) and MIB-1 index of the entire tumor were assessed. All the tissue microarray blocks were stained with commercially available antibodies to E-cadherin (cytoplasmic and extracellular domains), beta-catenin, APC, and GSK-3beta. Twenty-seven were male patients and 30 female, ranging in age from 23 to 80 years (mean, 51.7 y). Six patients had MEN1 syndrome and 1 von Hippel Lindau disease. The tumors ranged in size from 0.8 to 9.8 cm with a mean of 3.4 cm. Sixteen patients had lymph node spread and 7 had liver metastasis. The Ki-67 labeling index ranged from 1% to 30% and the mitotic counts from 0 to 27 per 50 HPF. Thirty of 57 cases (52.6%) cases showed abnormal beta-catenin expression. Thirteen of the 16 cases with lymph node metastasis and all 7 cases with liver spread showed abnormalities of beta-catenin immunostaining. Only 2 cases showed nuclear beta-catenin. The average size of tumors with beta-catenin abnormalities was 4.8 cm. Thirty-four of the 57 (59.6%) cases showed loss of normal membranous immunoreactivity for both antibodies E-cadherin, including nuclear localization in 18 cases with the antibody that recognizes the cytoplasmic domain. E-cadherin decrease and/or loss was identical to beta-catenin with the same 13 cases showing nodal involvement and all 7 cases with liver metastasis displaying aberrant E-cadherin staining. Seven of the 18 cases with nuclear E-cadherin had lymph node spread and 3 liver metastases. The mean size of the 34 cases with abnormal E-cadherin expression was 4.4 cm, compared to the series mean of 3.4 cm. Interestingly, cases with nuclear E-cadherin had a mean size of 5.2 cm. beta-catenin and E-cadherin abnormalities did not correlate with other clinicopathological parameters. All 57 cases showed cytoplasmic immunoreactivity for APC, and cytoplasmic and nuclear positivity for GSK-3beta. APC and GSK-3beta did not show any correlation with beta-catenin or E-cadherin staining. Abnormalities of beta-catenin and E-cadherin immunoexpression are seen in the majority of PETs. Nuclear beta-catenin is rare in PET but nuclear E-cadherin, a previously unrecognized staining pattern in PETs was seen 18 of 57 cases with the antibody detecting the cytoplasmic fragment of E-cadherin. Aberrant expression of both beta-catenin and E-cadherin correlated strongly with lymph node spread and liver metastases.
Collapse
|
|
36
|
Matusiewicz M, Krzystek-Korpacka M, Diakowska D, Grabowski K, Augoff K, Blachut K, Paradowski L, Kustrzeba-Wojcicka I, Piast M, Banas T. Serum sulfatase activity is more elevated in colonic adenomas than cancers. Int J Colorectal Dis 2008; 23:383-7. [PMID: 18193432 DOI: 10.1007/s00384-007-0434-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/13/2007] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS Elucidation of molecular basis of the adenomatous polyps (AP) and colorectal cancer (CRC) development is crucial for their prevention, early detection, and treatment. According to the recent discoveries, sulfatases are implied in extracellular matrix remodeling and degradation and also in the regulation of certain signaling pathways. However, their exact role in carcinogenesis remains unclear. Because the majority of CRCs arise from AP, the aim of our studies was the investigation of sulfatase activity in adenomas and adenocarcinomas and verification of possible usefulness of sulfatase activity determination as an indicator of the presence and discrimination between adenomas and carcinomas. PATIENT-METHODS: One hundred twenty individuals were enrolled in the study. We assayed serum sulfatase activity in 79 patients with colorectal neoplasms (38 CRC and 41 AP) and 41 controls. Enzyme activity was determined colorimetrically. RESULTS We found statistically higher serum sulfatase activity in patients with colonic neoplasms than in controls (124; 112-139 vs. 79.5; 73-87 U). The activity was more elevated in adenomas (149; 128-173 U) than in cancers (103; 90-112 U). Sulfatase activity exceeded the cutoff value in 71% of AP and 47% of CRC patients. It increased with number of adenomas and tended to decrease with tumor progression. CONCLUSIONS Sulfatases seem to be involved in the early stages of colonic neoplastic transformation which is reflected in their serum activity. The likelihood of elevated sulfatase activity is almost ten times higher in subjects with than without polyps. Sulfatase upregulation in majority of adenomas and their correlation tendencies warrants reconsideration of sulfatase determination as a possible diagnostic tool.
Collapse
Affiliation(s)
- Malgorzata Matusiewicz
- Medical Biochemistry Department, Wroclaw Medical University, Chalubinskiego 10, 50-368 Wroclaw, Poland.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
37
|
Huang D, Du X. Crosstalk between tumor cells and microenvironment via Wnt pathway in colorectal cancer dissemination. World J Gastroenterol 2008; 14:1823-7. [PMID: 18350618 PMCID: PMC2700405 DOI: 10.3748/wjg.14.1823] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Invasion and metastasis are the deadly face of malignant tumors. Considering the high rate of incidence and mortality of colorectal cancer, it is critical to determine the mechanisms of its dissemination. In the parallel investigation of the invasive front and tumor center area of colorectal cancer (CRC), observation of heterogeneous β-catenin distribution and epithelial-mesenchymal transition (EMT) at the invasive front suggested that there might be a crosstalk between tumor cells and the tumor microenvironment. Wnt signaling pathway is also involved in the cancer progression due to its key role in CRC tumorigenesis. Moreover, in recent years, there is increasing evidence that the regulators of microenvironment, including extracellular matrix, growth factors and inflammatory factors, are associated with the activation of Wnt pathway and the mobility of tumor cells. In this review, we will try to explain how these molecules trigger metastasis via the Wnt pathway.
Collapse
|
|
38
|
Hashimoto K, Shimizu Y, Suehiro Y, Okayama N, Hashimoto S, Okada T, Hiura M, Ueno K, Hazama S, Higaki S, Hamanaka Y, Oka M, Sakaida I, Hinoda Y. Hypermethylation status of APC inversely correlates with the presence of submucosal invasion in laterally spreading colorectal tumors. Mol Carcinog 2008; 47:1-8. [PMID: 17620311 DOI: 10.1002/mc.20363] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Little is known about epigenetic alterations in laterally spreading colorectal tumors (LSTs). The goal of the present study was to elucidate the epigenetic background of LSTs and compare the methylation status of DNA CpG islands (CGIs) with clinicopathologic features. Methylation of MINT1, MINT2, MINT31, p16, O(6)-methylguanine-DNA methyltransferase (MGMT), adenomatous polyposis coli (APC), and human MutL homologue 1 (hMLH1) in 42 LSTs was assessed by methylation-specific polymerase chain reaction (MSP) and compared with clinicopathologic parameters. The frequency of hypermethylation was 12.5% (4/32) for MINT1, 40.0% (16/40) for MINT2, 25.0% (10/40) for MINT31, 25.7% (9/35) for p16, 7.7% (3/39) for hMLH1, 26.5% (9/34) for MGMT, and 35.9% (14/39) for APC. APC methylation was inversely associated with submucosal invasion (P = 0.034), which was not found in any of 14 LST cases with APC methylation, whereas submucosal invasion was present in 8 of 25 (32.0%) cases without APC methylation. These data suggest that hypermethylation of APC could be a predictive marker for the absence of submucosal invasion of LSTs.
Collapse
Affiliation(s)
- Kazuo Hashimoto
- Department of Molecular Science and Applied Medicine (Gastroenterology and Hepatology), Yamaguchi University Graduate School of Medicine, 1-1-1 Minami Kogushi, Ube, Yamaguchi, Japan
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
39
|
Kim YD, Park CH, Kim HS, Choi SK, Rew JS, Kim DY, Koh YS, Jeung KW, Lee KH, Lee JS, Juhng SW, Lee JH. Genetic alterations of Wnt signaling pathway-associated genes in hepatocellular carcinoma. J Gastroenterol Hepatol 2008; 23:110-8. [PMID: 18171349 DOI: 10.1111/j.1440-1746.2007.05250.x] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Recently, abnormal activation of the Wnt pathway has been found to be involved in the carcinogenesis of HCC. However, the relationship between genetic changes in the Wnt pathway-associated genes and its protein expression has not been studied in patients with HCC and cirrhotic nodules. The purpose of this study is to explore the contribution of inappropriate activation of the Wnt pathway in liver carcinogenesis. METHODS Somatic mutation in exons 3-5 of AXIN1 and exon 3 of beta-catenin were analyzed by direct sequencing and expression of axin and beta-catenin proteins by immunohistochemistry in a series of 36 patients with HCC and cirrhosis. RESULTS The AXIN1 and beta-catenin gene mutations were observed in 25% (9/36) and 2.8% (1/36) of HCCs, respectively. All mutations detected in AXIN1 and beta-catenin genes were missense point mutations. Abnormal nuclear expression of beta-catenin was observed in 11 of 36 cases of HCCs (30.6%), but not in cirrhotic nodules. Reduced or absent expression of axin was seen in 24 of 36 HCCs (66.7%). The abnormal expression of beta-catenin and axin proteins was closely correlated with mutations of AXIN1 and beta-catenin (P < 0.0001 and P = 0.008, respectively). CONCLUSIONS These data suggest that mutation of AXIN1 gene is a frequent and late event for HCC associated with cirrhosis, and is correlated significantly with abnormal expression of axin and beta-catenin. Therefore, activation of Wnt signaling through AXIN1 rather than beta-catenin mutation might play an important role in liver carcinogenesis.
Collapse
Affiliation(s)
- Young-Dae Kim
- Department of Internal Medicine, College of Medicine, Chosun University, Gwangju, Korea
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
40
|
Itatsu K, Zen Y, Ohira S, Ishikawa A, Sato Y, Harada K, Ikeda H, Sasaki M, Nimura Y, Nakanuma Y. Immunohistochemical analysis of the progression of flat and papillary preneoplastic lesions in intrahepatic cholangiocarcinogenesis in hepatolithiasis. Liver Int 2007; 27:1174-84. [PMID: 17919228 DOI: 10.1111/j.1478-3231.2007.01577.x] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Two types of precursor lesions, flat-type 'biliary intraepithelial neoplasia (BilIN)' and papillary-type 'intraductal papillary neoplasm of the bile duct (IPNB)', are proposed in the tumorigenesis of intrahepatic cholangiocarcinoma (ICC) in hepatolithiasis. METHODS In this study, the participation of cancer-related molecules in the progression of these two precursor lesions was examined, using 64 hepatolithiatic livers with BilIN lesions (45 livers) and IPNB lesions (19 livers) and 10 hepatolithiatic livers without neoplastic lesions as a control. The expression of E-cadherin, beta-catenin, matrix metalloproteinase-7 (MMP-7), membrane type 1-MMP (MT1-MMP), cyclin D1 and c-myc was immunohistochemically examined. RESULTS The membranous expression of beta-catenin decreased along with the progression in both BilIN and IPNB lineages. Membranous expression of E-cadherin was significantly decreased in invasive ICC with BilIN and IPNB in comparison with non-invasive counterparts. MMP-7 and MT1-MMP were commonly expressed in invasive ICC with BilIN (100%), while non-invasive lesions (BilIN-1, -2, -3) and the IPNB lineage were only occasionally and weakly positive for these molecules. Cyclin D1 and c-myc, target molecules of Wnt signalling, were frequently positive in the IPNB lineage (65 and 54% respectively), and interestingly nuclear beta-catenin staining, reflecting activation of Wnt signalling, was observed only in the IPNB lineage (22%) (P<0.05). CONCLUSIONS Decreased membranous expression of beta-catenin and E-cadherin is an early event in the tumorigenesis of both BilIN and IPNB lineages. The expression of MMP-7 and MT1-MMP was closely associated with invasive growth of the BilIN lineage. The Wnt signalling pathway may play an important role in the tumorigenesis of the IPNB lineage.
Collapse
Affiliation(s)
- Keita Itatsu
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
41
|
Sun S, Lee NPY, Poon RTP, Fan ST, He QY, Lau GK, Luk JM. Oncoproteomics of hepatocellular carcinoma: from cancer markers' discovery to functional pathways. Liver Int 2007; 27:1021-38. [PMID: 17845530 DOI: 10.1111/j.1478-3231.2007.01533.x] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Hepatocellular carcinoma (HCC) is a heterogeneous cancer with no promising treatment and remains one of the most prevailing and lethal malignancies in the world. Researchers in many biological areas now routinely identify and characterize protein markers by a mass spectrometry-based proteomic approach, a method that has been commonly used to discover diagnostic biomarkers for cancer detection. The proteomic research platforms span from the classical two-dimensional polyacrylamide gel electrophoresis (2-DE) to the latest Protein Chip or array technology, which are often integrated with the MALDI (matrix-assisted laser-desorption ionization), SELDI (surface-enhanced laser desorption/ionization) or tandem mass spectrometry (MS/MS). New advances on quantitative proteomic analysis (e.g. SILAC, ICAT, and ITRAQ) and multidimensional protein identification technology (MudPIT) have greatly enhanced the capability of proteomic methods to study the expressions, modifications and functions of protein markers. The present article reviews the latest proteomic development and discovery of biomarkers in HCC that may provide insights into the underlying mechanisms of hepatocarcinogenesis and the readiness of biomarkers for clinical uses.
Collapse
Affiliation(s)
- Stella Sun
- Department of Surgery, LKS Faculty of Medicine, Jockey Club Clinical Research Center, The University of Hong Kong, Pokfulam, Hong Kong
| | | | | | | | | | | | | |
Collapse
|
|
42
|
Failor KL, Desyatnikov Y, Finger LA, Firestone GL. Glucocorticoid-induced degradation of glycogen synthase kinase-3 protein is triggered by serum- and glucocorticoid-induced protein kinase and Akt signaling and controls beta-catenin dynamics and tight junction formation in mammary epithelial tumor cells. Mol Endocrinol 2007; 21:2403-15. [PMID: 17595317 DOI: 10.1210/me.2007-0143] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Glucocorticoid hormones stimulate adherens junction and tight junction formation in Con8 mammary epithelial tumor cells and induce the production of a stable nonphosphorylated beta-catenin protein localized exclusively to the cell periphery. Glycogen synthase kinase-3 (GSK3) phosphorylation of beta-catenin is known to trigger the degradation of this adherens junction protein, suggesting that steroid-activated cascades may be targeting this protein kinase. We now demonstrate that treatment with the synthetic glucocorticoid dexamethasone induces the ubiquitin-26S proteasome-mediated degradation of GSK3 protein with no change in GSK3 transcript levels. In transfected cells, deletion of the N-terminal nine amino acids or mutation of the serine-9 phosphorylation site on GSK3-beta prevented its glucocorticoid-induced degradation. Expression of stabilized GSK3 mutant proteins ablated the glucocorticoid-induced tight junction sealing and resulted in production of a nonphosphorylated beta-catenin that localizes to both the nucleus and the cell periphery in steroid-treated cells. Serine-9 on GSK3 can be phosphorylated by Sgk (serum- and glucocorticoid-induced protein kinase) and by Akt. Expression of dominant-negative forms of either Sgk- or Akt-inhibited glucocorticoid induced GSK3 ubiquitination and degradation and disrupted the dexamethasone-induced effects on beta-catenin dynamics. Furthermore, the steroid-induced tight junction sealing is attenuated in cells expressing dominant-negative forms of either Sgk or Akt, although the effect of blunting Sgk signaling was significantly greater. Taken together, we have uncovered a new cellular cascade in which Sgk and Akt trigger the glucocorticoid-regulated phosphorylation, ubiquitination, and degradation of GSK3, which alters beta-catenin dynamics, leading to the formation of adherens junctions and tight junction sealing.
Collapse
Affiliation(s)
- Kim L Failor
- Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, California 94720-3200, USA
| | | | | | | |
Collapse
|
|
43
|
Stein U, Schlag PM. Clinical, biological, and molecular aspects of metastasis in colorectal cancer. RECENT RESULTS IN CANCER RESEARCH. FORTSCHRITTE DER KREBSFORSCHUNG. PROGRES DANS LES RECHERCHES SUR LE CANCER 2007; 176:61-80. [PMID: 17607917 DOI: 10.1007/978-3-540-46091-6_7] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Colorectal cancer is one of the most frequent malignant tumors with a still increasing incidence in Western countries. Currently, colorectal cancer is the second most common cancer in Europe both in terms of incidence and mortality. Approximately 90% of all cancer deaths arise from the metastatic dissemination of primary tumors. Thus, metastasis is the most lethal attribute of colorectal cancer. Today, colorectal cancer and metastasis thereof are understood as the results of early changes during tumor progression that determine the metastasis capacity. Much is known about molecules contributing to the metastasis phenotype, the pathways they control, and the genes they regulate. However, patient prognosis is mainly defined by histopathological staging, a static description of the anatomical extent of tumor spread within a surgical specimen. This review demonstrates the need for and possibilities of molecular-based staging as an essential prerequisite for improved diagnosis, prognosis, and therapy. Molecular determinants for progression and metastasis of colorectal cancer are discussed representing both potential markers for metastasis prognosis and targets for intervention strategies aiming at the ultimate goal of metastasis prevention.
Collapse
Affiliation(s)
- Ulrike Stein
- Max Delbrück Center for Molecular Medicine, Berlin, Germany
| | | |
Collapse
|
|
44
|
Jilong Y, Jian W, Xiaoyan Z, Xiaoqiu L, Xiongzeng Z. Analysis of APC/beta-catenin genes mutations and Wnt signalling pathway in desmoid-type fibromatosis. Pathology 2007; 39:319-25. [PMID: 17558858 DOI: 10.1080/00313020701329823] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
OBJECTIVE The abnormalities of the Wnt signalling pathway in desmoid-type fibromatosis were analysed, with the purpose of exploring the mechanism of tumorigenesis and progression. METHODS The clinical and histopathological features of 96 cases were analysed. Beta-catenin, cyclin-D1, c-myc, and Ki-67 proteins were detected in 69 cases using formalin-fixed, paraffin-embedded tissues. Using the same materials, apoptosis of the tumour cells was investigated by terminal deoxynucleotidyl transferase mediated dUTP nick end-labelling (TUNEL) testing. Polymerase chain reaction (PCR), denaturing high performance liquid chromatography (DHPLC) assay, and sequencing were performed to detect abnormalities of the adenomatous polyposis coli (APC) and beta-catenin genes. RESULTS APC gene mutations were found in 18 cases (26.1%, 18/69). Somatic mutations of codon 41 in exon 3 of beta-catenin were detected in 13 cases (18.8%, 13/69). No correlation of beta-catenin abnormal expression with the mutations of APC gene or beta-catenin gene was identified (p>0.05). The cases with abnormal beta-catenin expression showed a higher level of c-myc protein expression (69.7%, 23/33) than those without (22.2%, 8/36, p = 0.001). The apoptotic indices (AIs) were significantly lower in cyclin-D1 positive cases and c-myc positive cases (p = 0.015, p = 0.007). CONCLUSIONS There are somatic mutations of the APC and beta-catenin gene in desmoid-type fibromatosis, and there are abnormalities in the Wnt signalling pathway. These abnormalities may result in aberrant cell proliferation and apoptosis, which are likely to be important factors in tumorigenesis and progression.
Collapse
Affiliation(s)
- Yang Jilong
- Department of Bone and Soft Tissue Tumor, Cancer Hospital, Tianjin Medical University. Tianjin, China.
| | | | | | | | | |
Collapse
|
|
45
|
Monahan TS, Andersen ND, Panossian H, Kalish JA, Daniel S, Shrikhande GV, Ferran C, Logerfo FW. A novel function for cadherin 11/osteoblast-cadherin in vascular smooth muscle cells: modulation of cell migration and proliferation. J Vasc Surg 2007; 45:581-9. [PMID: 17321345 DOI: 10.1016/j.jvs.2006.12.016] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2006] [Accepted: 12/03/2006] [Indexed: 01/06/2023]
Abstract
OBJECTIVE Intimal hyperplasia is a common cause of vein graft failure in cardiovascular surgery. The molecular basis for intimal hyperplasia remains poorly defined. We have previously identified, by gene chip analysis of vein grafts, increased messenger (mRNA) for the adhesion molecule cadherin 11/osteoblast-cadherin (CDH11). The function of CDH11 in vascular cells is unknown. The aim of the present study is to confirm CDH11 expression in vein grafts and characterize its role in vascular remodeling. METHODS Cephalic vein interposition grafts were implanted in a canine model and harvested at predetermined time points. CDH11 protein expression was determined by immunohistochemistry. Early passage human coronary artery smooth muscle cells (SMCs) were used for in vitro studies. Real-time polymerase chain reaction was used to assess cellular CDH11 mRNA levels. CDH11 signaling was inhibited by either transfection with silencing RNA targeting CDH11 or with a blocking antibody to CDH11. Cellular migration was evaluated and cellular proliferation was assessed. RESULTS Expression of CDH11 was increased in medial SMCs of vein grafts recovered at 7, 14, and 30 days after surgery compared with control veins from the same animals. In vitro CDH11 mRNA was up-regulated 1.8 +/- 0.2-fold (P = .003) in SMCs after treatment with tumor necrosis factor-alpha. Cellular migration was attenuated by inhibition of CDH11 both with a blocking antibody (0.67 +/- 0.09; P = .063) and gene knockdown mediated by small interfering RNA (0.67 +/- 0.14; P = .036). SMC proliferation decreased by 3.1-fold (P = .006) in the presence of CDH11-blocking antibody. Knockdown of CDH11 mediated by small interfering RNA resulted in a 1.3-fold (P = .018) decrease in proliferation. CONCLUSIONS CDH11 is up-regulated in SMC in vivo and in vitro as part of the response to injury. Inhibition of CDH11 decreases SMC migration and proliferation, two pathogenic effectors of intimal hyperplasia.
Collapse
MESH Headings
- Anastomosis, Surgical
- Animals
- Antibodies/pharmacology
- Cadherins/biosynthesis
- Cadherins/genetics
- Cadherins/immunology
- Cell Cycle/drug effects
- Cell Movement
- Cell Proliferation
- Cells, Cultured
- Coronary Vessels/metabolism
- Coronary Vessels/physiopathology
- Dogs
- Femoral Artery/surgery
- Humans
- Hyperplasia
- Models, Animal
- Muscle, Smooth, Vascular/drug effects
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Muscle, Smooth, Vascular/physiopathology
- Myocytes, Smooth Muscle/drug effects
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- RNA Interference
- RNA, Messenger/metabolism
- RNA, Small Interfering/metabolism
- Time Factors
- Tumor Necrosis Factor-alpha/pharmacology
- Up-Regulation
- Veins/metabolism
- Veins/physiopathology
- Veins/transplantation
Collapse
Affiliation(s)
- Thomas S Monahan
- Department of Surgery, Division of Vascular Surgery, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | | | | | | | | | | | | | | |
Collapse
|
|
46
|
Oishi Y, Nagasaki K, Miyata S, Matsuura M, Nishimura SI, Akiyama F, Iwai T, Miki Y. Functional pathway characterized by gene expression analysis of supraclavicular lymph node metastasis-positive breast cancer. J Hum Genet 2007; 52:271-279. [PMID: 17285241 DOI: 10.1007/s10038-007-0111-z] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2006] [Accepted: 12/22/2006] [Indexed: 11/26/2022]
Abstract
The outcome of breast cancer patients with supraclavicular lymph node metastasis is generally poor, but some patients do survive for a long time. Consequently, the ability to predict the outcome is important in terms of choosing the appropriate therapy for breast cancer patients with supraclavicular lymph node metastasis. In this study, we attempted to identify functional pathways that determine the outcome of breast cancer patients with supraclavicular lymph node metastasis by profiling cDNA microarrays. Thirty-one breast cancer patients with supraclavicular lymph node metastasis without distant metastasis comprised the study cohort; these were divided into three groups based on prognosis - poor, intermediate, and good. Two functional pathways, the Wnt signaling pathway and the mitochondrial apoptosis pathway, were constructed using six genes (DVL1, VDAC2, BIRC5, Stathmin1, PARP1, and RAD21) that were differently expressed between the good and poor outcome groups. Our results indicate that these two functional pathways may play an important role in determining the outcome of breast cancer patients with supraclavicular lymph node metastasis. We also determined that immunohistostaining for the Stathmin1 gene product is a potential tool for predicting the outcome of breast cancer patients with supraclavicular lymph node metastasis.
Collapse
Affiliation(s)
- Yoko Oishi
- Department of Molecular Diagnosis, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
- Department of Vascular Surgery, Tokyo Medical and Dental University, Tokyo, Japan
| | - Koichi Nagasaki
- Genome Center, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Satoshi Miyata
- Genome Center, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Masaaki Matsuura
- Genome Center, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Sei-Ichiro Nishimura
- Department of Breast surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Futoshi Akiyama
- Department Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Takehisa Iwai
- Department of Vascular Surgery, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yoshio Miki
- Department of Molecular Diagnosis, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
- Genome Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
- Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
| |
Collapse
|
|
47
|
Zhang Z, Schittenhelm J, Guo K, Bühring HJ, Trautmann K, Meyermann R, Schluesener HJ. Upregulation of frizzled 9 in astrocytomas. Neuropathol Appl Neurobiol 2006; 32:615-24. [PMID: 17083476 DOI: 10.1111/j.1365-2990.2006.00770.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Wnt/frizzled (FZD) cascades play important roles in controlling cell fate, proliferation, migration, tissue architecture and organogenesis during embryonic development and in adult organisms. The potential involvement of this pathway in tumorigenesis has been established in several types of cancers. Frizzled 9 (FZD9) is expressed in brain and its aberrant expression in gastric cancer was observed. However, its association with astrocytomas remains unknown therefore we studied FZD9 expression in astrocytomas of different malignancy. In the present study, FZD9 expression in 25 astrocytomas was investigated using immunohistochemistry with specific antibodies. Further FZD9 expression in native human brain tissue and glioblastoma cell line were analysed using real-time reverse transcription polymerase chain reaction (RT-PCR). In human astrocytomas, FZD9 immunoreactivity (IR) was observed in both microvessels and neoplastic cells. The percentage of FZD9+ microvessels in relation to FZD9+ vessels was significantly higher in malignant astrocytomas than in low-grade astrocytomas and positively correlated with the astrocytoma World Health Organization (WHO) grading (r = 1, P = 0.04). Furthermore, the FZD9 IR scores positively correlated with astrocytoma WHO grading (r = 1, P = 0.04) and proliferating activity (r = 0.77, P < 0.001). Real-time RT-PCR data showed that FZD9 expression in human glioblastoma was significant higher than in normal brain (P < 0.05) but FZD9 expression was only slightly induced in cobalt chloride-treated human glioblastoma T98G cells compared with untreated cells (P > 0.05). FZD9 is upregulated in astrocytomas, suggesting that FZD9 could be important in the tumorigenesis of human astrocytomas.
Collapse
Affiliation(s)
- Z Zhang
- Institute of Brain Research, University of Tuebingen, Tuebingen, Germany.
| | | | | | | | | | | | | |
Collapse
|
|
48
|
Steffensen IL, Schut HAJ, Nesland JM, Tanaka K, Alexander J. Role of nucleotide excision repair deficiency in intestinal tumorigenesis in multiple intestinal neoplasia (Min) mice. MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS 2006; 611:71-82. [PMID: 16962818 DOI: 10.1016/j.mrgentox.2006.07.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/07/2006] [Revised: 06/23/2006] [Accepted: 07/08/2006] [Indexed: 10/24/2022]
Abstract
Mice deficient in the Xeroderma pigmentosum group A (Xpa) gene are defective in nucleotide excision repair (NER) and highly susceptible to skin carcinogenesis after dermal exposure to UV light or chemicals. Min (multiple intestinal neoplasia) mice, heterozygous for a germline nonsense mutation in the tumor suppressor gene adenomatous polyposis coli (Apc), develop intestinal tumors spontaneously and show additional intestinal tumors after exposure to the food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). In this study, we investigated the impact of loss of XPA function on PhIP-induced intestinal tumorigenesis in F1 offspring of Min/+ (Apc(+/-)) mice crossed with Xpa gene-deficient mice. Apc(+/-) mice lacking both alleles of Xpa had higher susceptibility towards toxicity of PhIP, higher levels of PhIP-DNA adducts in the middle and distal small intestines, as well as in liver, and a higher number of small intestinal tumors at 11 weeks, compared with Apc(+/-) mice with one or two intact Xpa alleles. Localization of tumors was not affected, being highest in middle and distal small intestines in all genotypes. At 11 weeks of age, the number of spontaneous intestinal tumors was not significantly increased by homozygous loss of Xpa, but untreated Apc(+/-)/Xpa(-/-) mice had significantly shorter life-spans than their XPA-proficient littermates. Heterozygous loss of Xpa did not affect any of the measured end points. In conclusion, the Xpa gene and the NER pathway are involved in repair of bulky PhIP-DNA adducts in the intestines and the liver, and most probably of DNA lesions leading to spontaneous intestinal tumors. These results confirm a role of the NER pathway also in protection against cancer in internal organs, additional to its well-known importance in protection against skin cancer. An effect of Apc(+/-) on adduct levels, additional to that of Xpa(-/-), indicates that the truncated APC protein may affect a repair pathway other than NER.
Collapse
Affiliation(s)
- Inger-Lise Steffensen
- Department of Food Toxicology, Division of Environmental Medicine, Norwegian Institute of Public Health, NO-0403 Oslo, Norway.
| | | | | | | | | |
Collapse
|
|
49
|
Qi J, Zhu YQ, Luo J, Tao WH. Hypermethylation and expression regulation of secreted frizzled-related protein genes in colorectal tumor. World J Gastroenterol 2006; 12:7113-7. [PMID: 17131472 PMCID: PMC4087771 DOI: 10.3748/wjg.v12.i44.7113] [Citation(s) in RCA: 93] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the functions of promoter hyper-methylation of secreted frizzled-related proteins (sFRPs) genes in colorectal tumorigenesis and progression.
METHODS: The promoter hypermethylation and expression of sFRP genes in 72 sporadic colorectal carcinomas, 33 adenomas, 18 aberrant crypt foci (ACF) and colorectal cancer cell lines RKO, HCT116 and SW480 were detected by methylation-specific PCR and reverse transcription PCR, respectively.
RESULTS: None of the normal colorectal mucosa tissues showed methylated bands of any of four sFRP genes. sFRP1, 2, 4 and 5 were frequently methylated in colorectal carcinoma, adenoma and ACF (sFRP1 > 85%, sFRP2 >75%, sFRP5 > 50%), and the differences between three colorectal tissues were not significant (P > 0.05). Methylation in colorectal tumors was more frequent than in normal mucosa and adjacent normal mucosa. The mRNA of sFRP1-5 genes was expressed in all normal colorectal mucosa samples. Expression of sFRP1, 2, 4 and 5 and sFRP1, 2 and 5 was downregulated in carcinoma and adenoma, respectively. The downregulation of sFRP2, 4 and 5 was more frequent in carcinoma than in adenoma. Expression of sFRP3 which promoter has no CpG island was downregulated in only a few of colorectal tumor samples (7/105). The downregulation of sFRP1, 2, 4 and 5 expression was significantly associated with promoter hypermethylation in colorectal tumor. After cells were treated by DAC/TSA combination, the silenced sFRP mRNA expression could be effectively re-expressed in colorectal cancer cell lines.
CONCLUSION: Hypermethylation of sFRP genes is a common early event in the evolution of colorectal tumor, occurring frequently in ACF, which is regarded as the earliest lesion of multistage colorectal carcinogenesis. It appears to functionally silence sFRP genes expression. Methylation of sFRP1, 2 and 5 genes might serve as indicators for colorectal tumor.
Collapse
Affiliation(s)
- Jian Qi
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei Province, China
| | | | | | | |
Collapse
|
|
50
|
Weber A, Hengge UR, Stricker I, Tischoff I, Markwart A, Anhalt K, Dietz A, Wittekind C, Tannapfel A. Protein microarrays for the detection of biomarkers in head and neck squamous cell carcinomas. Hum Pathol 2006; 38:228-38. [PMID: 17020778 DOI: 10.1016/j.humpath.2006.07.012] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2006] [Revised: 07/18/2006] [Accepted: 07/25/2006] [Indexed: 11/17/2022]
Abstract
Protein microarrays are of increasing importance for high-throughput screening of fresh tissues. In our study, protein microarrays were generated by printing antibodies onto membranes to characterize protein profiles expressed by head and neck squamous cell carcinomas (HNSCCs). Cellular proteomes of 30 matched normal squamous epithelial cells and carcinoma specimens were analyzed after tissue microdissection using microarrays composed of 83 different antibodies. As controls, Western blot analysis and tissue microarrays (TMAs) containing 98 HNSCC specimens were used. Of the 83 proteins examined, 14 showed differential expression between HNSCCs and normal epithelium. The protein microarray approach revealed an upregulation of 8 proteins and a downregulation of 6 proteins. Bag-1, Cox-2, Hsp-70, Stat3, pescadillo, MMP-7 (matrilysin), IGF-2, and cyclin D1 were identified to be significantly upregulated, whereas suppressor of cytokine signaling 1, thrombospondin, TGF-beta1, Jun, Fos, and Fra-2 were downregulated. The differential expression of these proteins was confirmed using Western blot and TMA. Upon correlation of differentially regulated proteins with the clinicopathologic data of our patients, MMP-7 (matrilysin) was found to be associated with survival in univariate, but not multivariate, analysis. These data indicate that our protein arrays provide protein information in a systematic, reproducible, and also high-throughput fashion.
Collapse
Affiliation(s)
- Anette Weber
- Department of ENT, University of Leipzig, 04103 Leipzig, Germany
| | | | | | | | | | | | | | | | | |
Collapse
|