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Ren SS, Yuan F, Liu YH, Zhou LT, Li J. Effect of p27 gene combined with Pientzehuang ([characters: see text]) on tumor growth in osteosarcoma-bearing nude mice. Chin J Integr Med 2014; 21:830-6. [PMID: 25141818 DOI: 10.1007/s11655-014-1766-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2011] [Indexed: 12/31/2022]
Abstract
OBJECTIVE To observe the effect of p27 gene recombinant adenovirus combined with Chinese medicine Pientzehuang ([characters: see text]) on the growth of xenografted human osteosarcoma in nude mice. METHODS Tissue transplantation was used to construct the orthotopic model of human osteosarcoma Saos-2 cell in nude mice. Thirty tumor-bearing nude mice were randomly divided into 5 groups with 6 mice in each group: blank control group (model of osteosarcoma), empty vector group (recombinant adeno-associated virus-multiple cloning site), Pientzehuang group, p27 gene group and combined treatment group (p27 gene combined with Pientzehuang). The effect of combined treatment on human osteosarcoma was analyzed through the tumor formation, tumor volume and inhibition rate of tumor growth. The expression of p27 was measured by immunohistochemical staining and Western blot. RESULTS The orthotopic model of osteosarcoma in nude mice was successfully constructed. The general appearance of tumor-bearing nude mice in Pientzehuang and p27 gene groups was markedly improved compared with the blank control group; and in the combined treatment group it was significantly improved compared with the Pientzehuang and p27 gene groups. The tumor growth in the Pientzehuang and p27 gene groups was significantly inhibited compared with the blank control group P<0.05); while in the combined treatment group it was markedly inhibited compared with the Pientzehuang and p27 gene groups (P<0.05). The rates of tumor growth inhibition were 34.1%, 56.5% and 63.8% in the Pientzehuang, p27 gene and combined treatment groups, respectively. Meanwhile, the protein expression of p27 gene in the p27 gene group was significantly increased compared with the blank control group (P<0.05); and it was significantly increased in the combined treatment group compared with the p27 gene and Pientzehuang groups (P<0.05). CONCLUSION p27 gene introduced by adenovirus combined with Pientzehuang can inhibit the growth of human osteosarcoma cell Saos-2 in nude mice.
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Affiliation(s)
- Shou-song Ren
- Cheeloo Health Science Center of Shandong University, Jinan, 250012, China.,Department of Spine Surgery, Jimo City People's Hospital, Qingdao, Shandong Province, 266200, China
| | - Fang Yuan
- Department of Nephrology, the Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Ying-hong Liu
- Department of Nephrology, the Second Xiangya Hospital, Central South University, Changsha, 410011, China.
| | - Le-tian Zhou
- Department of Nephrology, the Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Jun Li
- Department of Nephrology, the Second Xiangya Hospital, Central South University, Changsha, 410011, China
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Anagnostopoulos GK, Stefanou D, Arkoumani E, Karagiannis J, Paraskeva K, Chalkley L, Habilomati E, Tsianos E, Agnantis NJ. Immunohistochemical expression of cell-cycle proteins in gastric precancerous lesions. J Gastroenterol Hepatol 2008; 23:626-31. [PMID: 18397488 DOI: 10.1111/j.1440-1746.2007.05219.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND The early indicator for the subject predisposed to gastric cancer is abnormal proliferation of gastric epithelial cells, such as atrophic gastritis (AG), intestinal metaplasia (IM), and dysplasia, which have been considered as precancerous lesions of gastric cancer. To determine whether p53 protein, cyclins D1, and D3, and p27(kip1) play a role in the carcinogenesis pathway of gastric cancer, we performed an immunohistochemical study of their expression in gastric precancerous lesions. METHODS A total of 1 45 endoscopic gastric biopsy specimens of AG, IM, and gastric dysplasia were studied. These molecular markers were localized by immunohistochemistry. RESULTS P53 was expressed in 15% of cases with gastric dysplasia and not in the pre-dysplastic stages of the gastric mucosa. All cases were concerning high-grade dysplasia. Cyclin D1 protein was almost undetectable in the precancerous lesions of gastric cancer. Cyclin D3 protein overexpression was seen in 10% of biopsies with IM, and 50% of biopsies with gastric dysplasia. High expression of p27(kip1) protein was demonstrated in all cases of chronic gastritis. As atrophy, IM, and dysplasia develop, expression of p27(kip1) protein is suppressed. In total, 15% of dysplastic cases showed no expression of p27(kip1) protein. CONCLUSIONS (i) P53 mutation must be a late event during the development of gastric cancer. (ii) Cyclin D1 protein overexpression may not play a role in the progression from normal to neoplastic gastric mucosa, while overexpression of cyclin D3 is an earlier event during gastric carcinogenesis, and its role must be further evaluated. (iii) Reduced expression of p27(kip1) is a rather early event in gastric tumorigenesis, before dysplastic changes occur.
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Mattioli E, Vogiatzi P, Sun A, Abbadessa G, Angeloni G, D'Ugo D, Trani D, Gaughan JP, Vecchio FM, Cevenini G, Persiani R, Giordano A, Claudio PP. Immunohistochemical analysis of pRb2/p130, VEGF, EZH2, p53, p16(INK4A), p27(KIP1), p21(WAF1), Ki-67 expression patterns in gastric cancer. J Cell Physiol 2007; 210:183-91. [PMID: 16998811 DOI: 10.1002/jcp.20833] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Although the considerable progress against gastric cancer, it remains a complex lethal disease defined by peculiar histological and molecular features. The purpose of the present study was to investigate pRb2/p130, VEGF, EZH2, p53, p16(INK4A), p27(KIP1), p21(WAF1), Ki-67 expressions, and analyze their possible correlations with clinicopathological factors. The expression patterns were examined by immunohistochemistry in 47 patients, 27 evaluated of intestinal-type, and 20 of diffuse-type, with a mean follow up of 56 months and by Western blot in AGS, N87, KATO-III, and YCC-2, -3, -16 gastric cell lines. Overall, stomach cancer showed EZH2 correlated with high levels of p53, Ki-67, and cytoplasmic pRb2/p130 (P < 0.05, and P < 0.01, respectively). Increased expression of EZH2 was found in the intestinal-type and correlated with the risk of distant metastasis (P < 0.05 and P < 0.01, respectively), demonstrating that this protein may have a prognostic value in this type of cancer. Interestingly, a strong inverse correlation was observed between p27(KIP1) expression levels and the risk of advanced disease and metastasis (P < 0.05), and a positive correlation between the expression levels of p21(WAF1) and low-grade (G1) gastric tumors (P < 0.05), confirming the traditionally accepted role for these tumor-suppressor genes in gastric cancer. Finally, a direct correlation was found between the expression levels of nuclear pRb2/p130 and low-grade (G1) gastric tumors that was statistically significant (P < 0.05). Altogether, these data may help shed some additional light on the pathogenetic mechanisms related to the two main gastric cancer histotypes and their invasive potentials.
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Affiliation(s)
- Eliseo Mattioli
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania 19122, USA
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Galizia G, Ferraraccio F, Lieto E, Orditura M, Castellano P, Imperatore V, La Manna G, Pinto M, Ciardiello F, La Mura A, De Vita F. p27 downregulation and metallothionein overexpression in gastric cancer patients are associated with a poor survival rate. J Surg Oncol 2006; 93:241-52. [PMID: 16482605 DOI: 10.1002/jso.20402] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
BACKGROUND AND OBJECTIVES As a significant number of curatively treated gastric cancer patients will ultimately relapse, there is an urgent need to investigate new prognostic markers for identification of high-risk patients. In this study, we investigated the possible role of molecular markers involved in cell cycle regulation (B1 and D3 cyclins, and p27) and cell protection (metallothionein, MT) in predicting tumor behavior and clinical outcome in gastric cancer patients. METHODS Analysis of the above indicators was performed by immunohistochemistry on 73 gastric cancer patient samples and 25 normal gastric mucosa specimens. RESULTS Normal gastric mucosa cells displayed low expressions of B1 and D3 cyclins and MT, and intense p27 staining. Conversely, gastric tumor cells showed higher cyclin D3 and MT, and lower p27 expressions. B1 cyclin expressions were not different between normal and tumor tissue. p27 and MT expressions were altered in almost all cancer samples, and were strongly correlated with tumor progression. Advanced extent of the primary tumor, nodal metastasis, low p27, and high MT expressions were the best combination of variables for prediction of poor clinical outcome. Each marker predicted outcome better than staging based on tumor-node (TNM) system. Survival and recurrence rates decreased as molecular alterations increased. Finally, molecular profile determination correctly predicted the prognosis in patients with same TNM stage. CONCLUSIONS p27 and MT expressions strongly correlated with clinical outcome allowing to identify an unfavorable group of patients that may benefit from tailored treatments. The role of B1 and D3 cyclins in gastric cancer remains to be elucidated.
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Affiliation(s)
- Gennaro Galizia
- Division of Surgical Oncology, F. Magrassi-A. Lanzara Department of Clinical and Experimental Medicine and Surgery, Second University of Naples School of Medicine, Naples, Italy.
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Kuzushita N, Rogers AB, Monti NA, Whary MT, Park MJ, Aswad BI, Shirin H, Koff A, Eguchi H, Moss SF. p27kip1 deficiency confers susceptibility to gastric carcinogenesis in Helicobacter pylori-infected mice. Gastroenterology 2005; 129:1544-56. [PMID: 16285954 DOI: 10.1053/j.gastro.2005.07.056] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2004] [Accepted: 07/21/2005] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Determining how Helicobacter pylori promotes gastric cancer and whether H pylori eradication decreases cancer risk would be helped by suitable murine models. Mice lacking the cyclin-dependent kinase inhibitor p27kip1 are susceptible to carcinogen-induced tumors. Furthermore, p27 stimulates gastric epithelial apoptosis and inhibits proliferation, expression is decreased by H pylori, and low levels are associated with a poor prognosis in gastric cancer. We therefore evaluated p27-deficient mice as a model for H pylori-associated gastric cancer. METHODS Wild-type and p27-/- C57BL/6 mice were infected with H pylori mouse-adapted Sydney strain at 6-8 weeks of age and 6-10 mice of each type were euthanized 15, 30, 45, 60, and 75 weeks later. RESULTS Uninfected p27-/- mice developed gastric hyperplasia. H pylori-infected p27-/- mice frequently developed intestinal metaplasia (40% at 30 weeks, 67% at 45 weeks), and after 60 weeks 7 of 12 mice developed significant dysplasia and gastric cancer, recapitulating human intestinal-type gastric carcinogenesis. Wild-type mice developed intestinal metaplasia only after 75 weeks of infection; significant gastric dysplasia was observed in 1 animal (P < .05 for each comparison with p27-/- mice). No disease developed in uninfected mice. H pylori infection in p27-/- mice was associated with significantly decreased apoptosis and increased epithelial proliferation, inflammation, and H pylori density compared with infection in wild-type mice. CONCLUSIONS p27 loss and H pylori colonization cooperate to produce gastric cancer. The p27-deficient mouse affords opportunities to examine the pathogenesis of H pylori in gastric carcinogenesis and to test eradication and chemopreventive strategies.
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Affiliation(s)
- Noriyoshi Kuzushita
- Division of Gastroenterology, Department of Medicine, Rhode Island Hospital/Brown University, Providence, Rhode Island 02903, USA
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Al-Moundhri MS, Nirmala V, Al-Hadabi I, Al-Mawaly K, Burney I, Al-Nabhani M, Thomas V, Ganguly SS, Grant C. The prognostic significance of p53, p27 kip1, p21 waf1, HER-2/neu, and Ki67 proteins expression in gastric cancer: a clinicopathological and immunohistochemical study of 121 Arab patients. J Surg Oncol 2005; 91:243-52. [PMID: 16121348 DOI: 10.1002/jso.20324] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
BACKGROUND The variability of prognosis within a pathological stage of gastric cancer (GC) at presentation, underscores the need for specific biological markers to identify subgroups of patients with aggressive course for intensive treatment. To our knowledge, this is the first study from an Arab population reporting on the relationship of p53, p27 kip1, p21 waf1, HER-2/neu, and Ki67 expression, and clinicopathological features and their prognostic significance. METHODS Formalin-fixed paraffin-embedded tumors were studied by immunohistochemistry, using monoclonal antibodies to p53, p27 kip1, p21 waf1, HER-2/neu, and Ki67. The results were correlated with clinicopathological features and survival. RESULTS M:F = 80:41; median age = 60 years; stage III and IV = 71%; and median follow-up = 34.4 months. Positive expression rates of p53, p27 kip1, p21 waf1, Ki67, and HER-2/neu were 54%, 40%, 8.3%, 70%, and 12% respectively. p53 expression correlated with age <60 years (P = 0.03), tumor size >5 cm (P = 0.01), p27 kip1 and Ki67 expression (P = 0.0001), and HER-2/neu (P = 0.04). p21 waf1 correlated inversely with T-stage (P = 0.008) and Her-2/neu expression correlated with histological grade (P = 0.04) and T-stage (P = 0.008). Univariate analysis showed that p53 overexpression (P = 0.01), fungating and infiltrative macroscopic appearance (P = 0.02), size >5 cm (P = 0.0001), lymph node metastasis (P = 0.0001), p T3 and T4 disease (P = 0.01), and overall stage III and IV (P = 0.0001) disease were adverse prognostic factors. Patients with tumor profiles p53 (-)/p27 (+) had better survival than those with p53 (+)/p27 kip1 (-)(P = 0.02). On multivariate analysis by Cox regression model, the expression of p53 (P = 0.03) and lymph node involvement (P = 0.01) were significant adverse prognostic factors for overall survival. CONCLUSIONS The expression of p53 in Arab patients with GC correlates with aggressive tumor characteristics and is an independent prognostic factor. The combined analysis of p53 and p27 kip1 is of added prognostic value.
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Affiliation(s)
- M S Al-Moundhri
- Department of Medicine, Medical Oncology Unit, College of Medicine, Sultan Qaboos University, Sultanate of Oman.
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Abstract
GOALS The purpose of this review is to look at the evidence presented in the literature on the immunoexpression of p27 in cancers of the gastrointestinal tract and liver. BACKGROUND Cell cycle proteins have been shown to play an important role in the oncogenesis of many tumors. Several of these proteins have been examined in concert and in isolation, and some have been put forward as putative tumor markers. p27, which is an important inhibitory protein in the cell cycle and belonging to a group of cyclin-dependent kinase inhibitors, has also been studied in several malignancies, most notably breast, lung, bladder, and prostate cancers. Considerable work has also been done on the expression of this protein in cancers occurring within the gastrointestinal tract. RESULTS Cancers occurring in the major sites of the gastrointestinal tract (esophagus, stomach, and colorectum) and liver show a similar pattern with regard to p27 protein levels. p27 emerges as a statistically significant predictor of survival and tumor behavior. It has been suggested that p27 loss occurs early in the carcinogenesis process, with dysplastic epithelium having decreased expression. The more aggressive, metastasizing cancers tend to lack p27 expression as well. Some studies have also invoked the subcellular localization of p27 (cytoplasmic versus nuclear) as also being of prognostic value. CONCLUSION Therefore, in gastrointestinal and hepatic cancers, low p27 expression is regarded as an important adverse prognostic factor.
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Yang L, Kuang LG, Zheng HC, Li JY, Wu DY, Zhang SM, Xin Y. PTEN encoding product: A marker for tumorigenesis and progression of gastric carcinoma. World J Gastroenterol 2003; 9:35-9. [PMID: 12508347 PMCID: PMC4728244 DOI: 10.3748/wjg.v9.i1.35] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To detect the expression of PTEN encoding product in normal mucosa, intestinal metaplasia (IM), dysplasia and carcinoma of the stomach, and to investigate its clinical implication in tumorigenesis and progression of gastric carcinoma.
METHODS: Formalin-fixed paraffin embedded specimens from 184 cases of gastric carcinoma, their adjacent normal mucosa, IM and dysplasia were evaluated for PTEN protein expression by SABC immunohistochemistry. PTEN expression was compared with tumor stage, lymph node metastasis, Lauren’s and WHO’s histological classification of gastric carcinoma. Expression of VEGF was also detected in 60 cases of gastric carcinoma and its correlation with PTEN was concerned.
RESULTS: The positive rates of PTEN protein were 100% (102/102), 98.5% (65/66), 66.7% (4/6) and 47.8% (88/184) in normal mucosa, IM, dysplasia and carcinoma of the stomach, respectively. The positive rates in dysplasia and carcinoma were lower than in normal mucosa and IM (P < 0.01). Advanced gastric cancers expressed less frequent PTEN than early gastric cancer (42.9% vs 67.6%, P < 0.01). The positive rate of PTEN protein was lower in gastric cancer with than without lymph node metastasis (40.3% vs 63.3%, P < 0.01). PTEN was less expressed in diffuse-type than in intestinal-type gastric cancer (41.5% vs 57.8%, P < 0.05). Signet ring cell carcinoma showed the expression of PTEN at the lowest level (25.0%, 7/28); less than well and moderately differentiated ones (P < 0.01). Expression of PTEN was not correlated with expression of VEGF (P > 0.05).
CONCLUSION: Loss or reduced expression of PTEN protein occures commonly in tumorigenesis and progression of gastric carcinoma. It is suggested that PTEN can be an objective marker for pathologically biological behaviors of gastric carcinoma.
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Affiliation(s)
- Lin Yang
- No.4 Lab, Cancer Institute, The First Affiliated Hospital, China Medical University, Shenyang 110001, China.
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