Protective effect and mechanisms of Weining granule on N-methyl-N'-nitro-N-nitrosoguanidine-induced gastric cancer in rats
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摘要
OBJECTIVE:To investigate the protective effect and molecular mechanisms of Weining granule on N-methyl-N'-nitro-N-nitrosoguanidine(MNNG)-induced gastric cancer in rats.METHODS:A total of sixty healthy male wistar rats were randomly divided into five groups,including control group(CG),gastric cancer model group(MG),low-dose Weining granule treated group(LWT),medium-dose Weining granule treated group(MWT),and high-dose Weining granule treated group(HWT).Except the control group,the other groups were treated with MNNG to establish a rat model of gastric cancer.Low-dose Weining granule treated group,medium-dose Weining granule treated group,and high-dose Weining granule treated group were fed 9.0,18.0 and 36.0 g/kg Weining granule,respectively.Histopathologic and molecular biologic technology were adopted to determine the protective effect of Weining granule on MNNG-induced gastric cancer in rats.The pathological changes of gastrointestinal tissue were observed.Meanwhile,the differential expression of proliferation,apoptosis and angiogenesis markers were determined,including proliferating cell nuclear antigen(PCNA),pokemon,cyclin D1,B-cell lymphoma-2(Bcl-2),caspase-3,phosphatase and tensin homolog(PTEN)and vascular endothelial growth factor(VEGF).RESULTS:After the MNNG treated,the pathological changes of stomach tissue were improved noticeably,including the intestinal metaplasia and atypic hyperplasia.The experiment was completed in 58 rats(96.67%).As compared with gastric cancer model group,the general states of rats were improved significantly after treated with different dose Weining granule.Moreover,treatment with different doses of Weining granule could inhibit the protein and mRNA expression of PCNA,pokemon,cyclin D1,Bcl-2,and VEGF,while increase caspase-3 and PTEN(P<0.01).CONCLUSION:Weining granule could improve gas tric cancer by suppressing cell proliferation,promoting tumor cell apoptosis,and inhibiting angiogenesis.
OBJECTIVE:To investigate the protective effect and molecular mechanisms of Weining granule on N-methyl-N'-nitro-N-nitrosoguanidine(MNNG)-induced gastric cancer in rats.METHODS:A total of sixty healthy male wistar rats were randomly divided into five groups,including control group(CG),gastric cancer model group(MG),low-dose Weining granule treated group(LWT),medium-dose Weining granule treated group(MWT),and high-dose Weining granule treated group(HWT).Except the control group,the other groups were treated with MNNG to establish a rat model of gastric cancer.Low-dose Weining granule treated group,medium-dose Weining granule treated group,and high-dose Weining granule treated group were fed 9.0,18.0 and 36.0 g/kg Weining granule,respectively.Histopathologic and molecular biologic technology were adopted to determine the protective effect of Weining granule on MNNG-induced gastric cancer in rats.The pathological changes of gastrointestinal tissue were observed.Meanwhile,the differential expression of proliferation,apoptosis and angiogenesis markers were determined,including proliferating cell nuclear antigen(PCNA),pokemon,cyclin D1,B-cell lymphoma-2(Bcl-2),caspase-3,phosphatase and tensin homolog(PTEN)and vascular endothelial growth factor(VEGF).RESULTS:After the MNNG treated,the pathological changes of stomach tissue were improved noticeably,including the intestinal metaplasia and atypic hyperplasia.The experiment was completed in 58 rats(96.67%).As compared with gastric cancer model group,the general states of rats were improved significantly after treated with different dose Weining granule.Moreover,treatment with different doses of Weining granule could inhibit the protein and mRNA expression of PCNA,pokemon,cyclin D1,Bcl-2,and VEGF,while increase caspase-3 and PTEN(P<0.01).CONCLUSION:Weining granule could improve gas tric cancer by suppressing cell proliferation,promoting tumor cell apoptosis,and inhibiting angiogenesis.
OBJECTIVE:To investigate the protective effect and molecular mechanisms of Weining granule on N-methyl-N'-nitro-N-nitrosoguanidine(MNNG)-induced gastric cancer in rats.METHODS:A total of sixty healthy male wistar rats were randomly divided into five groups,including control group(CG),gastric cancer model group(MG),low-dose Weining granule treated group(LWT),medium-dose Weining granule treated group(MWT),and high-dose Weining granule treated group(HWT).Except the control group,the other groups were treated with MNNG to establish a rat model of gastric cancer.Low-dose Weining granule treated group,medium-dose Weining granule treated group,and high-dose Weining granule treated group were fed 9.0,18.0 and 36.0 g/kg Weining granule,respectively.Histopathologic and molecular biologic technology were adopted to determine the protective effect of Weining granule on MNNG-induced gastric cancer in rats.The pathological changes of gastrointestinal tissue were observed.Meanwhile,the differential expression of proliferation,apoptosis and angiogenesis markers were determined,including proliferating cell nuclear antigen(PCNA),pokemon,cyclin D1,B-cell lymphoma-2(Bcl-2),caspase-3,phosphatase and tensin homolog(PTEN)and vascular endothelial growth factor(VEGF).RESULTS:After the MNNG treated,the pathological changes of stomach tissue were improved noticeably,including the intestinal metaplasia and atypic hyperplasia.The experiment was completed in 58 rats(96.67%).As compared with gastric cancer model group,the general states of rats were improved significantly after treated with different dose Weining granule.Moreover,treatment with different doses of Weining granule could inhibit the protein and mRNA expression of PCNA,pokemon,cyclin D1,Bcl-2,and VEGF,while increase caspase-3 and PTEN(P<0.01).CONCLUSION:Weining granule could improve gas tric cancer by suppressing cell proliferation,promoting tumor cell apoptosis,and inhibiting angiogenesis.
引文
1 Ferlay J,Soerjomataram I,Dikshit R,et al.Cancer incidence and mortality worldwide:Sources,methods and major patterns in GLOBOCAN 2012.Int J Cancer 2015;136(5):E359-E386.
2 Fock K M.Review article:the epidemiology and prevention of gastric cancer.Aliment Pharm Therap 2014;40(3):250-260.
3 Marrelli D.Multimodal treatment of gastric cancer in the west:Where are we going?World J Gastroenterol 2015;21(26):7954-7969.
4 Venerito M,Nardone G,Selgrad M,et al.Gastric cancer--epidemiologic and clinical aspects.Helicobacter2015;19(s1):32-37.
5 Yin GY,Zhang WN,Shen XJ,et al.Ultrastructure and molecular biological changes of chronic gastritis,gastric cancer and gastric precancerous lesions:A comparative study.World J Gastroenterol 2003;9(4):851-857.
6 Wang Z,Dabrosin C,Yin X,et al.Broad targeting of angiogenesis for cancer prevention and therapy.Semin Cancer Biol 2015;35 Suppl:S224-S243.
7 Li X,Yang G,Zhang Y,et al.Traditional Chinese Medicine in cancer care:a review of controlled clinical studies published in chinese.PLoS One 2013;8(4):e60338.
8 Tao W,Xuan X,Min L,et al.Astragalus saponins affect proliferation,invasion and apoptosis of gastric cancer BGC-823 cells.Diagn Pathol 2013;8(1):1-6.
9 Chen CC,Chen Y,Hsi YT,et al.Chemical constituents and anticancer activity of Curcuma zedoaria roscoe essential oil against non-small cell lung carcinoma cells in vitro and in vivo.J Agr Food Chem 2013;61(47):11418-11427.
10 Yao Y,Tong L,Feng M,Fan H.Study on anti-tumor effect of different extracts of Astragalus and Curcuma zedoaria Rosc.Zhong Guo Xian Dai Yi Sheng 2017;55(7):33-36.
11 Liang J,Deng X,Huang RB.Effects of Weining decoction on proliferation and apoptosis of human gastric cancer SGC-7910 cells.Shanghai Zhong Yi Yao Za Zhi 2006;40(9):65-67.
12 Deng X,Liang J,Liu DH.Experiment research of Weining granule on precancerous lesions of gastric moucose.Zhong Liu Fang Zhi Yan Jiu 2009;35(5):137-138.
13 Deng X,Liang J,Liu DH,Zhou W,Qing LK,Li LH.Inhibiting of Weining granule on the growth and metastas is of orthotopic human gastric carcinoma.Nanjing Yi Ke Da Xue Xue Bao 2008;28(8):994-997.
14 Zhou XX,Deng X,Liang J,Jiang MJ.The regulation of Weining granules on methylation of gene E-cadherin,P16,c-myc on PLGC.Shi Zhen Guo Yi Guo Yao 2014;25(5):1037-1040.
15 Deng X,Liu Z W,Wu F S,et al.A clinical study of Weining granules in the treatment of gastric precancerous lesions.J Tradit Chin Med 2012;32(2):164-172.
16 Wei C,Luo Q,Sun X,et al.microRNA-497 induces cell apoptosis by negatively regulating Bcl-2 protein expression at the posttranscriptional level in human breast cancer.Int J Exp Pathol 2015;8(7):7729.
17 Deng X,Liang J,Liu D,Zhu C,Li L,Qin L.An experimental research of Weining granule in treating gastric precancerous lesions.Zhong Liu Fang Zhi Yan Jiu 2019;8(3):137-141.
18 Deng X,Liang J,Liu DH,Zhou W,Li KQ,LI LH.Inhibiting of Weining granule on the growth and metastasis of orthotopic human gastric carcinoma.Nanjing Yi Ke Daxue Xue Bao 2008;28(1):994-953.
19 Deng X,Liang J,Liu DH,Zhu CY,Long-Hua LI.Experiment research of Weining granule on precancerous lesions of gastric moucose.Zhong Liu Fang Zhi Yan Jiu 2008;35(5):313-316.
20 Feitelson MA,Arzumanyan A,Kulathinal RJ,et al.Sustained proliferation in cancer:mechanisms and novel therapeutic targets.Semin Cancer Biol 2015;35 Suppl:S25-S54.
21 Gao D,Zhao Y,Liu Y.The significance of expression of EZH2,PCNA,P16 in gastric cancer and its correlation withpatient'sprognosis.HebeiYiYao2014;36(4):492-494.
22 Kim JK,Diehl JA.Nuclear cyclin D1:an oncogenic driver in human cancer.J Cell Physiol 2010;220(2):292-296.
23 Donnellan R,Chetty R.Cyclin D1 and human neoplasia.Molecular Pathology Mp 1998;51(1):1-7.
24 Takasu S,Tsukamoto T,Ushijima T,et al.Cyclin D1 overexpression in N-methyl-N′-nitro-N-nitrosoguanidine-induced rat gastric adenocarcinomas.Exp Toxicol Pathol2007;59(3-4):171-175.
25 Kaneko M.Different genetic alterations in rat forestomach tumors induced by genotoxic and non-genotoxic carcinogens.Carcinogenesis 2002;23(10):1729-1735.
26 Maeda T,Hobbs RM,Merghoub T,et al.Role of the proto-oncogene Pokemon in cellular transformation and ARFrepression.Nature 2005;433(7023):278-285.
27 Zhao Y,Yao YH,Li L,et al.Pokemon enhances proliferation,cell cycle progression and anti-apoptosis activity of colorectal cancer independently of p14ARF-MDM2-p53pathway.Med Oncol 2014;31(12):288.
28 Guleng B,Lin CC,Ren JL.Mo1947 silencing of pokemon attenuates the proliferation of hepatocellular carcinoma HEPG2 cells in vitro and in vivo by inhibiting the PI3K/AKT pathway.Gastroenterology 2012;142(5):e51916-51924.
29 Sedlak TW,Oltvai Z N,Yang E,et al.Multiple Bcl-2 family members demonstrate selective dimerizations with Bax.P Natl Acad Sci 1995;92(17):7834-7838.
30 Sundblad AS,Tamayo R.Expression of MIB-1/KI-67and bcl-2 in gastric carcinoma.Relationship with clinico-pathological factors.ACTA Gastroenterol Latinoamericana 1995;25(2):67-72.
31 Kaneko T,Zhang Z,Mantellini MG,et al.Bcl-2 orchestrates a cross-talk between endothelial and tumor cells that promotes tumor growth.Cancer Res 2007;67(20):9685-9693.
32 Jin J,Dai J,Zhao J,Guo Y.The mechanism of apoptosis regulation by IAP antagonist Smac/DIABLO.Mol Mech Programmed Cell Death 2003;13(1):195-211.
33 Li J,Yuan J.Caspases in apoptosis and beyond.Oncogene2008;27(48):6194-6206.
34 Li Y,Guessous F,Kwon S,et al.PTEN has tumor-promoting properties in the setting of gain-of-function p53 mutations.Cancer Res 2008;68(6):1723-1731.
35 Xu WT,Yang Z,Lu NH.Roles of PTEN(phosphatase and tensin homolog)in gastric cancer development and progression.Asian Pac J Cancer Prev 2014;15(1):17-24.
36 Bai Z,Ye YJ,Chen D,et al.Homeoprotein Cdx2 and nuclear PTEN expression profiles are related to gastric cancer prognosis.Apmis Acta Pathologica Microbiologica Et Immunologica Scandinavica 2007;115(12):1383-1390.
37 Kakeji Y,Maehara Y,Sumiyoshi Y,et al.Angiogenesis as a target for gastric cancer.Surgery 2002;131(1):S48-S54.
38 Takahashi Y,Saga Y,Koyanagi T,et al.Vasohibin-1 expression inhibits advancement of ovarian cancer producing various angiogenic factors.Cancer Sci,2016,107(5):629-637.
39 Park do J,Thomas NJ,Yoon C,Yoon SS.Vascular endothelial growth factor a inhibition in gastric cancer.Gastric Cancer 2015;18(1):33-42.
40 Lee SH,Jeong D,Han YS,Baek MJ.Pivotal role of vascular endothelial growth factor pathway in tumor angiogenesis.Ann Surg Treat Res 2015;89(1):1-8.
41 Wang GD,Li X,Wang LC.Expression of VEGF and EG-FR in gastric cancer undergoing potentially curative surgery and its significance.Shi Yong ZhongLiu Za Zhi2009;24(1):34-39.
2 Fock K M.Review article:the epidemiology and prevention of gastric cancer.Aliment Pharm Therap 2014;40(3):250-260.
3 Marrelli D.Multimodal treatment of gastric cancer in the west:Where are we going?World J Gastroenterol 2015;21(26):7954-7969.
4 Venerito M,Nardone G,Selgrad M,et al.Gastric cancer--epidemiologic and clinical aspects.Helicobacter2015;19(s1):32-37.
5 Yin GY,Zhang WN,Shen XJ,et al.Ultrastructure and molecular biological changes of chronic gastritis,gastric cancer and gastric precancerous lesions:A comparative study.World J Gastroenterol 2003;9(4):851-857.
6 Wang Z,Dabrosin C,Yin X,et al.Broad targeting of angiogenesis for cancer prevention and therapy.Semin Cancer Biol 2015;35 Suppl:S224-S243.
7 Li X,Yang G,Zhang Y,et al.Traditional Chinese Medicine in cancer care:a review of controlled clinical studies published in chinese.PLoS One 2013;8(4):e60338.
8 Tao W,Xuan X,Min L,et al.Astragalus saponins affect proliferation,invasion and apoptosis of gastric cancer BGC-823 cells.Diagn Pathol 2013;8(1):1-6.
9 Chen CC,Chen Y,Hsi YT,et al.Chemical constituents and anticancer activity of Curcuma zedoaria roscoe essential oil against non-small cell lung carcinoma cells in vitro and in vivo.J Agr Food Chem 2013;61(47):11418-11427.
10 Yao Y,Tong L,Feng M,Fan H.Study on anti-tumor effect of different extracts of Astragalus and Curcuma zedoaria Rosc.Zhong Guo Xian Dai Yi Sheng 2017;55(7):33-36.
11 Liang J,Deng X,Huang RB.Effects of Weining decoction on proliferation and apoptosis of human gastric cancer SGC-7910 cells.Shanghai Zhong Yi Yao Za Zhi 2006;40(9):65-67.
12 Deng X,Liang J,Liu DH.Experiment research of Weining granule on precancerous lesions of gastric moucose.Zhong Liu Fang Zhi Yan Jiu 2009;35(5):137-138.
13 Deng X,Liang J,Liu DH,Zhou W,Qing LK,Li LH.Inhibiting of Weining granule on the growth and metastas is of orthotopic human gastric carcinoma.Nanjing Yi Ke Da Xue Xue Bao 2008;28(8):994-997.
14 Zhou XX,Deng X,Liang J,Jiang MJ.The regulation of Weining granules on methylation of gene E-cadherin,P16,c-myc on PLGC.Shi Zhen Guo Yi Guo Yao 2014;25(5):1037-1040.
15 Deng X,Liu Z W,Wu F S,et al.A clinical study of Weining granules in the treatment of gastric precancerous lesions.J Tradit Chin Med 2012;32(2):164-172.
16 Wei C,Luo Q,Sun X,et al.microRNA-497 induces cell apoptosis by negatively regulating Bcl-2 protein expression at the posttranscriptional level in human breast cancer.Int J Exp Pathol 2015;8(7):7729.
17 Deng X,Liang J,Liu D,Zhu C,Li L,Qin L.An experimental research of Weining granule in treating gastric precancerous lesions.Zhong Liu Fang Zhi Yan Jiu 2019;8(3):137-141.
18 Deng X,Liang J,Liu DH,Zhou W,Li KQ,LI LH.Inhibiting of Weining granule on the growth and metastasis of orthotopic human gastric carcinoma.Nanjing Yi Ke Daxue Xue Bao 2008;28(1):994-953.
19 Deng X,Liang J,Liu DH,Zhu CY,Long-Hua LI.Experiment research of Weining granule on precancerous lesions of gastric moucose.Zhong Liu Fang Zhi Yan Jiu 2008;35(5):313-316.
20 Feitelson MA,Arzumanyan A,Kulathinal RJ,et al.Sustained proliferation in cancer:mechanisms and novel therapeutic targets.Semin Cancer Biol 2015;35 Suppl:S25-S54.
21 Gao D,Zhao Y,Liu Y.The significance of expression of EZH2,PCNA,P16 in gastric cancer and its correlation withpatient'sprognosis.HebeiYiYao2014;36(4):492-494.
22 Kim JK,Diehl JA.Nuclear cyclin D1:an oncogenic driver in human cancer.J Cell Physiol 2010;220(2):292-296.
23 Donnellan R,Chetty R.Cyclin D1 and human neoplasia.Molecular Pathology Mp 1998;51(1):1-7.
24 Takasu S,Tsukamoto T,Ushijima T,et al.Cyclin D1 overexpression in N-methyl-N′-nitro-N-nitrosoguanidine-induced rat gastric adenocarcinomas.Exp Toxicol Pathol2007;59(3-4):171-175.
25 Kaneko M.Different genetic alterations in rat forestomach tumors induced by genotoxic and non-genotoxic carcinogens.Carcinogenesis 2002;23(10):1729-1735.
26 Maeda T,Hobbs RM,Merghoub T,et al.Role of the proto-oncogene Pokemon in cellular transformation and ARFrepression.Nature 2005;433(7023):278-285.
27 Zhao Y,Yao YH,Li L,et al.Pokemon enhances proliferation,cell cycle progression and anti-apoptosis activity of colorectal cancer independently of p14ARF-MDM2-p53pathway.Med Oncol 2014;31(12):288.
28 Guleng B,Lin CC,Ren JL.Mo1947 silencing of pokemon attenuates the proliferation of hepatocellular carcinoma HEPG2 cells in vitro and in vivo by inhibiting the PI3K/AKT pathway.Gastroenterology 2012;142(5):e51916-51924.
29 Sedlak TW,Oltvai Z N,Yang E,et al.Multiple Bcl-2 family members demonstrate selective dimerizations with Bax.P Natl Acad Sci 1995;92(17):7834-7838.
30 Sundblad AS,Tamayo R.Expression of MIB-1/KI-67and bcl-2 in gastric carcinoma.Relationship with clinico-pathological factors.ACTA Gastroenterol Latinoamericana 1995;25(2):67-72.
31 Kaneko T,Zhang Z,Mantellini MG,et al.Bcl-2 orchestrates a cross-talk between endothelial and tumor cells that promotes tumor growth.Cancer Res 2007;67(20):9685-9693.
32 Jin J,Dai J,Zhao J,Guo Y.The mechanism of apoptosis regulation by IAP antagonist Smac/DIABLO.Mol Mech Programmed Cell Death 2003;13(1):195-211.
33 Li J,Yuan J.Caspases in apoptosis and beyond.Oncogene2008;27(48):6194-6206.
34 Li Y,Guessous F,Kwon S,et al.PTEN has tumor-promoting properties in the setting of gain-of-function p53 mutations.Cancer Res 2008;68(6):1723-1731.
35 Xu WT,Yang Z,Lu NH.Roles of PTEN(phosphatase and tensin homolog)in gastric cancer development and progression.Asian Pac J Cancer Prev 2014;15(1):17-24.
36 Bai Z,Ye YJ,Chen D,et al.Homeoprotein Cdx2 and nuclear PTEN expression profiles are related to gastric cancer prognosis.Apmis Acta Pathologica Microbiologica Et Immunologica Scandinavica 2007;115(12):1383-1390.
37 Kakeji Y,Maehara Y,Sumiyoshi Y,et al.Angiogenesis as a target for gastric cancer.Surgery 2002;131(1):S48-S54.
38 Takahashi Y,Saga Y,Koyanagi T,et al.Vasohibin-1 expression inhibits advancement of ovarian cancer producing various angiogenic factors.Cancer Sci,2016,107(5):629-637.
39 Park do J,Thomas NJ,Yoon C,Yoon SS.Vascular endothelial growth factor a inhibition in gastric cancer.Gastric Cancer 2015;18(1):33-42.
40 Lee SH,Jeong D,Han YS,Baek MJ.Pivotal role of vascular endothelial growth factor pathway in tumor angiogenesis.Ann Surg Treat Res 2015;89(1):1-8.
41 Wang GD,Li X,Wang LC.Expression of VEGF and EG-FR in gastric cancer undergoing potentially curative surgery and its significance.Shi Yong ZhongLiu Za Zhi2009;24(1):34-39.