Impact of Helicobacter pylori on the growth of hepatic orthotopic graft tumors in mice

Wang,Junwei; Wang,Xiaoqian; Tang,Nanhong; Chen,Yanling; She,Feifei

doi:10.3892/ijo.2015.3107

Impact of Helicobacter pylori on the growth of hepatic orthotopic graft tumors in mice

Authors:
- Junwei Wang
- Xiaoqian Wang
- Nanhong Tang
- Yanling Chen
- Feifei She
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Affiliations: Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian 350001, P.R. China, Department of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, P.R. China
Published online on: July 28, 2015 https://doi.org/10.3892/ijo.2015.3107
Pages: 1416-1428

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Abstract

Helicobacter pylori is a well-known causative organism of chronic gastric diseases and has been found in many hepatic carcinoma samples. To explore the expression of apoptosis-related proteins and carcinoma development in H. pylori-infected livers, we utilized BALB/cAnSlac mice to establish an H. pylori-infected model by oral inoculation and orthotopic grafts of hepatic tumors by H22 cells, respectively. We found that H. pylori colonies could not be cultured from all liver and tumor samples. However, its 16S rRNA was detectable in 85.3% of livers and 66.7% of tumors in the infected mice. Inflammatory cells were observed and thinly distributed in the lobule portions of the liver, and H. pylori mainly existed in the infected hepatic sinusoids and the necrotic areas of the infected tumors. No significant difference was found in liver to body weight ratio between the infected and uninfected. Moreover, the pathological tumor difference was unremarkable between the two. The proliferating cell nuclear antigen (PCNA) and Bcl-2-associated X protein (Bax) expression in the infected tumors was significantly higher and lower, respectively, than those of the uninfected tumors. However, no significant difference in Bcl-2 (B-cell lymphoma 2) expression existed. The results indicate that H. pylori found in the livers which were infected by H. pylori oral inoculation could contribute to the infiltration of inflammatory cells in livers. Although H. pylori has no significant impact on the liver to body weight ratio or tumor Bcl-2 expression, it may upregulate PCNA expression and downregulate Bax expression, respectively. All our findings show that H. pylori may promote proliferation and inhibit apoptosis of tumor cells.

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1	Rybicka M, Nakonieczna J, Stalke P and Bielawski KP: Host response to the presence of Helicobacter spp. DNA in the liver of patients with chronic liver diseases. Pol J Microbiol. 60:175–178. 2011.PubMed/NCBI
2	Schistosomes, liver flukes and Helicobacter pylori. In: IARC Working Group on the Evaluation of Carcinogenic Risks to Humans; Lyon. 7–14 June 1994; IARC monographs on the evaluation of carcinogenic risks to humans. World Health Organization, International Agency for Research on Cancer; 61. pp. 1–241. 1994
3	Wedi B and Kapp A: Helicobacter pylori infection in skin diseases: a critical appraisal. Am J Clin Dermatol. 3:273–282. 2002. View Article : Google Scholar : PubMed/NCBI
4	Pellicano R, Menard A, Rizzetto M and Megraud F: Helicobacter species and liver diseases: association or causation? Lancet Infect Dis. 8:254–260. 2008. View Article : Google Scholar : PubMed/NCBI
5	Farsak B, Yildirir A, Akyön Y, Pinar A, Oç M, Böke E, Kes S and Tokgözoğlu L: Detection of Chlamydia pneumoniae and Helicobacter pylori DNA in human atherosclerotic plaques by PCR. J Clin Microbiol. 38:4408–4411. 2000.PubMed/NCBI
6	Ameriso SF, Fridman EA, Leiguarda RC and Sevlever GE: Detection of Helicobacter pylori in human carotid atheroscle-rotic plaques. Stroke. 32:385–391. 2001. View Article : Google Scholar : PubMed/NCBI
7	Danesh J, Koreth J, Youngman L, Collins R, Arnold JR, Balarajan Y, McGee J and Roskell D: Is Helicobacter pylori a factor in coronary atherosclerosis? J Clin Microbiol. 37:16511999.PubMed/NCBI
8	Nilsson I, Lindgren S, Eriksson S and Wadstrom T: Serum antibodies to Helicobacter hepaticus and Helicobacter pylori in patients with chronic liver disease. Gut. 46:410–414. 2000. View Article : Google Scholar : PubMed/NCBI
9	Pellicano R, Leone N, Berrutti M, Cutufia MA, Fiorentino M, Rizzetto M and Ponzetto A: Helicobacter pylori seroprevalence in hepatitis C virus positive patients with cirrhosis. J Hepatol. 33:648–650. 2000. View Article : Google Scholar : PubMed/NCBI
10	Ponzetto A, Pellicano R, Leone N, Berrutti M, Turrini F and Rizzetto M: Helicobacter pylori seroprevalence in cirrhotic patients with hepatitis B virus infection. Neth J Med. 56:206–210. 2000. View Article : Google Scholar : PubMed/NCBI
11	Ponzetto A, Pellicano R, Leone N, Cutufia MA, Turrini F, Grigioni WF, D'Errico A, Mortimer P, Rizzetto M and Silengo L: Helicobacter infection and cirrhosis in hepatitis C virus carriage: is it an innocent bystander or a troublemaker? Med Hypotheses. 54:275–277. 2000. View Article : Google Scholar : PubMed/NCBI
12	Queiroz DM, Rocha AM, Rocha GA, Cinque SM, Oliveira AG, Godoy A and Tanno H: Association between Helicobacter pylori infection and cirrhosis in patients with chronic hepatitis C virus. Dig Dis Sci. 51:370–373. 2006. View Article : Google Scholar : PubMed/NCBI
13	Avenaud P, Marais A, Monteiro L, Le Bail B, Bioulac Sage P, Balabaud C and Mégraud F: Detection of Helicobacter species in the liver of patients with and without primary liver carcinoma. Cancer. 89:1431–1439. 2000. View Article : Google Scholar : PubMed/NCBI
14	Xuan SY, Li N, Qiang X, Zhou RR, Shi YX and Jiang WJ: Helicobacter infection in hepatocellular carcinoma tissue. World J Gastroenterol. 12:2335–2340. 2006.PubMed/NCBI
15	Farazi PA and DePinho RA: Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer. 6:674–687. 2006. View Article : Google Scholar : PubMed/NCBI
16	Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 136:E359–E386. 2015. View Article : Google Scholar
17	Parkin DM, Bray F, Ferlay J and Pisani P: Global cancer statistics, 2002. CA Cancer J Clin. 55:74–108. 2005. View Article : Google Scholar : PubMed/NCBI
18	Iwatsuki S, Starzl TE, Sheahan DG, Yokoyama I, Demetris AJ, Todo S, Tzakis AG, Van Thiel DH, Carr B, Selby R, et al: Hepatic resection versus transplantation for hepatocellular carcinoma. Ann Surg. 214:221–228; discussion 228–229. 1991. View Article : Google Scholar : PubMed/NCBI
19	McPeake JR, O'Grady JG, Zaman S, Portmann B, Wight DG, Tan KC, Calne RY and Williams R: Liver transplantation for primary hepatocellular carcinoma: tumor size and number determine outcome. J Hepatol. 18:226–234. 1993. View Article : Google Scholar : PubMed/NCBI
20	Kensler TW, Roebuck BD, Wogan GN and Groopman JD: Aflatoxin: a 50-year odyssey of mechanistic and translational toxicology. Toxicol Sci. 120(Suppl 1): S28–S48. 2011. View Article : Google Scholar :
21	Chuang SC, La Vecchia C and Boffetta P: Liver cancer: Descriptive epidemiology and risk factors other than HBV and HCV infection. Cancer Lett. 286:9–14. 2009. View Article : Google Scholar
22	Arzumanyan A, Reis HM and Feitelson MA: Pathogenic mechanisms in HBV- and HCV-associated hepatocellular carcinoma. Nat Rev Cancer. 13:123–135. 2013. View Article : Google Scholar : PubMed/NCBI
23	Goo MJ, Ki MR, Lee HR, Yang HJ, Yuan DW, Hong IH, Park JK, Hong KS, Han JY, Hwang OK, et al: Helicobacter pylori promotes hepatic fibrosis in the animal model. Lab Invest. 89:1291–1303. 2009. View Article : Google Scholar : PubMed/NCBI
24	Ito K, Nakamura M, Toda G, Negishi M, Torii A and Ohno T: Potential role of Helicobacter pylori in hepatocarcinogenesis. Int J Mol Med. 13:221–227. 2004.PubMed/NCBI
25	Ito K, Yamaoka Y, Ota H, El-Zimaity H and Graham DY: Adherence, internalization, and persistence of Helicobacter pylori in hepatocytes. Dig Dis Sci. 53:2541–2549. 2008. View Article : Google Scholar : PubMed/NCBI
26	Zhang Y, Fan XG, Huang YK, Chen R and Dai H: Helicobacter pylori enhances cyclin D1, PCNA expression in HepG2 cell line. Zhonghua Gan Zang Bing Za Zhi. 12:695–696. 2004.(In Chinese). PubMed/NCBI
27	Chen R, Fan XG, Huang Y, Li N and Chen CH: In vitro cytotoxicity of Helicobacter pylori on hepatocarcinoma HepG2 cells. Ai Zheng. 23:44–49. 2004.(In Chinese). PubMed/NCBI
28	Karita M, Li Q, Cantero D and Okita K: Establishment of a small animal model for human Helicobacter pylori infection using germ-free mouse. Am J Gastroenterol. 89:208–213. 1994.PubMed/NCBI
29	Thalmaier U, Lehn N, Pfeffer K, Stolte M, Vieth M and Schneider-Brachert W: Role of tumor necrosis factor alpha in Helicobacter pylori gastritis in tumor necrosis factor receptor 1-deficient mice. Infect Immun. 70:3149–3155. 2002. View Article : Google Scholar : PubMed/NCBI
30	Algood HM, Allen SS, Washington MK, Peek RM Jr, Miller GG and Cover TL: Regulation of gastric B cell recruitment is dependent on IL-17 receptor A signaling in a model of chronic bacterial infection. J Immunol. 183:5837–5846. 2009. View Article : Google Scholar : PubMed/NCBI
31	Maurer KJ, Ihrig MM, Rogers AB, Ng V, Bouchard G, Leonard MR, Carey MC and Fox JG: Identification of cholelithogenic enterohepatic Helicobacter species and their role in murine cholesterol gallstone formation. Gastroenterology. 128:1023–1033. 2005. View Article : Google Scholar : PubMed/NCBI
32	Lee CW, Rickman B, Rogers AB, Muthupalani S, Takaishi S, Yang P, Wang TC and Fox JG: Combination of sulindac and antimicrobial eradication of Helicobacter pylori prevents progression of gastric cancer in hypergastrinemic INS-GAS mice. Cancer Res. 69:8166–8174. 2009. View Article : Google Scholar : PubMed/NCBI
33	Yao X, Hu JF, Daniels M, Yien H, Lu H, Sharan H, Zhou X, Zeng Z, Li T, Yang Y, et al: A novel orthotopic tumor model to study growth factors and oncogenes in hepatocarcinogenesis. Clin Cancer Res. 9:2719–2726. 2003.PubMed/NCBI
34	Aprahamian M, Bour G, Akladios CY, Fylaktakidou K, Greferath R, Soler L, Marescaux J, Egly JM, Lehn JM and Nicolau C: Myo-InositolTrisPyroPhosphate treatment leads to HIF-1α suppression and eradication of early hepatoma tumors in rats. Chem Biochem. 12:777–783. 2011.
35	Fox JG, Dewhirst FE, Shen Z, Feng Y, Taylor NS, Paster BJ, Ericson RL, Lau CN, Correa P, Araya JC, et al: Hepatic Helicobacter species identified in bile and gallbladder tissue from Chileans with chronic cholecystitis. Gastroenterology. 114:755–763. 1998. View Article : Google Scholar : PubMed/NCBI
36	Leone N, Pellicano R, Brunello F, Cutufia MA, Berrutti M, Fagoonee S, Rizzetto M and Ponzetto A: Helicobacter pylori seroprevalence in patients with cirrhosis of the liver and hepatocellular carcinoma. Cancer Detect Prev. 27:494–497. 2003. View Article : Google Scholar : PubMed/NCBI
37	Ponzetto A, Pellicano R, Redaelli A, Rizzetto M and Roffi L: Helicobacter pylori infection in patients with hepatitis C Virus positive chronic liver diseases. New Microbiol. 26:321–328. 2003.PubMed/NCBI
38	Spinzi G, Pellicano R, Minoli G, Terreni N, Cutufia MA, Fagoonee S, Rizzetto M and Ponzetto A: Helicobacter pylori seroprevalence in hepatitis C virus positive patients with cirrhosis. The Como cross-sectional study. Panminerva Med. 43:85–87. 2001.PubMed/NCBI
39	Fan XG, Zou YY, Wu AH, Li TG, Hu GL and Zhang Z: Seroprevalence of Helicobacter pylori infection in patients with hepatitis B. Br J Biomed Sci. 55:176–178. 1998.
40	Zhang S, Bao Y and Zu MH: Research of relationship between Hp infection and HCC. Chin J Clin Oncol. 45–48. 2004.
41	Huang Y, Fan XG, Wang ZM, Zhou JH, Tian XF and Li N: Identification of helicobacter species in human liver samples from patients with primary hepatocellular carcinoma. J Clin Pathol. 57:1273–1277. 2004. View Article : Google Scholar : PubMed/NCBI
42	Pellicano R, Mazzaferro V, Grigioni WF, Cutufia MA, Fagoonee S, Silengo L, Rizzetto M and Ponzetto A: Helicobacter species sequences in liver samples from patients with and without hepatocellular carcinoma. World J Gastroenterol. 10:598–601. 2004. View Article : Google Scholar : PubMed/NCBI
43	Leelawat K, Suksumek N, Leelawat S and Lek-Uthai U: Detection of VacA gene specific for Helicobactor pylori in hepatocellular carcinoma and cholangiocarcinoma specimens of Thai patients. Southeast Asian J Trop Med Public Health. 38:881–885. 2007.PubMed/NCBI
44	de Magalhaes Queiroz DM and Santos A: Isolation of a Helicobacter strain from the human liver. Gastroenterology. 121:1023–1024. 2001. View Article : Google Scholar : PubMed/NCBI
45	Matsukura N, Yokomuro S, Yamada S, Tajiri T, Sundo T, Hadama T, Kamiya S, Naito Z and Fox JG: Association between Helicobacter bilis in bile and biliary tract malignancies: H. bilis in bile from Japanese and Thai patients with benign and malignant diseases in the biliary tract. Jpn J Cancer Res. 93:842–847. 2002. View Article : Google Scholar : PubMed/NCBI
46	García A, Feng Y, Parry NM, McCabe A, Mobley MW, Lertpiriyapong K, Whary MT and Fox JG: Helicobacter pylori infection does not promote hepatocellular cancer in a transgenic mouse model of hepatitis C virus pathogenesis. Gut Microbes. 4:577–590. 2013. View Article : Google Scholar : PubMed/NCBI
47	Rocha M, Avenaud P, Menard A, Le Bail B, Balabaud C, Bioulac-Sage P, de Magalhães Queiroz DM and Mégraud F: Association of Helicobacter species with hepatitis C cirrhosis with or without hepatocellular carcinoma. Gut. 54:396–401. 2005. View Article : Google Scholar : PubMed/NCBI
48	Hanninen ML: Sensitivity of Helicobacter pylori to different bile salts. Eur J Clin Microbiol Infect Disy. 10:515–518. 1991. View Article : Google Scholar
49	Caldwell MT, McDermott M, Jazrawi S, O'Dowd G, Byrne PJ, Walsh TN, Hourihane DO and Hennessy TP: Helicobacter pylori infection increases following cholecystectomy. Ir J Med Sci. 164:52–55. 1995. View Article : Google Scholar : PubMed/NCBI
50	Kawaguchi M, Saito T, Ohno H, Midorikawa S, Sanji T, Handa Y, Morita S, Yoshida H, Tsurui M, Misaka R, et al: Bacteria closely resembling Helicobacter pylori detected immunohistologically and genetically in resected gallbladder mucosa. J Gastroenterol. 31:294–298. 1996. View Article : Google Scholar : PubMed/NCBI
51	Guyton JE and Hall AC: Textbook of Medical Physiology. Saunders Elsevier; Philadelphia, PA: 2011
52	Kelly SM, Pitcher MC, Farmery SM and Gibson GR: Isolation of Helicobacter pylori from feces of patients with dyspepsia in the United Kingdom. Gastroenterology. 107:1671–1674. 1994.PubMed/NCBI
53	Thomas JE, Gibson GR, Darboe MK, Dale A and Weaver LT: Isolation of Helicobacter pylori from human faeces. Lancet. 340:1194–1195. 1992. View Article : Google Scholar : PubMed/NCBI
54	Narikawa S, Kawai S, Aoshima H, Kawamata O, Kawaguchi R, Hikiji K, Kato M, Iino S and Mizushima Y: Comparison of the nucleic acids of helical and coccoid forms of Helicobacter pylori. Clin Diagn Lab Immunol. 4:285–290. 1997.PubMed/NCBI
55	Dore MP, Realdi G, Mura D, Graham DY and Sepulveda AR: Helicobacter infection in patients with HCV-related chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Dig Dis Sci. 47:1638–1643. 2002. View Article : Google Scholar : PubMed/NCBI
56	Silva LD, Rocha AM, Rocha GA, de Moura SB, Rocha MM, Dani R, de Melo FF, Guerra JB, de Castro LP, Mendes GS, et al: The presence of Helicobacter pylori in the liver depends on the Th1, Th17 and Treg cytokine profile of the patient. Mem Inst Oswaldo Cruz. 106:748–754. 2011. View Article : Google Scholar : PubMed/NCBI
57	Boonyanugomol W, Chomvarin C, Sripa B, Bhudhisawasdi V, Khuntikeo N, Hahnvajanawong C and Chamsuwan A: Helicobacter pylori in Thai patients with cholangiocarcinoma and its association with biliary inflammation and proliferation. HPB (Oxford). 14:177–184. 2012. View Article : Google Scholar
58	Myung SJ, Kim MH, Shim KN, Kim YS, Kim EO, Kim HJ, Park ET, Yoo KS, Lim BC, Seo DW, et al: Detection of Helicobacter pylori DNA in human biliary tree and its association with hepatolithiasis. Dig Dis Sci. 45:1405–1412. 2000. View Article : Google Scholar : PubMed/NCBI
59	Chen W, Li D, Cannan RJ and Stubbs RS: Common presence of Helicobacter DNA in the gallbladder of patients with gallstone diseases and controls. Dig Liver Dis. 35:237–243. 2003. View Article : Google Scholar : PubMed/NCBI
60	Silva CP, Pereira-Lima JC, Oliveira AG, Guerra JB, Marques DL, Sarmanho L, Cabral MM and Queiroz DM: Association of the presence of Helicobacter in gallbladder tissue with cholelithiasis and cholecystitis. J Clin Microbiol. 41:5615–5618. 2003. View Article : Google Scholar : PubMed/NCBI
61	Maurer KJ, Rogers AB, Ge Z, Wiese AJ, Carey MC and Fox JG: Helicobacter pylori and cholesterol gallstone formation in C57L/J mice: A prospective study. Am J Physiol Gastrointest Liver Physiol. 290:G175–G182. 2006. View Article : Google Scholar
62	Abayli B, Colakoglu S, Serin M, Erdogan S, Isiksal YF, Tuncer I, Koksal F and Demiryurek H: Helicobacter pylori in the etiology of cholesterol gallstones. J Clin Gastroenterol. 39:134–137. 2005.PubMed/NCBI
63	Kowalski M, Rees W, Konturek PC, Grove R, Scheffold T, Meixner H, Brunec M, Franz N, Konturek JW, Pieniazek P, et al: Detection of Helicobacter pylori specific DNA in human atheromatous coronary arteries and its association to prior myocardial infarction and unstable angina. Dig Liver Dis. 34:398–402. 2002. View Article : Google Scholar : PubMed/NCBI
64	Kusters JG, Gerrits MM, Van Strijp JA and Vandenbroucke-Grauls CM: Coccoid forms of Helicobacter pylori are the morphologic manifestation of cell death. Infect Immun. 65:3672–3679. 1997.PubMed/NCBI
65	Andersen LP, Dorland A, Karacan H, Colding H, Nilsson HO, Wadström T and Blom J: Possible clinical importance of the transformation of Helicobacter pylori into coccoid forms. Scand J Gastroenterol. 35:897–903. 2000. View Article : Google Scholar : PubMed/NCBI
66	Tian XF, Fan XG, Fu CY, Huang Y and Zhu C: Experimental study on the pathological effect of Helicobacter pylori on liver tissues. Zhonghua Gan Zang Bing Za Zhi. 13:780–783. 2005.(In Chinese). PubMed/NCBI
67	Egelkrout EM, Mariconti L, Settlage SB, Cella R, Robertson D and Hanley-Bowdoin L: Two E2F elements regulate the proliferating cell nuclear antigen promoter differently during leaf development. Plant Cell. 14:3225–3236. 2002. View Article : Google Scholar : PubMed/NCBI
68	Essers J, Theil AF, Baldeyron C, van Cappellen WA, Houtsmuller AB, Kanaar R and Vermeulen W: Nuclear dynamics of PCNA in DNA replication and repair. Mol Cell Biol. 25:9350–9359. 2005. View Article : Google Scholar : PubMed/NCBI
69	Shivji KK, Kenny MK and Wood RD: Proliferating cell nuclear antigen is required for DNA excision repair. Cell. 69:367–374. 1992. View Article : Google Scholar : PubMed/NCBI
70	Leonardi E, Girlando S, Serio G, Mauri FA, Perrone G, Scampini S, Dalla Palma P and Barbareschi M: PCNA and Ki67 expression in breast carcinoma: correlations with clinical and biological variables. J Clin Pathol. 45:416–419. 1992. View Article : Google Scholar : PubMed/NCBI
71	Kobayashi I, Matsuo K, Ishibashi Y, Kanda S and Sakai H: The proliferative activity in dysplasia and carcinoma in situ of the uterine cervix analyzed by proliferating cell nuclear antigen immunostaining and silver-binding argyrophilic nucleolar organizer region staining. Hum Pathol. 25:198–202. 1994. View Article : Google Scholar : PubMed/NCBI
72	Allegranza A, Girlando S, Arrigoni GL, Veronese S, Mauri FA, Gambacorta M, Pollo B, Dalla Palma P and Barbareschi M: Proliferating cell nuclear antigen expression in central nervous system neoplasms. Virchows Arch A Pathol Anat Histopathol. 419:417–423. 1991. View Article : Google Scholar : PubMed/NCBI
73	Tsai ST and Jin YT: Proliferating cell nuclear antigen (PCNA) expression in oral squamous cell carcinomas. J Oral Pathol Med. 24:313–315. 1995. View Article : Google Scholar : PubMed/NCBI
74	Willett CG1, Warland G, Hagan MP, Daly WJ, Coen J, Shellito PC and Compton CC: Tumor proliferation in rectal cancer following preoperative irradiation. J Clin Oncol. 13:1417–1424. 1995.PubMed/NCBI
75	Prosperi E: Multiple roles of the proliferating cell nuclear antigen: DNA replication, repair and cell cycle control. Prog Cell Cycle Res. 3:193–210. 1997. View Article : Google Scholar : PubMed/NCBI
76	Moldovan GL, Pfander B and Jentsch S: PCNA, the maestro of the replication fork. Cell. 129:665–679. 2007. View Article : Google Scholar : PubMed/NCBI
77	Wang SC, Nakajima Y, Yu YL, Xia W, Chen CT, Yang CC, McIntush EW, Li LY, Hawke DH, Kobayashi R and Hung MC: Tyrosine phosphorylation controls PCNA function through protein stability. Nat Cell Biol. 8:1359–1368. 2006. View Article : Google Scholar : PubMed/NCBI
78	Pal HC1, Sharma S, Strickland LR, Agarwal J, Athar M, Elmets CA and Afaq F: Delphinidin reduces cell proliferation and induces apoptosis of non-small-cell lung cancer cells by targeting EGFR/VEGFR2 signaling pathways. PLoS One. 8:e772702013. View Article : Google Scholar : PubMed/NCBI
79	Aziz MH, Wheeler DL, Bhamb B and Verma AK: Protein kinase C delta overexpressing transgenic mice are resistant to chemically but not to UV radiation-induced development of squamous cell carcinomas: A possible link to specific cytokines and cyclo-oxygenase-2. Cancer Res. 66:713–722. 2006. View Article : Google Scholar : PubMed/NCBI
80	Ojeh N, Hiilesvuo K, Warri A, Salmivirta M, Henttinen T and Maatta A: Ectopic expression of syndecan-1 in basal epidermis affects keratinocyte proliferation and wound re-epithelialization. J Invest Dermatol. 128:26–34. 2008. View Article : Google Scholar
81	Tian XF, Fan XG, Huang Y, Zhang Y and Zhu C: Expression of cyclin D1 proliferating cell nuclear antigen in liver of C57BL/6 mice infected with Helicobacter pylori. World Chin J Digestol. 14:1341–1345. 2006.
82	Zhang Y, Fan XG, Chen R, Xiao ZQ, Feng XP, Tian XF and Chen ZH: Comparative proteome analysis of untreated and Helicobacter pylori-treated HepG2. World J Gastroenterol. 11:3485–3489. 2005. View Article : Google Scholar : PubMed/NCBI
83	Komatsu K1, Miyashita T, Hang H, Hopkins KM, Zheng W, Cuddeback S, Yamada M, Lieberman HB and Wang HG: Human homologue of S. pombe Rad9 interacts with BCL-2/BCL-xL and promotes apoptosis. Nat Cell Biol. 2:1–6. 2000.PubMed/NCBI
84	Lin B, Kolluri SK, Lin F, Liu W, Han YH, Cao X, Dawson MI, Reed JC and Zhang XK: Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3. Cell. 116:527–540. 2004. View Article : Google Scholar : PubMed/NCBI
85	Hoetelmans RW: Nuclear partners of Bcl-2: Bax and PML. DNA Cell Biol. 23:351–354. 2004. View Article : Google Scholar : PubMed/NCBI
86	Oltvai ZN, Milliman CL and Korsmeyer SJ: Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell. 74:609–619. 1993. View Article : Google Scholar : PubMed/NCBI
87	Tsujimoto Y, Finger LR, Yunis J, Nowell PC and Croce CM: Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation. Science. 226:1097–1099. 1984. View Article : Google Scholar : PubMed/NCBI
88	Cleary ML, Smith SD and Sklar J: Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation. Cell. 47:19–28. 1986. View Article : Google Scholar : PubMed/NCBI
89	Yang LJ, Cao XT and Yu LZ: Bcl-2 and Bax in apoptosis of tumor cells. Chin J Cancer Biother. 10:232–234. 2003.
90	Yin XM, Oltvai ZN and Korsmeyer SJ: BH1 and BH2 domains of Bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax. Nature. 369:321–323. 1994. View Article : Google Scholar : PubMed/NCBI
91	Yang E and Korsmeyer SJ: Molecular thanatopsis: a discourse on the BCL2 family and cell death. Blood. 88:386–401. 1996.PubMed/NCBI
92	Yang E, Zha J, Jockel J, Boise LH, Thompson CB and Korsmeyer SJ: Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death. Cell. 80:285–291. 1995. View Article : Google Scholar : PubMed/NCBI
93	Cotran RS, Kumar V and Collins T: Robbins Pathologic Basis of Disease. 6th edition. W.B Saunders Company; Philadelphia, PA: 1998