Cho, CH

Liu, ESL

Shin, VY

Wong, BCY

Ye, YN

Yuen, ST

Hong Kong Medical Journal

HKU Scholars Hub

Title Mechanism of inflammation-associated colonic tumorigenesispromoted by cigarette smokeAuthor(s) Ye, YN; Liu, ESL; Shin, VY; Wong, BCY; Yuen, ST; Cho, CHCitationThe 8th Medical Research Conference Abstracts, Hong KongMedical Journal, Hong Kong, China, 25-26 January 2003, v. 9 n. 1Supp 1, p. 55Issued Date 2003URL http://hdl.handle.net/10722/54127Rights Hong Kong Medical Journal. Copyright © Hong Kong MedicalAssociation.HKMJ Vol 9 No 1 February 2003 Supplement      55Cigarette smoke promoted human xenograft tumors through the upregulation ofcyclin D1 and cyclin-dependent kinasesVY Shin, ESL Liu, YN Ye, WL Koo & CH Cho. Department of Pharmacology, Faculty of Medicine, The University ofHong Kong, Hong Kong, ChinaIntroduction: Previous studies reported that cigarette smoke could delay gastric ulcer healing, however, its effecton gastric tumor growth is not well established. Cell cycle control is important in carcinogenesis and cancer growth.Cyclin D1 and cyclin-dependent kinase (Cdk) are necessary for the transition from early to mid G1 phase. These cellregulators are actively involved in human gastric cancer. This study aims to delineate the biological pathways ofhow cigarette smoke promotes gastric cancer in humans.Method: Male athymic BALB/c nude mice were used as a human gastric cancer model to study the biologicalactions of cigarette smoke. Human gastric carcinoma cells (AGS) were implanted into the gastric walls of the mice.Cells were pretreated in the presence or absence of cigarette smoke extract (CSE, 100 µg/ml) prior to the injectionof cells into the stomach.Results: Cigarette smoke promoted the growth of xenograft tumors, which was accompanied with the upregulationof cyclin D1. Overexpression of cyclin D1 were found in all tumor tissues, and cigarette smoke further upregulatedthis protein by 30%. Tumor tissues had a 5-fold increase in the expression of Cdk6, and cigarette smoke promotedthis protein upregulation. Cdk4, another important binding partner of cyclin D1, was also induced by cigarettesmoke when compared with the normal tissues. In CSE-treated group, the expressions of tumor suppressor proteins(p21WAF1/Cip1 and p27Kip1) were decreased by 20% and 30% respectively in tumor tissues.Conclusion: These results suggested that cigarette smoke promoted the growth of gastric tumor through themodulation of cell cycle regulatory proteins. High expression of cyclin D1 and Cdks are important parameters forthe progression of gastric tumor growth induced by cigarette smoke. This study provides an insight to develop anew strategy for the treatment of gastric cancer in humans.Mechanism of inflammation-associated colonic tumorigenesis promoted bycigarette smokeYN Ye, ESL Liu, VY Shin, BCY Wong, ST Yuen & CH Cho. Departments of Pharmacology, Medicine & Pathology, Faculty ofMedicine, The University of Hong Kong, Hong kong, ChinaIntroduction: Our previous study showed that passive cigarette smoking promoted inflammation-associatedadenoma formation in colon, but the underlied mechanism remains unknown. 5-lipoxygenase (5-LOX) is anenzyme that converts arachidonic acid to 5-s-HETE, which in turn is converted to LTA4 and then to LTB4, LTC 4 andLTD 4. Several studies have suggested that 5-LOX and its products can enhance tumorigenesis. The purpose of thepresent study was to investigate the possible involvement of 5-LOX in the tumorigenesis enhanced by cigarettesmoke in the colon.Method: Male balb/c mice were allocated into 4 groups: control, cigarette smoke (CS), dextran sulfate sodium(DSS) and DSS+CS. They were given water or 3% DSS in drinking water for 7 days to induce colitis, with orwithout 1-hour daily exposure to 2% CS. They were then allowed to drink water for 14 days. The cycle of 7-dayDSS ± CS/14-day H2O treatment was repeated twice. Mice were sacrificed either immediately (when no adenomawas found) or 1 month after the three cycles of treatments (when cigarette smoke promoted inflammationassociated adenoma formation). Colon tissues were collected for assessment.Results showed that: (1) After 3 DSS cycles, 5-LOX protein expression was significantly increased in the DSS+CSgroup compared with the control and the DSS groups. Similar results were found with vascular endothelial growthfactor (VEGF) and matrix metalloproteinase-2 (MMP-2) which are important mediators for tumor progression andangiogenesis; (2) One month after the cycles, 5-LOX was enhanced only in adenomas induced in the DSS+CSgroup but not in the DSS group, while VEGF and MMP-2 were both increased in the tumors induced in either DSSor DSS+CS group. In addition, we also found that mice treated with MK886 (a specific 5-LOX inhibitor, 20mg/kgP.O. once daily) throughout the whole 3 DSS cycles significantly reduced tumor formation promoted by cigarettesmoke. This was associated with the down-regulation of VEGF and MMP-2 expression. Moreover, we found thatcigarette smoke extract had a direct effect on colon cancer cells to release these angiogenic mediators.Conclusion: Taken together, these results strongly suggest that 5-LOX is involved in the formation of colonicadenoma which is promoted by cigarette smoke. This action is probably via the VEGF and MMP-2 activation onthe angiogenic pathway.GIH-23GIH-24

Mechanism of inflammation-associated colonic tumorigenesis promoted by cigarette smoke

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Mechanism of inflammation-associated colonic tumorigenesis promoted by cigarette smoke

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