FHIT is up-regulated by inflammatory stimuli and inhibits prostaglandin E2-mediated cancer progression
FHIT is up-regulated by inflammatory stimuli and inhibits prostaglandin E2-mediated cancer progression
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DOI：
10.1158/0008-5472.can-05-2509
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发表时间：
2006-03-01
期刊：
影响因子：
11.2
通讯作者：
Mori, M
中科院分区：
文献类型：
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作者：
Mimori, K;Ishii, H;Mori, M
已知 FHIT 基因对环境致癌物敏感。前列腺素 E-2 (PGE(2)) 的形成由环氧合酶-2 (COX-2) 催化，可能影响结直肠癌的恶性表型。我们探讨了 HUT 是否可能通过炎症相关的 PGE2 活性在结直肠癌的进展中发挥作用。在 92 个结直肠癌肿瘤中进行了 COX-2 和 FHIT 表达的免疫组织化学研究。我们还使用了由松甾酮 A 诱导的表达 FHIT 的癌细胞系 (11460) 和两种 FHIT 小干扰 RNA 处理的结直肠癌细胞系 (CCK81 和 DLD1)。 PGE(2)刺激后，我们比较了PGE2的合成（ELISA测定）和细胞增殖[3-(4,5二炔噻唑-2-yi)-2,5-二苯基溴化四唑测定]。免疫组织化学显示结直肠癌中 COX-2 和 FHIT 表达显着相关（P < 0.01）。在 41 个表达 COX-2 的肿瘤的子集中，12 个 FHIT- 肿瘤比 29 个 FHIT+ 肿瘤显示出更深的癌症浸润 (P < 0.01)。然而，实验研究表明FHIT 和COX-2 之间没有直接相互作用。考虑到另一项表皮生长因子受体 (EGFR) 实验的结果，我们假设 FHIT 和 COX-2 可能受到共同分子（例如 EGFR）的调节。此外，体外PGE2合成与FHIT之间存在负相关和正相关，这表明FHIT对肿瘤的假定抗侵袭作用是通过PGE(2)而非COX-2实现的。结直肠癌中 FHIT 表达缺失表明其恶性潜力较高。我们得出结论，FHIT 通过直接抑制 PGE2 的合成但不影响 COX-2 的合成来抑制这种恶性肿瘤中的癌细胞增殖。
The FHIT gene is known to be susceptible to environmental carcinogens. Formation of prostaglandin E-2 (PGE(2)) is catalyzed by cyclooxygenase-2 (COX-2) and may influence malignant phenotype in colorectal cancer. We explored whether HUT might Play a role in progression of colorectal cancer through inflammation-associated PGE2 activity. Immunohistochemical study of COX-2 and FHIT expression was done in 92 colorectal cancer tumors. We also used a FHIT-expressing cancer cell line (11460) induced by ponasterone A and two FHIT small interfering RNA-treated colorectal cancer cell lines (CCK81 and DLD1). After PGE(2) stimulation,we compared synthesis of PGE2 (ELISA assay) and cell proliferation [3-(4,5diinethvithiazol-2-yi)-2,5-diphenyltetrazolium bromide assay]. Immunohistochemistry showed a significant association between COX-2 and FHIT expression in colorectal cancers (P < 0.01). In a subset of 41 COX-2-expressing tumors, 12 FHIT- tumors showed deeper cancer invasion than 29 FHIT+ tumors (P < 0.01). Experimental study, however, showed there was no direct interaction between FHIT and COX-2. Considered with results from another experiment with epidermal growth factor receptor (EGFR), we hypothesize that FHIT and COX-2 might be regulated by a common molecule, such as EGFR. Additionally, there was an inverse and direct correlation between PGE2 synthesis and FHIT in vitro, suggesting that FHIT's postulated antiaggressive effect on tumor goes through PGE(2) but not COX-2. Loss of done FHIT expression in colorectal cancer suggests higher malignant potential. We conclude that FHIT suppressed cancer cell proliferation in this malignancy by directly inhibiting synthesis of PGE2 but not affecting that of COX-2.