Fez1/Lzts1-deficient mice are more susceptible to N-butyl-N-(4-hydroxybutil) nitrosamine (BBN) carcinogenesis
Fez1/Lzts1-deficient mice are more susceptible to N-butyl-N-(4-hydroxybutil) nitrosamine (BBN) carcinogenesis
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DOI：
10.1093/carcin/bgn006
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发表时间：
2008-04-01
期刊：
影响因子：
4.7
通讯作者：
Croce, Carlo M.
中科院分区：
文献类型：
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作者：
Baffa, Raffaele;Fassan, Matteo;Croce, Carlo M.
FEZ1/LZTS1 是一种肿瘤抑制基因，在不同组织型的人类癌症中经常发生改变。我们之前曾报道过，LZTS1 在高级膀胱癌中下调，并且其恢复可抑制尿路上皮癌细胞的致瘤性。为了进一步研究 LZTS1 在膀胱癌发展中的作用，我们在化学诱导的致癌模型中使用了杂合子和无效 Lzts1 小鼠。由 25 个 Lzts1(+/+)、17 个 Lzts1(+/-) 和 16 个 Lzts1(-/-) 组成的 58 只小鼠接受 N-丁基-N-(4-羟基丁酯)亚硝胺 (BBN) 治疗。结果显示，BBN 治疗后，与 Lzts1(+/-) (8.0%) 小鼠相比，Lzts1(+/-) (82.3%) 和 Lzts1(-/-) (93.8%) 小鼠的肿瘤病变显着增加。 Lzts1(+/-) 和 Lzts1(-/-) 之间的癌症发病率没有观察到差异。总的来说，这些发现表明，一个或两个 LZTS1 等位基因的缺失会阻碍尿路上皮细胞对致癌物的正常防御，从而有利于膀胱癌的发展。因此，LZTS1可能成为晚期膀胱癌基因治疗的绝佳靶点。
FEZ1/LZTS1 is a tumor suppressor gene that is frequently altered in human cancers of different histotypes. We have reported previously that LZTS1 is downregulated in high-grade bladder cancer and that its restoration suppresses tumorigenicity in urothelial carcinoma cells. To further investigate the role of LZTS1 in the development of bladder cancer, we utilized heterozygous and nullizygous Lzts1 mice in a chemically induced carcinogenesis model. Fifty-eight mice consisting of 25 Lzts1(+/+), 17 Lzts1(+/-) and 16 Lzts1(-/-) were treated with N-butyl-N-(4-hydroxybutil) nitrosamine (BBN). Results showed that there was a significant increase in neoplastic lesions in the Lzts1(+/-) (82.3%) and Lzts1(-/-) (93.8%) versus Lzts1(+/+) (8.0%) mice after BBN treatment. No difference in cancer incidence between Lzts1(+/-) and Lzts1(-/-) was observed. Collectively, these findings indicate that loss of one or both LZTS1 alleles hampers the normal defenses of urothelial cells against carcinogens, favoring bladder cancer development. Therefore, LZTS1 may become an excellent target for gene therapy in advanced bladder carcinoma.