Molecular mechanism of adenomatous polyposis coli-induced blockade of base excision repair pathway in colorectal carcinogenesis.
Molecular mechanism of adenomatous polyposis coli-induced blockade of base excision repair pathway in colorectal carcinogenesis.
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DOI：
10.1016/j.lfs.2015.08.019
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发表时间：
2015-10-15
期刊：
影响因子：
6.1
通讯作者：
Sharma R
中科院分区：
文献类型：
--
作者：
Narayan S;Sharma R
结直肠癌（CRC）是北美男性和女性的第三大死亡原因。尽管化疗的努力，CRC是与高程度的发病率和死亡率。因此，为了开发有效的CRC治疗策略，需要了解癌症发展和癌症耐药性的发病机制。这表明结肠肿瘤或细胞系具有截短的腺瘤性结肠息肉病（APC），没有DNA修复抑制（DRI）结构域。APC基因的产物通过与Pol-β和flap内切酶1（Fen-1）相互作用调节碱基切除修复（BER）途径，介导CRC细胞凋亡。所提出的替莫唑胺（TMZ）疗法利用了这一特定途径;然而，由于错配修复（MMR）缺陷，高比例的结直肠肿瘤继续对化疗产生耐药性。在目前的通信中，我们已经全面审查了一个关键的问题，以前没有得到解决：一种新的机制，APC诱导的单核苷酸（SN）和长补丁（LP）-BER的封锁发挥作用的DNA烷基化损伤诱导的结直肠癌发生。
Colorectal cancer (CRC) is the third leading cause of death in both men and women in North America. Despite chemotherapeutic efforts, CRC is associated with a high degree of morbidity and mortality. Thus, to develop effective treatment strategies for CRC, one needs knowledge of the pathogenesis of cancer development and cancer resistance. It is suggested that colonic tumors or cell lines harbor truncated adenomatous polyposis coli (APC) without DNA repair inhibitory (DRI)-domain. It is also thought that the product of the APC gene can modulate base excision repair (BER) pathway through an interaction with Pol-β and flap endonuclease 1 (Fen-1) to mediate CRC cell apoptosis. The proposed therapy with temozolomide (TMZ) exploits this particular pathway; however, a high percentage of colorectal tumors continue to develop resistance to chemotherapy due to mismatch repair (MMR)-deficiency. In the present communication, we have comprehensively reviewed a critical issue that has not been addressed previously: a novel mechanism by which APC-induced blockage of single nucleotide (SN)- and long-patch (LP)-BER play role in DNA-alkylation damage-induced colorectal carcinogenesis.