Pinlaor Somchai, Sripa Banchob, Ma Ning, Hiraku Yusuke, Yongvanit Puangrat, Wongkham Sopit, Pairojkul Chawalit, Bhudhisawasdi Vajarabhongsa, Oikawa Shinji, Murata Mariko, Semba Reiji, Kawanishi Shosuke
Department of Parasitology, Khon Kaen University, Thailand.
World J Gastroenterol. 2005 Aug 14;11(30):4644-9. doi: 10.3748/wjg.v11.i30.4644.
Nitrative and oxidative DNA damage such as 8-nitroguanine and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) formation has been implicated in initiation and/or promotion of inflammation-mediated carcinogenesis. The aim of this study is to clarify whether these DNA lesions participate in the progression of intrahepatic cholangiocarcinoma.
We investigated the relation of the formation of 8-nitroguanine and 8-oxodG and the expression of hypoxia-inducible factor-1alpha (HIF-1alpha) with tumor invasion in 37 patients with intra-hepatic cholangiocarcinoma.
Immunohistochemical analyses revealed that 8-nitroguanine and 8-oxodG formation occurred to a much greater extent in cancerous tissues than in non-cancerous tissues. HIF-1alpha could be detected in cancerous tissues in all patients, suggesting low oxygen tension in the tumors. HIF-1alpha expression was correlated with inducible nitric oxide synthase (iNOS) expression (r = 0.369 and P = 0.025) and 8-oxodG formation (r = 0.398 and P = 0.015). Double immunofluorescence study revealed that iNOS and HIF-1alpha co-localized in cancerous tissues. Notably, the formation of 8-oxodG was correlated significantly with lymphatic invasion (r = 0.386 and P = 0.018). Moreover, 8-nitroguanine and 8-oxodG in non-cancerous tissues were associated significantly with neural invasion (P = 0.042 and P = 0.026, respectively). These results suggest that reciprocal activation between HIF-1alpha and iNOS mediates persistent DNA damage, which induces tumor invasiveness via mutations, resulting in poor prognosis.
The formation of 8-nitroguanine and 8-oxodG plays an important role in multiple steps of genetic changes leading to tumor progression, including invasiveness.
硝化和氧化DNA损伤，如8-硝基鸟嘌呤和8-氧代-7,8-二氢-2'-脱氧鸟苷（8-氧代脱氧鸟苷，8-oxodG）的形成，与炎症介导的致癌作用的起始和/或促进有关。本研究的目的是阐明这些DNA损伤是否参与肝内胆管癌的进展。
我们调查了37例肝内胆管癌患者中8-硝基鸟嘌呤和8-oxodG的形成以及缺氧诱导因子-1α（HIF-1α）的表达与肿瘤侵袭的关系。
免疫组织化学分析显示，癌组织中8-硝基鸟嘌呤和8-oxodG的形成程度远高于非癌组织。所有患者的癌组织中均可检测到HIF-1α，提示肿瘤内存在低氧张力。HIF-1α表达与诱导型一氧化氮合酶（iNOS）表达相关（r = 0.369，P = 0.025），与8-oxodG形成相关（r =
0.398，P = 0.015）。双重免疫荧光研究显示，iNOS和HIF-1α在癌组织中共定位。值得注意的是，8-oxodG的形成与淋巴侵袭显著相关（r =
0.386，P = 0.018）。此外，非癌组织中的8-硝基鸟嘌呤和8-oxodG与神经侵袭显著相关（分别为P = 0.042和P = 0.026）。这些结果表明，HIF-1α和iNOS之间的相互激活介导了持续性DNA损伤，后者通过突变诱导肿瘤侵袭性，导致预后不良。
8-硝基鸟嘌呤和8-oxodG的形成在导致肿瘤进展（包括侵袭性）的多个基因变化步骤中起重要作用。
