Transcription factors GATA-4 and GATA-6 in normal and neoplastic human gastrointestinal mucosa.
Transcription factors GATA-4 and GATA-6 in normal and neoplastic human gastrointestinal mucosa.
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DOI：
10.1186/1471-230x-8-9
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发表时间：
2008-04-11
影响因子：
2.4
通讯作者：
Heikinheimo M
中科院分区：
文献类型：
--
作者：
Haveri H;Westerholm-Ormio M;Lindfors K;Mäki M;Savilahti E;Andersson LC;Heikinheimo M
人的胃肠道粘膜在整个生命过程中再生旺盛，但对成熟粘膜中控制细胞命运的因素知之甚少。加塔转录因子指导许多器官中的细胞增殖和分化，并且与肿瘤发生有关。加塔-4和加塔-6被认为对小鼠胃肠道粘膜的形成至关重要，但它们在人胃肠道中的作用尚未被探索。我们详细研究了这两个加塔因子和一个加塔-6下游靶点印度刺猬（Ihh）在正常人胃肠道粘膜中的表达模式。由于这些因素被认为是重要的增殖和分化，我们也探讨了可能的改变，在胃肠道肿瘤的表达。与加塔因子相比，还研究了致癌相关蛋白印度刺猬的表达。正常和肿瘤的胃肠道样品从儿童和成人进行RNA原位杂交与33 P标记的探针和免疫组化，使用亲和素-生物素免疫过氧化物酶系统。检查的病理组织包括慢性和萎缩性胃炎以及结肠和直肠的腺瘤和腺癌的样品。加塔-4在胃肠道近端部分的分化上皮细胞中丰富，但在远端部分不存在。相反，加塔-6在整个胃肠上皮中表达，并且在远端肠中，其表达在隐窝底部（即具有增殖能力的细胞）最强烈。这两个因素也存在于巴雷特食管和胃化生。加塔-6在结肠癌中表达降低。Ihh与加塔-6的表达有重叠，尤其在胃肠道良性肿瘤中。结果表明加塔-4和加塔-6在正常胃肠道粘膜中具有不同但重叠的功能。此外，加塔-4、加塔-6和Ihh表达在癌前发育异常病变中改变，在明显癌症中降低。
Human gastrointestinal mucosa regenerates vigorously throughout life, but the factors controlling cell fate in mature mucosa are poorly understood. GATA transcription factors direct cell proliferation and differentiation in many organs, and are implicated in tumorigenesis. GATA-4 and GATA-6 are considered crucial for the formation of murine gastrointestinal mucosa, but their role in human gastrointestinal tract remains unexplored. We studied in detail the expression patterns of these two GATA factors and a GATA-6 down-stream target, Indian hedgehog (Ihh), in normal human gastrointestinal mucosa. Since these factors are considered important for proliferation and differentiation, we also explored the possible alterations in their expression in gastrointestinal neoplasias. The expression of the carcinogenesis-related protein Indian hedgehog was also investigated in comparison to GATA factors. Samples of normal and neoplastic gastrointestinal tract from children and adults were subjected to RNA in situ hybridization with 33P labelled probes and immunohistochemistry, using an avidin-biotin immunoperoxidase system. The pathological tissues examined included samples of chronic and atrophic gastritis as well as adenomas and adenocarcinomas of the colon and rectum. GATA-4 was abundant in the differentiated epithelial cells of the proximal parts of the gastrointestinal tract but was absent from the distal parts. In contrast, GATA-6 was expressed throughout the gastrointestinal epithelium, and in the distal gut its expression was most intense at the bottom of the crypts, i.e. cells with proliferative capacity. Both factors were also present in Barrett's esophagus and metaplasia of the stomach. GATA-6 expression was reduced in colon carcinoma. Ihh expression overlapped with that of GATA-6 especially in benign gastrointestinal neoplasias. The results suggest differential but overlapping functions for GATA-4 and GATA-6 in the normal gastrointestinal mucosa. Furthermore, GATA-4, GATA-6 and Ihh expression is altered in premalignant dysplastic lesions and reduced in overt cancer.