Factor inhibiting HIF1α (FIH-1) functions as a tumor suppressor in human colorectal cancer by repressing HIF1α pathway
Factor inhibiting HIF1α (FIH-1) functions as a tumor suppressor in human colorectal cancer by repressing HIF1α pathway
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DOI：
10.1080/15384047.2014.1002346
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发表时间：
2015-02-01
影响因子：
3.6
通讯作者：
Zhong, Yun-Shi
中科院分区：
文献类型：
--
作者：
Chen, Tao;Ren, Zhong;Zhong, Yun-Shi
结直肠癌（CRC）是世界上最常见的癌症之一。CRC发生的分子机制涉及一个多步骤的过程，包括遗传和表观遗传变化的积累。为了深入了解CRC肿瘤的发生和发展，因此迫切需要在识别新机制和关键因素方面取得进展。在此，我们研究了抑制HIF-1（FIH-1）表达的因子与结直肠癌临床病理特征的相关性。发现FIH-1不仅在肿瘤组织中显著降低，而且与肿瘤浸润深度、淋巴结受累和转移显著相关，这表明FIH-1在CRC发展中作为肿瘤抑制因子的作用。为了进一步支持上述假设，我们进行了体外和体内实验以鉴定FIH-1在CRC发展中的作用。发现FIH-1在体外抑制CRC细胞增殖、迁移、侵袭和集落形成。FIH-1还显示在体内抑制LOVO异种移植肿瘤生长。为了解释其机制，我们检测了HIF-1及其靶基因的表达水平。我们发现FIH-1能够抑制HIF 1介导的CRC细胞中GLUT 1和VEGF的转录。上述观察结果表明，FIH-1基因表达的缺失或降低可能导致HIF-1的组成性激活和HIF-1靶点如GLUT-1和VEGF的改变。这些发现强调了FIH-1在CRC中的关键作用，并表明FIH-1通过抑制HIF 1通路在人类CRC中作为肿瘤抑制因子发挥作用。
Colorectal cancer (CRC) is one of the most common cancers worldwide. The molecular mechanisms underlying CRC development involve a multistep process with the accumulation of both genetic and epigenetic changes. To deeply understand CRC tumorigenesis and progression, advances in identification of novel mechanisms and key factors are therefore in an urgent need. Here, we examined the correlation of factor inhibiting HIF-1 (FIH-1) expression with clinicopathological features of CRC. The finding that FIH-1 was not only significantly decreased in tumor tissue but also was significantly correlated with tumor invading depth, lymph node involvement, and metastasis suggested the role of FIH-1 as a tumor suppressor in CRC development. To further support the above hypothesis, we performed both in vitro and in vivo experiments to identify the role of FIH-1 in CRC development. FIH-1 was found to inhibit CRC cell proliferation, migration, invasion, and colony formation in vitro. FIH-1 was also shown to repress LOVO xenograft tumor growth in vivo. To decipher the mechanism, we examined the expression level of HIF-1 and its target genes. We found that FIH-1 was able to inhibit HIF1 mediated transcription of GLUT1 and VEGF in CRC cells. The above observation points to the possibility that loss or decreased expression of FIH-1 gene may lead to a constitutive activation of HIF1 and an alteration of HIF-1 targets such as GLUT-1 and VEGF. These findings highlight the critical role of FIH-1 in CRC and indicate FIH-1 functions as a tumor suppressor in human CRC by repressing HIF1 pathway.