title: Factor inhibiting HIF1α (FIH-1) functions as a tumor suppressor in human colorectal cancer by repressing HIF1α pathway.
abstract: 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-1α (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-1α and its target genes. We found that FIH-1 was able to inhibit HIF1α 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 HIF1α 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 HIF1α pathway.
authors.affiliation: a Endoscopy Center ; Zhongshan Hospital of Fudan University ; Shanghai , China.
authors.forename: Tao
authors.initials: T
authors.lastname: Chen
authors.forename: Zhong
authors.initials: Z
authors.lastname: Ren
authors.forename: Le-Chi
authors.initials: LC
authors.lastname: Ye
authors.forename: Ping-Hong
authors.initials: PH
authors.lastname: Zhou
authors.forename: Jian-Min
authors.initials: JM
authors.lastname: Xu
authors.forename: Qiang
authors.initials: Q
authors.lastname: Shi
authors.forename: Li-Qing
authors.initials: LQ
authors.lastname: Yao
authors.forename: Yun-Shi
authors.initials: YS
authors.lastname: Zhong
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008875:Middle Aged; D011379:Prognosis; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D051272:Glucose Transporter Type 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A
keywords: CRC, colorectal cancer; FIH-1; FIH-1, Factor inhibiting HIF1α; GLUT1, glucose transporter 1; HIF1α pathway; HIF1α, Hypoxia-inducible transcription factor 1α; IHC, immunohistochemistry; TMA, tissue microarrays; VEGF, vascular endothelial growth factor; colorectal cancer; prognosis; progression; tumor suppressor; tumorigenesis