Downregulation of miR-377 contributes to IRX3 deregulation in hepatocellular carcinoma

Wang,Pei; Zhuang,Chunbo; Huang,Da; Xu,Keshu

doi:10.3892/or.2016.4815

Downregulation of miR-377 contributes to IRX3 deregulation in hepatocellular carcinoma

Authors:
- Pei Wang
- Chunbo Zhuang
- Da Huang
- Keshu Xu
View Affiliations

Affiliations: Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China, Department of Clinical Laboratory Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
Published online on: May 18, 2016 https://doi.org/10.3892/or.2016.4815
Pages: 247-252

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Iroquois homeobox (IRX) gene family, which plays essential roles in embryonic development, has recently been reported to be involved in tumor progression. However, the association of IRX3, a member of the IRX family, with hepatocellular carcinoma (HCC) has not previously been studied. In the present study, we found that IRX3 was upregulated in HCC cell lines (HepG2 and SMMC7721). We investigated the regulatory mechanism of IRX3 in HCC cells. Western blot and luciferase reporter assays identified that IRX3 is a direct target of miR-377. In addition, miR-377 was downregulated in HepG2 and SMMC7721 cell lines, and overexpression of miR-377 inhibited HepG2 cell proliferation, migration and invasion. Moreover, miR-377 restoration significantly abrogated IRX3-induced proliferation, migration and invasion of SMMC7721 cells. These findings demonstrate the tumor-promoting potential of IRX3, and that downregulation of miR-377 may contribute to the upregulation of IRX3 in HCC. The present study provides insights into HCC progression and a novel potential therapeutic target of HCC treatment.

View Figures

View References

1	Maluccio M and Covey A: Recent progress in understanding, diagnosing, and treating hepatocellular carcinoma. CA Cancer J Clin. 62:39992012. View Article : Google Scholar
2	Gómez-Skarmeta JL and Modolell J: Iroquois genes: Genomic organization and function in vertebrate neural development. Curr Opin Genet Dev. 12:40082002. View Article : Google Scholar
3	Kudoh T and Dawid IB: Role of the iroquois3 homeobox gene in organizer formation. Proc Natl Acad Sci USA. 98:7858572001. View Article : Google Scholar
4	Kim KH, Rosen A, Bruneau BG, Hui CC and Backx PH: Iroquois homeodomain transcription factors in heart development and function. Circ Res. 110:1515242012. View Article : Google Scholar
5	Guo X, Liu W, Pan Y, Ni P, Ji J, Guo L, Zhang J, Wu J, Jiang J, Chen X, et al: Homeobox gene IRX1 is a tumor suppressor gene in gastric carcinoma. Oncogene. 29:3909202010. View Article : Google Scholar
6	Werner S, Stamm H, Pandjaitan M, Kemming D, Brors B, Pantel K and Wikman H: Iroquois homeobox 2 suppresses cellular motility and chemokine expression in breast cancer cells. BMC Cancer. 15:8962015. View Article : Google Scholar : PubMed/NCBI
7	Myrthue A, Rademacher BL, Pittsenbarger J, Kutyba-Brooks B, Gantner M, Qian DZ and Beer TM: The iroquois homeobox gene 5 is regulated by 1,25-dihydroxyvitamin D₃ in human prostate cancer and regulates apoptosis and the cell cycle in LNCaP prostate cancer cells. Clin Cancer Res. 14:3565702008. View Article : Google Scholar
8	Ordway JM, Bedell JA, Citek RW, Nunberg A, Garrido A, Kendall R, Stevens JR, Cao D, Doerge RW, Korshunova Y, et al: Comprehensive DNA methylation profiling in a human cancer genome identifies novel epigenetic targets. Carcinogenesis. 27:2404232006. View Article : Google Scholar
9	Seol MA, Chu IS, Lee MJ, Yu GR, Cui XD, Cho BH, Ahn EK, Leem SH, Kim IH and Kim DG: Genome-wide expression patterns associated with oncogenesis and sarcomatous transdifferentation of cholangiocarcinoma. BMC Cancer. 11:782011. View Article : Google Scholar : PubMed/NCBI
10	Evenepoel L, Van Nederveen FH, Oudijk L, Papathomas TG, Restuccia DF, Belt EJ, Franssen GJ, Feelders RA, Van Eeden S, Timmers H, et al: 9b09: Identification of markers predictive for malignant behavior of pheochromocytomas and paragangliomas. J Hypertens. 33(Suppl 1): e1222015. View Article : Google Scholar
11	Sabates-Bellver J, Van der Flier LG, de Palo M, Cattaneo E, Maake C, Rehrauer H, Laczko E, Kurowski MA, Bujnicki JM, Menigatti M, et al: Transcriptome profile of human colorectal adenomas. Mol Cancer Res. 5:1262752007. View Article : Google Scholar
12	Yang ZQ, Liu G, Bollig-Fischer A, Giroux CN and Ethier SP: Transforming properties of 8p12 amplified genes in human breast cancer. Cancer Res. 70:8484972010. View Article : Google Scholar
13	Morey SR, Smiraglia DJ, James SR, Yu J, Moser MT, Foster BA and Karpf AR: DNA methylation pathway alterations in an autochthonous murine model of prostate cancer. Cancer Res. 66:116516672006. View Article : Google Scholar
14	Mengelbier LH, Karlsson J, Lindgren D, Øra I, Isaksson M, Frigyesi I, Frigyesi A, Bras J, Sandstedt B and Gisselsson D: Deletions of 16q in Wilms tumors localize to blastemal-anaplastic cells and are associated with reduced expression of the IRXB renal tubulogenesis gene cluster. Am J Pathol. 177:2606212010. View Article : Google Scholar
15	Bartel DP: MicroRNAs: Target recognition and regulatory functions. Cell. 136:21332009. View Article : Google Scholar
16	Szabo G and Bala S: MicroRNAs in liver disease. Nat Rev Gastroenterol Hepatol. 10:54522013. View Article : Google Scholar
17	He Y, Lin J, Kong D, Huang M, Xu C, Kim TK, Etheridge A, Luo Y, Ding Y and Wang K: Current state of circulating microRNAs as cancer biomarkers. Clin Chem. 61:1131552015. View Article : Google Scholar
18	Li Y, Xie J, Xu X, Wang J, Ao F, Wan Y and Zhu Y: MicroRNA-548 down-regulates host antiviral response via direct targeting of IFN-λ1. Protein Cell. 4:13412013. View Article : Google Scholar
19	van Tuyl M, Liu J, Groenman F, Ridsdale R, Han RN, Venkatesh V, Tibboel D and Post M: Iroquois genes influence proximo-distal morphogenesis during rat lung development. Am J Physiol Lung Cell Mol Physiol. 290:L777–L789. 2006. View Article : Google Scholar
20	Houweling AC, Dildrop R, Peters T, Mummenhoff J, Moorman AF, Rüther U and Christoffels VM: Gene and cluster-specific expression of the Iroquois family members during mouse development. Mech Dev. 107:16742001. View Article : Google Scholar
21	Chen G, Lu L, Liu C, Shan L and Yuan D: MicroRNA-377 suppresses cell proliferation and invasion by inhibiting TIAM1 expression in hepatocellular carcinoma. PLoS One. 10:e01177142015. View Article : Google Scholar : PubMed/NCBI
22	Smemo S, Tena JJ, Kim KH, Gamazon ER, Sakabe NJ, Gómez-Marín C, Aneas I, Credidio FL, Sobreira DR, Wasserman NF, et al: Obesity-associated variants within FTO form long-range functional connections with IRX3. Nature. 507:37752014. View Article : Google Scholar
23	Scarlett K, Pattabiraman V, Barnett P, Liu D and Anderson LM: The proangiogenic effect of iroquois homeobox transcription factor Irx3 in human microvascular endothelial cells. J Biol Chem. 290:6303152015. View Article : Google Scholar
24	Martorell Ò, Barriga FM, Merlos-Suárez A, Stephan-Otto Attolini C, Casanova J, Batlle E, Sancho E and Casali A: Iro/IRX transcription factors negatively regulate Dpp/TGF-β pathway activity during intestinal tumorigenesis. EMBO Rep. 15:1212182014. View Article : Google Scholar
25	Zhang SS, Kim KH, Rosen A, Smyth JW, Sakuma R, Delgado-Olguín P, Davis M, Chi NC, Puviindran V, Gaborit N, et al: Iroquois homeobox gene 3 establishes fast conduction in the cardiac His-Purkinje network. Proc Natl Acad Sci USA. 108:135735812011.