Document Type : Original Article(s)

Authors

1 Department of Medical Genetics, Tehran University of Medical Sciences, Tehran, Iran

2 Department of Animal Biology, Faculty of Natural Sciences, Tabriz University, Tabriz, Iran

3 Cancer Research Center, Cancer Institute of Iran, Tehran University of Medical Sciences, Tehran, Iran

Abstract

Background: Homeodomain transcriptional regulatory proteins, which are encoded by Homeobox (HOX) genes, play critical roles in both normal development and carcinogenesis. Previous studies have shown that the expression of HOX genes is deregulated in numerous tumors and this expression is specific to each cancer based on the arising embryonic origin tissue and the site of tumor.
Method: In this in vitro study, the expression levels of HOXA10, CDX1, CDX2, TGIFLX, TGIFLY, and OCT1 genes were compared across 10 different human colorectal cancer cell lines with different differentiation stages. Subsequently, the effect of TGIFLX siRNA-mediated knockdown on the expression levels of CDX1, CDX2, and OCT1 genes was analyzed in SW948 cell line.
Results: The obtained results revealed that these homeobox genes were differentially expressed in different colorectal cancer cell lines. Furthermore, the siRNA-mediated knockdown of TGIFLX led to higher levels of CDX1, CDX2, and OCT1 expression.
Conclusion: Our data suggested that TGIFLX plays an important role in the upstream regulation of CDX1, CDX2, and OCT1 genes.

Keywords

How to cite this article:

Shahryarhesami S, Heidari M, Heidari M, Sadighi N. Human homeobox TGIFLX regulates CDX1, CDX2, and OCT1 genes expression in colorectal cancer cell lines. Middle East J Cancer. 2022;13(2): 216-25. doi: 10. 30476/mejc.2021.86467.1345.

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5-29. doi: 10.3322/caac.21208.
  2. Taheri E, Ghorbani S, Safi M, Sani NS, Amoodizaj FF, Hajazimian S, et al. Inhibition of colorectal cancer cell line CaCo-2 by essential oil of eucalyptus camaldulensis through induction of apoptosis. Acta Med Iran. 2020;58(6):260-5.
  3. Bond JH. Clinical evidence for the adenoma-carcinoma sequence, and the management of patients with colorectal adenomas. Semin Gastrointest Dis. 2000;11:176-84.
  4. Astamal RV, Maghoul A, Taefehshokr S, Bagheri T, Mikaeili E, Derakhshani A, et al. Regulatory role of microRNAs in cancer through Hippo signaling pathway. Pathol-Res Pract. 2020;216(12):153241. doi: 10.1016/j.prp.2020.153241.
  5. Koshiji M, Yonekura Y, Saito T, Sakaida N, Uemura Y, Yoshioka K. Genetic alterations in normal epithelium of colorectal cancer patients may be a useful indicator for subsequent metachronous tumor development. Ann Surg Oncol. 2002;9:580-6. doi: 10.1007/BF02573895.
  6. Isazadeh A, Hajazimian S, Shadman B, Safaei S, Babazadeh Bedoustani A, Chvosh R, et al. Anti-cancer effects of probiotic lactobacillus acidophilus for colorectal cancer cell line caco-2 through apoptosis induction. Pharm Sci. 2020;1-5. doi: 10.34172/PS.2020.52.
  7. Sottoriva A, Kang H, Ma Z, Graham TA, Salomon MP, Zhao J, et al. A Big Bang model of human colorectal tumor growth. Nat Genet. 2015;47:209-16. doi: 10.1038/ng.3214.
  8. Firouzi Amoodizaj F, Baghaeifar S, Taheri E, Farhoudi Sefidan Jadid M, Safi M, Seyyed Sani N, et al. Enhanced anticancer potency of doxorubicin in combination with curcumin in gastric adenocarcinoma. J Biochem Mol Toxicol. 2020;e22486. doi: 10.1002/jbt.22486.
  9. Gehring WJ, Hiromi Y. Homeotic genes and the homeobox. Annu Rev Genet. 1986;20:147-73. doi: 10.1146/annurev.ge.20.120186.001051.
  10. Bhatlekar S, Fields JZ, Boman BM. HOX genes and their role in the development of human cancers. J Mol Med (Berl). 2014;92:811-23. doi: 10.1007/s00109-014-1181-y.
  11. Gehring WJ, Qian YQ, Billeter M, Furukubo-Tokunaga K, Schier AF, Resendez-Perez D, et al. Homeodomain-DNA recognition. Cell. 1994;78:211-23. doi: 10.1016/0092-8674(94)90292-5.
  12. Heidari M, Rice KL, Phillips JK, Kees UR, Greene WK. The nuclear oncoprotein TLX1/HOX11 associates with pericentromeric satellite 2 DNA in leukemic Tcells.
    2006;20(2):304-12. doi: 10.1038/sj.leu.2404071.
  13. Li X, Nie S, Chang C, Qiu T, Cao X. Smads oppose Hox transcriptional activities. Exp Cell Res. 2006;312: 854-64. doi: 10.1016/j.yexcr.2005.12.002.
  14. Banerjee-Basu S, Baxevanis AD. Molecular evolution of the homeodomain family of transcription factors. Nucleic Acids Res. 2001;29:3258-69. doi: 10.1093/nar/29.15.3258.
  15. Bürglin TR. Analysis of TALE superclass homeobox genes (MEIS, PBC, KNOX, Iroquois, TGIF) reveals a novel domain conserved between plants and animals. Nucleic Acids Res. 1997;25(21):4173-80. doi:10.1093/nar/25.21.4173.
  16. Blanco-Arias P, Sargent CA, Affara NA. The humanspecific Yp11.2/Xq21.3 homology block encodes a potentially functional testis-specific TGIF-like retroposon. Mamm Genome. 2002;13(8):463-8. doi:10.1007/s00335-002-3010-9.
  17. Domon-Dell C, Schneider A, Moucadel V, Guerin E, Guenot D, Aguillon S, et al. Cdx1 homeobox gene during human colon cancer progression. Oncogene. 2003;22(39):7913-21. doi: 10.1038/sj.onc.1206756.
  18. Mallo GV, Rechreche H, Frigerio JM, Rocha D, Zweibaum A, Lacasa M, et al. Molecular cloning, sequencing and expression of the mRNA encoding human Cdx1 and Cdx2 homeobox. Down-regulation of Cdx1 and Cdx2 mRNA expression during colorectal carcinogenesis. Int J Cancer. 1997;74(1):35-44. doi:10.1002/(sici)1097-0215(19970220)74:13.0.co;2-1.
  19. Vider BZ, Zimber A, Hirsch D, Estlein D, Chastre E, Prevot S, et al. Human colorectal carcinogenesis is associated with deregulation of homeobox gene expression. Biochem Biophys Res Commun. 1997;232:742-8. doi: 10.1006/bbrc.1997.6364.
  20. Zhou C, Tong Y, Wawrowsky K, Bannykh S, Donangelo I, Melmed S. Oct-1 induces pituitary tumor transforming gene expression in endocrine tumors. Endocr Relat Cancer. 2008;15(3):817-31. doi:10.1677/ERC-08-0060.
  21. Almeida R, Almeida J, Shoshkes M, Mendes N, Mesquita P, Silva E, et al. OCT-1 is over-expressed in intestinal metaplasia and intestinal gastric carcinomas and binds to, but does not transactivate, CDX2 in gastric cells. J Pathol. 2005;207(4):396-401. doi:10.1002/path.1861.
  22. Cantile M, Pettinato G, Procino A, Feliciello I, Cindolo L, Cillo C. In vivo expression of the whole HOX gene network in human breast cancer. Eur J Cancer. 2003;39:257-64. doi: 10.1016/S0959-8049(02)00599-3.
  23. Freschi G, Taddei A, Bechi P, Faiella A, Gulisano M, Cillo C, et al. Expression of HOX homeobox genes in the adult human colonic mucosa (and colorectal cancer?). Int J Mol Med. 2005;16:581-7. doi:10.3892/ijmm.16.4.581.
  24. Cillo C, Barba P, Freschi G, Bucciarelli G, Magli MC, Boncinelli E. HOX gene expression in normal and neoplastic human kidney. Int J Cancer. 1992;51:892-7. doi: 10.1002/ijc.2910510610.
  25. Shah N, Sukumar S. The Hox genes and their roles in oncogenesis. Nat Rev Cancer. 2010;10:361-71. doi:10.1038/nrc2826.
  26. Nguyen Kovochich A, Arensman M, Lay AR, Rao NP, Donahue T, Li X, et al. HOXB7 promotes invasion and predicts survival in pancreatic adenocarcinoma. Cancer. 2013;119:529-39. doi: 10.1002/cncr.27725.
  27. Hajazimian S, Maleki M, Mehrabad SD, Isazadeh A. Human Wharton’s jelly stem cells inhibit endometriosis through apoptosis induction. Reproduction. 2020;159(5):549-58. doi: 10.1530/REP-19-0597.
  28. Maroufi NF, Vahedian V, Akbarzadeh M, Mohammadian M, Zahedi M, Isazadeh A, et al. The apatinib inhibits breast cancer cell line MDA-MB-231 in vitro by inducing apoptosis, cell cycle arrest, and regulating nuclear factor-κB (NF-κB) and mitogenactivated protein kinase (MAPK) signaling pathways. Breast Cancer. 2020;27(4):613-20. doi: 10.1007/s12282-020-01055-6.
  29. Vahedian V, Asadi A, Esmaeili P, Zamani S, Zamani R, Hajazimian S, et al. Anti-inflammatory activity of emu oil-based nanofibrous scaffold through downregulation of IL-1, IL-6, and TNF-α proinflammatory cytokines. Horm Mol Biol Clin Investig. 2020;20190052. doi: 10.1515/hmbci-2019-0052.
  30. Li B, Huang Q, Wei GH. The role of HOX transcription factors in cancer predisposition and progression. Cancers. 2019;11(4):528. doi: 10.3390/cancers11040528.
  31. Seno HI, Oshima MA, Taniguchi MA, Usami KA, Ishikawa TO, Chiba TS, et al. CDX2 expression in the stomach with intestinal metaplasia and intestinaltype cancer: Prognostic implications. Int J Oncol. 2002;21(4):769-74. doi: 10.3892/ijo.21.4.769.
  32. Hryniuk A, Grainger S, Savory JG, Lohnes D. Cdx1 and Cdx2 function as tumor suppressors. J Biol Chem. 2014;289(48):33343-54. doi: 10.1136/gut.52.10.1465.
  33. Mallo GV, Soubeyran P, Lissitzky JC, André F, Farnarier C, Marvaldi J, et al. Expression of the Cdx1 and Cdx2 homeotic genes leads to reduced malignancy in colon cancer-derived cells. J Biol Chem. 1998;273(22):14030-6. doi: 10.1054/bjoc.2000.1544.
  34. Bonhomme C, Calon A, Martin E, Robine S, Neuville A, Kedinger M, et al. Cdx1, a dispensable homeobox gene for gut development with limited effect in intestinal cancer. Oncogene. 2008;27(32):4497-502. doi: 10.1038/onc.2008.78.
  35. Wong NA, Britton MP, Choi GS, Stanton TK, Bicknell DC, Wilding JL, et al. Loss of CDX1 expression in colorectal carcinoma: promoter methylation, mutation, and loss of heterozygosity analyses of 37 cell lines. Proc Natl Acad Sci USA. 2004;101(2):574-9.
  36. Calon A, Gross I, Lhermitte B, Martin E, Beck F, Duclos B, et al. Different effects of the Cdx1 and Cdx2 homeobox genes in a murine model of intestinal inflammation. Gut. 2007;56(12):1688-95. doi:10.1136/gut.2007.125542.
  37. Mann RS, Lelli KM, Joshi R. Hox specificity: unique roles for cofactors and collaborators. Cur Top Dev Biol. 2009;88:63-101. doi: 10.1016/S0070-2153(09)88003-4.
  38. Soubeyran P, Haglund K, Garcia S, Barth BU, Iovanna J, Dikic I. Homeobox gene Cdx1 regulates Ras, Rho and PI3 kinase pathways leading to transformation and tumorigenesis of intestinal epithelial cells. Oncogene. 2001;20(31):4180-7. doi: 10.1038/sj.onc.1204551.
  39. Joo MK, Park JJ, Chun HJ. Impact of homeobox genes in gastrointestinal cancer. World J Gastroenterol. 2016;22(37):8247. doi: 10.3748/wjg.v22.i37.8247.
  40. Magné S, Caron S, Charon M, Rouyez MC, Dusanter-Fourt I. STAT5 and Oct-1 form a stable complex that modulates cyclin D1 expression. Mol Cell Biol. 2003;23(24):8934-45. doi: 10.1128/MCB.23.24.8934–8945.2003.