Role of Brg1 in progression of esophageal squamous cell carcinoma

Document Type: Original Article


1 Medical Genetics Research Center, Medical School, Mashhad University of Medical Sciences, Mashhad, Iran

2 Division of Human Genetics, Immunology Research Center, Avicenna Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran

3 Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran

4 Medical Genetics Research Center, Medical School, Mashhad University of Medical Sciences, Mashhad, Iran 2 Division of Human Genetics, Immunology Research Center, Avicenna Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran


Objective(s): Epigenetic regulation of gene expression can be carried out through chromatin remodeling enzymes such as SWI/SNF. Brg1 also known as SMARCA4 is a catalytic subunit of SWI/SNF, which is necessary for MMPs expression. Matrix metalloproteinases (MMPs) are known as important player enzymes during tumor progression and metastasis. Aberrant epigenetic modification of chromatin should be precisely clarified to reveal probable unknown pathways in ESCC progression. Probable role of Brg1 in ESCC tumorigenesis and metastasis was studied through the assessment of Brg1 mRNA expression in KYSE30, and further evaluation about the biology of Brg1 was performed through the Brg1 silencing.
Materials and Methods: Level of Brg1 mRNA expression in KYSE30 was compared to normal tissues using the real time polymerase chain reaction (PCR). Moreover, KYSE30 cells were transfected with Brg1-siRNA to silence the Brg1.
Results: Our results showed for the first time that Brg1 mRNA expression was increased in KYSE30 cell line (ESCC cell line) compared with normal esophageal tissue of ESCC patients. Rate of transfection in KYSE30 was also between 40 to 50%, using the pSilencer-Brg1shRNA (1:1 ratio). Conclusion: Our data indicated that chromatin remodeling machinery is a novel aspect in tumor biology of ESCC, and overexpression of Brg1 as an important member of SWI/SNF might be involved in the migration and invasion of ESCC tumoral cells.


1.Abedi-Ardakani B, Sotoudeh M, Aghcheli K, Semnani S, Shakeri R, Taghavi N, et al. Esophagitis may not be a Major Precursor Lesion for Esophageal Squamous Cell Carcinoma in a High Incidence Area in North-Eastern Iran. Middle East J Dig Dis 3:28-34.

2.Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin2011;61:69-90.

3.Aghcheli K, Marjani HA, Nasrollahzadeh D, Islami F, Shakeri R, Sotoudeh M, et al. Prognostic factors for esophageal squamous cell carcinoma--a population-based study in Golestan Province, Iran, a high incidence area. PLoS One 2011; 6:e22152.

4. Crespi M, Munoz N, Grassi A, Aramesh B, Amiri G, Mojtabai A, et al. Oesophageal lesions in northern Iran: a premalignant condition? Lancet 1979 ; 2:217-221.

5. Li Y, Ma J, Guo Q, Duan F, Tang F, Zheng P, et al. Overexpression of MMP-2 and MMP-9 in esophageal squamous cell carcinoma. Dis Esophagus 2009; 22:664-667.

6. Moghbeli M, Abbaszadegan MR, Farshchian M, Montazer M, Raeisossadati R, Abdollahi A, et al. Association of PYGO2 and EGFR in esophageal squamous cell carcinoma. Med Oncol 2013; 30:516.

7. Moghbeli M, Forghanifard MM, Aarabi A, Mansourian A, Abbaszadegan MR. Clinicopathological sex- related relevance of musashi1 mRNA expression in esophageal squamous cell carcinoma patients. Pathol Oncol Res   2013; 28. [Epub ahead of print].

8. Moghbeli M, Moghbeli F, Forghanifard MM, Garayali A, Abbaszadegan MR. Cancer stem cell markers in esophageal cancer. Am J Cancer Sci 2013; 2:37-50.

9. Rydlova M, Holubec L Jr, Ludvikova M Jr, Kalfert D, Franekova J, Povysil C, et al. Biological activity and clinical implications of the matrix metalloproteinases. Anticancer Res 2008; 28:1389-1397.

10. Liotta LA, Tryggvason K, Garbisa S, Hart I, Foltz CM, Shafie S. Metastatic potential correlates with enzymatic degradation of basement membrane collagen. Nature 1980; 284:67-68.

11. Cavalli G. Chromatin and epigenetics in development: blending cellular memory with cell fate plasticity. Development 2006; 133:2089-2094.

12. Clapier CR, Cairns BR. The biology of chromatin remodeling complexes. Annu Rev Biochem 2009; 78:273-304.

13. Sif S. ATP-dependent nucleosome remodeling complexes: enzymes tailored to deal with chromatin. J Cell Biochem 2004; 91:1087-1098.

14. Asp P, Wihlborg M, Karlen M, Farrants AK. Expression of BRG1, a human SWI/SNF component, affects the organisation of actin filaments through the RhoA signalling pathway. J Cell Sci 2002; 115:2735-2746.

15. Bai J, Mei PJ, Liu H, Li C, Li W, Wu YP, et al. BRG1 expression is increased in human glioma and controls

glioma cell proliferation, migration and invasion
in vitro. J Cancer Res Clin Oncol; 138:991-998.

16. Ma Z, Chang MJ, Shah R, Adamski J, Zhao X, Benveniste EN. Brg-1 is required for maximal transcription of the human matrix metalloproteinase-2 gene. J Biol Chem 2004; 279:46326-46334.

17. Saladi SV, Keenen B, Marathe HG, Qi H, Chin KV, de la Serna IL. Modulation of extracellular matrix/adhesion molecule expression by BRG1 is associated with increased melanoma invasiveness. Mol Cancer  2010; 9:280-296.

18.Samantaray S, Sharma R, Chattopadhyaya TK, Gupta SD, Ralhan R. Increased expression of MMP-2 and MMP-9 in esophageal squamous cell carcinoma. J Cancer Res Clin Oncol 2004;130:37-44.

19.Brooks PC, Stromblad S, Sanders LC, von Schalscha TL, Aimes RT, Stetler-Stevenson WG, et al. Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin alpha v beta 3. Cell 1996;85:683-693.

20.Melnikova V, Bar-Eli M. Inflammation and melanoma growth and metastasis: the role of platelet-activating factor (PAF) and its receptor. Cancer Metastasis Rev 2007;26:359-371.

21. Chernov AV, Strongin AY. Epigenetic regulation of matrix metalloproteinases and their collagen substrates in cancer. Biomol Concepts 2011 ;2:135-147.

22. Piperi C, Papavassiliou AG. Molecular mechanisms regulating matrix metalloproteinases. Curr Top Med Chem 2012; 12:1095-10112.

23. Ma Z, Shah RC, Chang MJ, Benveniste EN. Coordination of cell signaling, chromatin remodeling, histone modifications, and regulator recruitment in human matrix metalloproteinase 9 gene transcription. Mol Cell Biol 2004; 24:5496-5509.

24. Narlikar GJ, Fan HY, Kingston RE. Cooperation between complexes that regulate chromatin structure and transcription. Cell 2002; 108:475-487.

25. de la Serna IL, Carlson KA, Imbalzano AN. Mammalian SWI/SNF complexes promote MyoD-mediated muscle differentiation. Nat Genet 2001; 27:187-190.

26. Huang M, Qian F, Hu Y, Ang C, Li Z, Wen Z. Chromatin-remodelling factor BRG1 selectively activates a subset of interferon-alpha-inducible genes. Nat Cell Biol 2002; 4:774-781.

27. Papineni S, Chintharlapalli S, Abdelrahim M, Lee SO, Burghardt R, Abudayyeh A, et al. Tolfenamic acid inhibits esophageal cancer through repression of specificity proteins and c-Met. Carcinogenesis 2009 ; 30:1193-1201.