Bmi-1 regulates stem cell-like properties of gastric cancer cells via modulating miRNAs

60Citations
Citations of this article
31Readers
Mendeley users who have this article in their library.

This article is free to access.

Abstract

Background: B cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) plays an important role in regulating stemness in some kinds of cancer. However, the mechanisms remain unclear. This study was to investigate whether and how Bmi-1 regulates stemness of gastric cancer. Methods: We firstly explored the role of Bmi-1 in regulating stem cell-like features in gastric cancer. Secondly, we screened out its downstream miRNAs and clarified whether these miRNAs are involved in the regulation of stemness. Finally, we investigated the mechanisms how Bmi-1 regulates miRNAs. Results: Bmi-1 positively regulates stem cell-like properties of gastric cancer and upregulates miR-21 and miR-34a. There was a positive correlation between Bmi-1 and miR-21 expression in gastric cancer tissues. MiR-21 mediated the function of Bmi-1 in regulating stem cell-like properties, while miR-34a negatively regulates stem cell-like characteristics via downregulating Bmi-1. Bmi-1 binds to PTEN promoter and directly inhibits PTEN and thereafter activates AKT. Bmi-1 also regulates p53 and PTEN via miR-21. Bmi-1 activated NF-kB via AKT and enhanced the binding of NF-kB to the promoter of miR-21 and miR-34a and increased their expression. Conclusions: Bmi-1 positively regulates stem cell-like properties via upregulating miR-21, and miR-34a negatively regulates stem cell-like characteristics by negative feedback regulation of Bmi-1 in gastric cancer. Bmi-1 upregulates miR-21 and miR-34a by activating AKT-NF-kB pathway.

Figures

  • Fig. 1 (See legend on next page.)
  • Table 1 The relation between the expression of Bmi-1 protein and clinicopathologic variables
  • Fig. 2 Bmi-1 regulates the expression of several miRNAs. a Bmi-1 overexpression upregulates the expression of miR-21, miR-34a, and miR-125a-5p. Fold change of miRNAs was detected by QRT-PCR in SGC7901 cells with Bmi-1 overexpression and control cells. b Bmi-1 knockdown downregulates the expression of miR-21, miR-34a, and miR-125a-5p. Fold change of miRNAs was detected by QRT-PCR, normalized to 5S in MKN45 cells with Bmi-1 knockdown and control cells. c Pearson correlation analysis showed there was a positive correlation between the expression level of Bmi-1 and miR-21. The expression of miR-21 in gastric cancer tissues with high Bmi-1 expression was higher than tissues with low Bmi-1 expression. The log10 of miR-21 expression level was plotted in Bmi-1 high and Bmi-1 low groups of gastric cancer tissues. d The expression of miR-34a was not different in gastric cancer tissues with high Bmi-1 expression from tissues with low Bmi-1 expression. The log10 of miR-34a expression level was plotted in Bmi-1 high and Bmi-1 low groups of gastric cancer tissues. Error bars in all panels represent the mean ± SD (*P < 0.05, **P < 0.01)
  • Table 2 Correlations between the expression level of Bmi-1, miR-21 or miR-34a, and clinical-pathologic variables
  • Fig. 3 miR-21 overexpression enhances stem cell-like properties of gastric cancer cells. a miR-21 is overexpressed in cancer stem-like cells of gastric cancer. Fold change of miR-21 in spheroid cells (SC) and parental cells (PC) of SGC7901 was analyzed by QRT-PCR. b miR-21 overexpression increases microsphere formation rate in gastric cancer cells. Microsphere formation rate was detected by serum-free culture (upper panel) and quantified (lower panel) in miR-21 overexpressing cells (miR-21) and control cells (Con). c miR-21 overexpression increases drug resistance in SGC7901 cells. Cell viability in miR-21 overexpressing cells (miR-21) and control cells (Con) treated with different doses of EPI for 48 h was determinated with CCK-8. d miR-21 overexpression promotes migration potential in SGC7901 cells. Migration ability of cells was detected by Transwell Assay and then photographed (upper pane) and quantified (lower panel). e miR-21 overexpression was confirmed in SGC7901 cells after infected by lentivirus with miR-21 overexpression. Fold change of miR-21 in miR-21 overexpressing cells (miR-21) and control cells (Con) was analyzed by QRT-PCR. f miR-21 overexpression upregulates the expression of stem cell markers in SGC7901 cells. The expression of stem cell markers and known miR-21 target and downstream genes (PTEN-AKT, P53) in the cell lysis was analyzed by Western blot. Error bars in all panels represent the mean ± SD (*P < 0.05, **P < 0.01 as compared with control)
  • Fig. 4 (See legend on next page.)
  • Fig. 5 (See legend on next page.)
  • Fig. 6 (See legend on next page.)

Cited by Powered by Scopus

Targeting cancer stem cell pathways for cancer therapy

1206Citations
1239Readers

This article is free to access.

537Citations
436Readers

This article is free to access.

201Citations
298Readers
Get full text

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Cite

CITATION STYLE

APA

Wang, X., Wang, C., Zhang, X., Hua, R., Gan, L., Huang, M., … Guo, W. (2016). Bmi-1 regulates stem cell-like properties of gastric cancer cells via modulating miRNAs. Journal of Hematology and Oncology, 9(1). https://doi.org/10.1186/s13045-016-0323-9

Readers over time

‘16‘17‘18‘19‘20‘21‘22‘23‘24036912

Readers' Seniority

Tooltip

PhD / Post grad / Masters / Doc 12

75%

Researcher 4

25%

Readers' Discipline

Tooltip

Biochemistry, Genetics and Molecular Bi... 10

67%

Agricultural and Biological Sciences 3

20%

Materials Science 1

7%

Social Sciences 1

7%

Save time finding and organizing research with Mendeley

Sign up for free
0