Overexpression of Bmi-1 contributes to the invasion and metastasis of hepatocellular carcinoma by increasing the expression of matrix metalloproteinase (MMP)‑2, MMP-9 and vascular endothelial growth factor via the PTEN/PI3K/Akt pathway

Li,Xiaolei; Yang,Zhaoxu; Song,Wenjie; Zhou,Liang; Li,Qingjun; Tao,Kaishan; Zhou,Jingshi; Wang,Xing; Zheng,Zhigang; You,Nan; Dou,Kefeng; Li,Haimin

doi:10.3892/ijo.2013.1992

Overexpression of Bmi-1 contributes to the invasion and metastasis of hepatocellular carcinoma by increasing the expression of matrix metalloproteinase (MMP)‑2, MMP-9 and vascular endothelial growth factor via the PTEN/PI3K/Akt pathway

Authors:
- Xiaolei Li
- Zhaoxu Yang
- Wenjie Song
- Liang Zhou
- Qingjun Li
- Kaishan Tao
- Jingshi Zhou
- Xing Wang
- Zhigang Zheng
- Nan You
- Kefeng Dou
- Haimin Li
View Affiliations

Affiliations: Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shannxi 710032, P.R. China, Department of Urology, Xinqiao Hospital, The Third Military Medical University, Chongqing 400038, P.R. China
Published online on: June 26, 2013 https://doi.org/10.3892/ijo.2013.1992
Pages: 793-802

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

Hepatocellular carcinoma (HCC) is one of the most common malignant tumours and it carries a poor prognosis due to a high rate of recurrence or metastasis after surgery. Bmi-1 plays a significant role in the growth and metastasis of many solid tumours. However, the exact mechanisms underlying Bmi-1-mediated cell invasion and metastasis, especially in HCC, are not yet known. In the present study, we sought to evaluate the expression of Bmi-1 in HCC samples and its relationship with clinicopathological characteristics and prognostic value, we also investigated related mechanisms underlying Bmi-1-mediated cell invasion in HCC. Our results showed that Bmi-1 is upregulated in HCC tissues compared to matched non-cancer liver tissues; and its expression is positively associated with tumour size, metastasis, venous invasion and AJCC TNM stage, respectively; multivariate analysis showed that high expression of Bmi-1 was an independent prognostic factor for overall survival. In addition, the shRNA-mediated inhibition of Bmi-1 reduced the invasiveness of two HCC cell lines in vitro by upregulating phosphatase and the tensin homolog deleted on chromosome 10 (PTEN) expression, inhibiting the phosphatidylinositol 3-kinase (PI3K)/Akt signalling pathway and downregulating the expression and activities of matrix metalloproteinase (MMP)-2 and MMP-9 and vascular endothelial growth factor (VEGF). These data demonstrate that Bmi-1 plays a vital role in HCC invasion and that Bmi-1 is a potential therapeutic target for HCC.

View Figures

View References

1	Tung-Ping PR, Fan ST and Wong J: Risk factors, prevention and management of postoperative recurrence after resection of hepatocellular carcinoma. Ann Surg. 232:10–24. 2000. View Article : Google Scholar : PubMed/NCBI
2	Thomas MB and Zhu AX: Hepatocellular carcinoma: the need for progress. J Clin Oncol. 23:2892–2899. 2005. View Article : Google Scholar : PubMed/NCBI
3	Jacobs JJ and van Lohuizen M: Polycomb repression: from cellular memory to cellular proliferation and cancer. Biochim Biophys Acta. 1602:151–161. 2002.PubMed/NCBI
4	Kondo Y, Shen L, Cheng AS, et al: Gene silencing in cancer by histone H3 lysine 27 trimethylation independent of promoter DNA methylation. Nat Genet. 40:741–750. 2008. View Article : Google Scholar : PubMed/NCBI
5	Raaphorst FM: Deregulated expression of Polycomb-group oncogenes in human malignant lymphomas and epithelial tumors. Hum Mol Genet. 14:R93–R100. 2005. View Article : Google Scholar : PubMed/NCBI
6	van Lohuizen M, Verbeek S, Scheijen B, Wientjens E, van der Gulden H and Berns A: Identification of cooperating oncogenes in E mu-myc transgenic mice by provirus tagging. Cell. 65:737–752. 1991.PubMed/NCBI
7	Liu S, Dontu G, Mantle ID, et al: Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res. 66:6063–6071. 2006. View Article : Google Scholar : PubMed/NCBI
8	Jacobs JJ, Kieboom K, Marino S, DePinho RA and van Lohuizen M: The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature. 397:164–168. 1999. View Article : Google Scholar : PubMed/NCBI
9	Dimri GP, Martinez JL, Jacobs JJ, et al: The Bmi-1 oncogene induces telomerase activity and immortalizes human mammary epithelial cells. Cancer Res. 62:4736–4745. 2002.PubMed/NCBI
10	Mihic-Probst D, Kuster A, Kilgus S, et al: Consistent expression of the stem cell renewal factor BMI-1 in primary and metastatic melanoma. Int J Cancer. 121:1764–1770. 2007. View Article : Google Scholar : PubMed/NCBI
11	Kim JH, Yoon SY, Jeong SH, et al: Overexpression of Bmi-1 oncoprotein correlates with axillary lymph node metastases in invasive ductal breast cancer. Breast. 13:383–388. 2004. View Article : Google Scholar : PubMed/NCBI
12	Qin ZK, Yang JA, Ye YL, et al: Expression of Bmi-1 is a prognostic marker in bladder cancer. BMC Cancer. 9:612009. View Article : Google Scholar : PubMed/NCBI
13	Song W, Tao K, Li H, et al: Bmi-1 is related to proliferation, survival and poor prognosis in pancreatic cancer. Cancer Sci. 101:1754–1760. 2010. View Article : Google Scholar : PubMed/NCBI
14	Effendi K, Mori T, Komuta M, Masugi Y, Du W and Sakamoto M: Bmi-1 gene is upregulated in early-stage hepatocellular carcinoma and correlates with ATP-binding cassette transporter B1 expression. Cancer Sci. 101:666–672. 2010. View Article : Google Scholar : PubMed/NCBI
15	Sasaki M, Ikeda H, Itatsu K, et al: The overexpression of polycomb group proteins Bmi1 and EZH2 is associated with the progression and aggressive biological behavior of hepatocellular carcinoma. Lab Invest. 88:873–882. 2008. View Article : Google Scholar : PubMed/NCBI
16	Wang H, Pan K, Zhang HK, et al: Increased polycomb-group oncogene Bmi-1 expression correlates with poor prognosis in hepatocellular carcinoma. J Cancer Res Clin Oncol. 134:535–541. 2008. View Article : Google Scholar : PubMed/NCBI
17	Sparmann A and van Lohuizen M: Polycomb silencers control cell fate, development and cancer. Nat Rev Cancer. 6:846–856. 2006. View Article : Google Scholar : PubMed/NCBI
18	Li DW, Tang HM, Fan JW, et al: Expression level of Bmi-1 oncoprotein is associated with progression and prognosis in colon cancer. J Cancer Res Clin Oncol. 136:997–1006. 2010. View Article : Google Scholar : PubMed/NCBI
19	Liu JH, Song LB, Zhang X, et al: Bmi-1 expression predicts prognosis for patients with gastric carcinoma. J Surg Oncol. 97:267–272. 2008. View Article : Google Scholar : PubMed/NCBI
20	Song LB, Zeng MS, Liao WT, et al: Bmi-1 is a novel molecular marker of nasopharyngeal carcinoma progression and immortalizes primary human nasopharyngeal epithelial cells. Cancer Res. 66:6225–6232. 2006. View Article : Google Scholar
21	Jiang Y, Su B, Meng X, et al: Effect of siRNA-mediated silencing of Bmi-1 gene expression on HeLa cells. Cancer Sci. 101:379–386. 2010. View Article : Google Scholar : PubMed/NCBI
22	Zhou L, Wang DS, Li QJ, Sun W, Zhang Y and Dou KF: Downregulation of the Notch signaling pathway inhibits hepatocellular carcinoma cell invasion by inactivation of matrix metalloproteinase-2 and -9 and vascular endothelial growth factor. Oncol Rep. 28:874–882. 2012.
23	Zheng H, Takahashi H, Murai Y, et al: Expressions of MMP-2, MMP-9 and VEGF are closely linked to growth, invasion, metastasis and angiogenesis of gastric carcinoma. Anticancer Res. 26:3579–3583. 2006.PubMed/NCBI
24	Song LB, Li J, Liao WT, et al: The polycomb group protein Bmi-1 represses the tumour suppressor PTEN and induces epithelial-mesenchymal transition in human nasopharyngeal epithelial cells. J Clin Invest. 119:3626–3636. 2009. View Article : Google Scholar
25	Pore N, Liu S, Haas-Kogan DA, O’Rourke DM and Maity A: PTEN mutation and epidermal growth factor receptor activation regulate vascular endothelial growth factor (VEGF) mRNA expression in human glioblastoma cells by transactivating the proximal VEGF promoter. Cancer Res. 63:236–241. 2003.
26	Liu B, Wu X, Liu B, et al: MiR-26a enhances metastasis potential of lung cancer cells via AKT pathway by targeting PTEN. Biochim Biophys Acta. 1822:1692–1704. 2012. View Article : Google Scholar : PubMed/NCBI
27	Chen JS, Wang Q, Fu XH, et al: Involvement of PI3K/PTEN/AKT/mTOR pathway in invasion and metastasis in hepatocellular carcinoma: association with MMP-9. Hepatol Res. 39:177–186. 2009. View Article : Google Scholar : PubMed/NCBI
28	Gomaa AI, Khan SA, Toledano MB, Waked I and Taylor-Robinson SD: Hepatocellular carcinoma: epidemiology, risk factors and pathogenesis. World J Gastroenterol. 14:4300–4308. 2008. View Article : Google Scholar : PubMed/NCBI
29	Guo BH, Feng Y, Zhang R, et al: Bmi-1 promotes invasion and metastasis and its elevated expression is correlated with an advanced stage of breast cancer. Mol Cancer. 10:102011. View Article : Google Scholar : PubMed/NCBI
30	Hoenerhoff MJ, Chu I, Barkan D, et al: BMI1 cooperates with H-RAS to induce an aggressive breast cancer phenotype with brain metastases. Oncogene. 28:3022–3032. 2009. View Article : Google Scholar : PubMed/NCBI
31	Deryugina EI and Quigley JP: Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev. 25:9–34. 2006. View Article : Google Scholar
32	Egeblad M and Werb Z: New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer. 2:161–174. 2002. View Article : Google Scholar : PubMed/NCBI
33	Fingleton B: Matrix metalloproteinases: roles in cancer and metastasis. Front Biosci. 11:479–491. 2006. View Article : Google Scholar : PubMed/NCBI
34	Zhang Q, Chen X, Zhou J, et al: CD147, MMP-2, MMP-9 and MVD-CD34 are significant predictors of recurrence after liver transplantation in hepatocellular carcinoma patients. Cancer Biol Ther. 5:808–814. 2006. View Article : Google Scholar
35	Giannelli G, Bergamini C, Marinosci F, et al: Clinical role of MMP-2/TIMP-2 imbalance in hepatocellular carcinoma. Int J Cancer. 97:425–431. 2002. View Article : Google Scholar : PubMed/NCBI
36	Wey JS, Fan F, Gray MJ, et al: Vascular endothelial growth factor receptor-1 promotes migration and invasion in pancreatic carcinoma cell lines. Cancer. 104:427–438. 2005. View Article : Google Scholar : PubMed/NCBI
37	Meng X, Wang Y, Zheng X, et al: shRNA-mediated knockdown of Bmi-1 inhibit lung adenocarcinoma cell migration and metastasis. Lung Cancer. 77:24–30. 2012. View Article : Google Scholar : PubMed/NCBI
38	Jiang L, Wu J, Yang Y, et al: Bmi-1 promotes the aggressiveness of glioma via activating the NF-kappaB/MMP-9 signaling pathway. BMC Cancer. 12:4062012. View Article : Google Scholar : PubMed/NCBI
39	Vivanco I and Sawyers CL: The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer. 2:489–501. 2002. View Article : Google Scholar : PubMed/NCBI
40	Chalhoub N and Baker SJ: PTEN and the PI3-kinase pathway in cancer. Annu Rev Pathol. 4:127–150. 2009. View Article : Google Scholar : PubMed/NCBI