High-mobility group box 1 is overexpressed in cervical carcinoma
and promotes cell invasion and migration in vitro

Pang,Xiaoao; Zhang,Yao; Zhang,Shulan

doi:10.3892/or.2016.5317

February-2017 Volume 37 Issue 2

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February-2017 Volume 37 Issue 2

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Article

High-mobility group box 1 is overexpressed in cervical carcinoma and promotes cell invasion and migration in vitro

Authors:
- Xiaoao Pang
- Yao Zhang
- Shulan Zhang
View Affiliations / Copyright

Affiliations: Department of Gynecology and Obstetrics, Shengjing Hospital of China Medical University, Heping, Shenyang, Liaoning 110004, P.R. China
Pages: 831-840
|
Published online on: December 14, 2016

https://doi.org/10.3892/or.2016.5317
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Abstract

The present study aimed to investigate the expression of high-mobility group box 1 protein (HMGB1) in cervical carcinoma and explore whether or not HMGB1 promotes cervical carcinoma cell invasion and migration in vitro and the related mechanism. HMGB1, nuclear factor-κB (NF-κB), E-cadherin and N-cadherin protein expression was analyzed in tissues from 48 cervical carcinomas, 51 cervical intraepithelial neoplasia (CIN) and tissues from 24 healthy controls using immunohistochemistry. HeLa cells were treated with different concentrations of HMGB1 (0, 10, 100, and 1,000 ng/ml) at different time-points (0, 24, 48 and 72 h), and changes in cell morphology and biological behaviors were observed. Changes in the expression levels of E-cadherin, N-cadherin, NF-κB and the inhibitor κB (IκB) in the treated cells were detected by western blot analysis and real-time PCR. HMGB1 expression exhibited a gradually increasing trend in the normal cervical tissues, CIN and cervical cancer, and there was statistical significance between the three groups (P<0.05). HMGB1 expression level was associated with FIGO stage, lymph node metastasis and differentiation (P<0.05). HMGB1 expression was positively related to N-cadherin and NF-κB; and HMGB1 had a negative relationship with E-cadherin. HMGB1 stimulation caused HeLa cells to lose cell polarity and transition from epithelial cells into spindle-shaped cells with sparse cell-cell junctions. The expression levels of E-cadherin and IκB in the cytoplasm were reduced, while N-cadherin expression was increased. The level of NF-κB expression in the nucleus was also increased. Treatment with NF-κB inhibitor (BAY11-7082) and receptor for advanced glycation end products (RAGE) antagonist (anti-RAGE) significantly suppressed HMGB1‑mediated epithelial-to-mesenchymal transition in the HeLa cervical cancer cells. The results suggest that HMGB1 is associated with outcomes of cervical cancer and promotes subsequent invasion and metastasis of cervical cancer cells by activating the NF-κB signaling pathway. This potential mechanism could be an important determinant of cervical cancer metastasis.

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1	Lee MY and Shen MR: Epithelial-mesenchymal transition in cervical carcinoma. Am J Transl Res. 4:1–13. 2012.PubMed/NCBI
2	Iwatsuki M, Mimori K, Yokobori T, Ishi H, Beppu T, Nakamori S, Baba H and Mori M: Epithelial-mesenchymal transition in cancer development and its clinical significance. Cancer Sci. 101:293–299. 2010. View Article : Google Scholar : PubMed/NCBI
3	Chen RC, Yi PP, Zhou RR, Xiao MF, Huang ZB, Tang DL, Huang Y and Fan XG: The role of HMGB1-RAGE axis in migration and invasion of hepatocellular carcinoma cell lines. Mol Cell Biochem. 390:271–280. 2014. View Article : Google Scholar : PubMed/NCBI
4	Evans A, Lennard TW and Davies BR: High-mobility group protein 1(Y): Metastasis-associated or metastasis-inducing? J Surg Oncol. 88:86–99. 2004. View Article : Google Scholar : PubMed/NCBI
5	Chen XY and Yuan R: Expression and significance of HMGB1 and E-cadherin in ovarian carcinoma. J Chongqing Med Univ. 37:614–616. 2012.(In Chinese).
6	Zhao FH, Tiggelaar SM, Hu SY, Xu LN, Hong Y, Niyazi M, Gao XH, Ju LR, Zhang LQ, Feng XX, et al: A multi-center survey of age of sexual debut and sexual behavior in Chinese women: Suggestions for optimal age of human papillomavirus vaccination in China. Cancer Epidemiol. 36:384–390. 2012. View Article : Google Scholar : PubMed/NCBI
7	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI
8	López-Novoa JM and Nieto MA: Inflammation and EMT: An alliance towards organ fibrosis and cancer progression. EMBO Mol Med. 1:303–314. 2009. View Article : Google Scholar : PubMed/NCBI
9	Savagner P: The epithelial-mesenchymal transition (EMT) phenomenon. Ann Oncol. 21:(Suppl 7). vii89–vii92. 2010. View Article : Google Scholar : PubMed/NCBI
10	Wu ST, Sun GH, Hsu CY, Huang CS, Wu YH, Wang HH and Sun KH: Tumor necrosis factor-α induces epithelial-mesenchymal transition of renal cell carcinoma cells via a nuclear factor kappa B-independent mechanism. Exp Biol Med (Maywood). 236:1022–1029. 2011. View Article : Google Scholar : PubMed/NCBI
11	Li CW, Xia W, Huo L, Lim SO, Wu Y, Hsu JL, Chao CH, Yamaguchi H, Yang NK, Ding Q, et al: Epithelial-mesenchymal transition induced by TNF-α requires NF-κB-mediated transcriptional upregulation of Twist1. Cancer Res. 72:1290–1300. 2012. View Article : Google Scholar : PubMed/NCBI
12	Chua HL, Bhat-Nakshatri P, Clare SE, Morimiya A, Badve S and Nakshatri H: NF-kappaB represses E-cadherin expression and enhances epithelial to mesenchymal transition of mammary epithelial cells: Potential involvement of ZEB-1 and ZEB-2. Oncogene. 26:711–724. 2007. View Article : Google Scholar : PubMed/NCBI
13	Wang SC, Lin XL, Wang HY, Qin YJ, Chen L, Li J, Jia JS, Shen HF, Yang S, Xie RY, et al: Hes1 triggers epithelial-mesenchymal transition (EMT)-like cellular marker alterations and promotes invasion and metastasis of nasopharyngeal carcinoma by activating the PTEN/AKT pathway. Oncotarget. 6:36713–36730. 2015.PubMed/NCBI
14	Lin Z, Li W, Zhang H, Wu W, Peng Y, Zeng Y, Wan Y, Wang J and Ouyang N: CCL18/PITPNM3 enhances migration, invasion, and EMT through the NF-κB signaling pathway in hepatocellular carcinoma. Tumour Biol. 37:3461–3468. 2016. View Article : Google Scholar : PubMed/NCBI
15	Lee MY, Chou CY, Tang MJ and Shen MR: Epithelial-mesenchymal transition in cervical cancer: Correlation with tumor progression, epidermal growth factor receptor overexpression, and snail up-regulation. Clin Cancer Res. 14:4743–4750. 2008. View Article : Google Scholar : PubMed/NCBI
16	Strippoli R, Benedicto I, Pérez Lozano ML, Cerezo A, López-Cabrera M and del Pozo MA: Epithelial-to-mesenchymal transition of peritoneal mesothelial cells is regulated by an ERK/NF-kappaB/Snail1 pathway. Dis Model Mech. 1:264–274. 2008. View Article : Google Scholar : PubMed/NCBI
17	Huber MA, Azoitei N, Baumann B, Grünert S, Sommer A, Pehamberger H, Kraut N, Beug H and Wirth T: NF-kappaB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Invest. 114:569–581. 2004. View Article : Google Scholar : PubMed/NCBI
18	Huber MA, Beug H and Wirth T: Epithelial-mesenchymal transition: NF-kappaB takes center stage. Cell Cycle. 3:1477–1480. 2004. View Article : Google Scholar : PubMed/NCBI
19	Dong XE, Ito N, Lotze MT, Demarco RA, Popovic P, Shand SH, Watkins S, Winikoff S, Brown CK, Bartlett DL, et al: High mobility group box I (HMGB1) release from tumor cells after treatment: Implications for development of targeted chemoimmunotherapy. J Immunother. 30:596–606. 2007. View Article : Google Scholar : PubMed/NCBI
20	Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M, Che J, Frazier A, Yang H, Ivanova S, Borovikova L, et al: HMG-1 as a late mediator of endotoxin lethality in mice. Science. 285:248–251. 1999. View Article : Google Scholar : PubMed/NCBI
21	Klune JR, Dhupar R, Cardinal J, Billiar TR and Tsung A: HMGB1: Endogenous danger signaling. Mol Med. 14:476–484. 2008. View Article : Google Scholar : PubMed/NCBI
22	Olkhanud PB, Damdinsuren B, Bodogai M, Gress RE, Sen R, Wejksza K, Malchinkhuu E, Wersto RP and Biragyn A: Tumor-evoked regulatory B cells promote breast cancer metastasis by converting resting CD4⁺ T cells to T-regulatory cells. Cancer Res. 71:3505–3515. 2011. View Article : Google Scholar : PubMed/NCBI
23	Tian J, Avalos AM, Mao SY, Chen B, Senthil K, Wu H, Parroche P, Drabic S, Golenbock D, Sirois C, et al: Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nat Immunol. 8:487–496. 2007. View Article : Google Scholar : PubMed/NCBI
24	Sha Y, Zmijewski J, Xu Z and Abraham E: HMGB1 develops enhanced proinflammatory activity by binding to cytokines. J Immunol. 180:2531–2537. 2008. View Article : Google Scholar : PubMed/NCBI
25	Yang D, Chen Q, Yang H, Tracey KJ, Bustin M and Oppenheim JJ: High mobility group box-1 protein induces the migration and activation of human dendritic cells and acts as an alarmin. J Leukoc Biol. 81:59–66. 2007. View Article : Google Scholar : PubMed/NCBI
26	Lynch J, Nolan S, Slattery C, Feighery R, Ryan MP and McMorrow T: High-mobility group box protein 1: A novel mediator of inflammatory-induced renal epithelial-mesenchymal transition. Am J Nephrol. 32:590–602. 2010. View Article : Google Scholar : PubMed/NCBI
27	He M, Kubo H, Ishizawa K, Hegab AE, Yamamoto Y, Yamamoto H and Yamaya M: The role of the receptor for advanced glycation end-products in lung fibrosis. Am J Physiol Lung Cell Mol Physiol. 293:L1427–L1436. 2007. View Article : Google Scholar : PubMed/NCBI
28	van Beijnum JR, Buurman WA and Griffioen AW: Convergence and amplification of toll-like receptor (TLR) and receptor for advanced glycation end products (RAGE) signaling pathways via high mobility group B1 (HMGB1). Angiogenesis. 11:91–99. 2008. View Article : Google Scholar : PubMed/NCBI
29	Sims GP, Rowe DC, Rietdijk ST, Herbst R and Coyle AJ: HMGB1 and RAGE in inflammation and cancer. Annu Rev Immunol. 28:367–388. 2010. View Article : Google Scholar : PubMed/NCBI
30	Palumbo R, Galvez BG, Pusterla T, De Marchis F, Cossu G, Marcu KB and Bianchi ME: Cells migrating to sites of tissue damage in response to the danger signal HMGB1 require NF-kappaB activation. J Cell Biol. 179:33–40. 2007. View Article : Google Scholar : PubMed/NCBI