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. 2019 May 2;39(5):BSR20181016.
doi: 10.1042/BSR20181016. Print 2019 May 31.

The effect of HMGB1 on the clinicopathological and prognostic features of cervical cancer

Pan Li  1 , Mengfei Xu  1 , Hongbing Cai  2 , Niresh Thapa  1 , Can He  1 , Ziye Song  1
Affiliations

The effect of HMGB1 on the clinicopathological and prognostic features of cervical cancer

Pan Li et al. Biosci Rep. .

Erratum in

Abstract

Cervical cancer is the third leading cause of cancer death among women in less-developed regions. Because of the poor survivorship of patients with advanced disease, finding new biomarkers for prognostic prediction is of great importance. In the current study, mRNA datasets (GSE9750 and GSE63514) were retrieved from Gene Expression Omnibus and was used to identify differentially expressed genes. The underlying molecular mechanisms associated with high-mobility group box 1 protein (HMGB1) were investigated using bioinformatics analysis. Immunohistochemical analysis of HMGB1 was performed on 239 cases of cervical cancer samples to investigate its possible correlation with clinicopathological characteristics and outcomes. A preliminary validation has been made to explore the possible correlation factors with HMGB1 that promote migration of cervical cancer cells. Bioinformatics analysis showed that adherens junction was significant for both P-value and enrichment scores, which was consistent with the clinical study. The underlying molecular mechanisms might be the interaction among HMGB1, RAC1, and CDC42. HMGB1 expression was significantly associated with tumor size, parametrial infiltration, the depth of cervical stromal invasion, and FIGO stage (P=0.003, 0.019, 0.013, and 0.003, respectively). FIGO stage, lymph mode metastasis, and HMGB1 expression were independent predictors of a poorer prognosis of patients with cervical cancer. Knockdown of HMGB1 inhibits migration of Siha and C33A cells in vitro Western blot and quantitative real-time PCR (qRT-PCR) showed that the expression of RAC1 and CDC42 was positively correlated with HMGB1. HMGB1 is a useful prognostic indicator and a potential biomarker of cervical cancer. RAC1 and CDC42 may be involved in the progression of cervical cancer migration induced by HMGB1.

Keywords: HMGB1; bioinformatics analysis; cervical cancer; prognosis.

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Conflict of interest statement

The authors declare that there are no competing interests associated with the manuscript.

Figures

Figure 1
Figure 1. Bioinformatics analysis of DEGs
(A) Flowchart of bioinformatics analysis. 862 integrated DEGs between two groups were chosen as the final DEGs. (B) PPIs network of DEGs. DEGs in the PPI networks with a connectivity degree >20 and with the combination score >0.9 were represented, of which the top 8 high-interaction score genes were identified as real hub genes. (C) Go analysis of DEGs showed the significantly over-represented biological processes, molecular function of DEGs, and KEGG pathway enrichment of DEGs showed the significantly over-represented pathways in DEGs.
Figure 2
Figure 2. Clinical-pathological analysis
(A) Survival curves using the Kaplan–Meier method by log-rank test for HMGB1 expression. OS rate was analyzed in 239 cervical cancer patients in relation to HMGB1 expression. Log-rank test P-value: 0.002. And disease-free time rate were analyzed in 239 cervical cancer patients in relation to HMGB1 expression. Log-rank test P-value: 0.009. (B) Representative immunohistochemistry samples of cervical cancer tissues demonstrating HMGB1 expression. Normal cervix tissue showed the negative HMGB1 staining reactivity. And cervical cancer tissue showed the positive HMGB1 staining reactivity. Magnification, ×400.
Figure 3
Figure 3. In vitro experiment of cervical cell lines
(A) The transfection efficiency of shRNAs in Siha and C33A cell lines (×200 magnification). The transfection efficiency of shRNA in Siha and c33a cell line. The level of HMGB1 expression was determined in cervical cancer cells upon transfection with shHMGB1 or NC scramble by qRT-PCR. (B–D) Wound-healing assay images of wounds of Siha/C33A cells and Siha/C33A cells transfected with the specific shRNA against HMGB1 taken 0, 12, and 24 h after the wounds were inflicted (analyzed by ttests) (×100). *P<0.05,**P<0.01. (C) Transwell assay. The migration cells were fixed in 75% alcohol and stained with crystal violet. The representative fields were photographed and counted at ×200 magnification. The cells were counted in five different fields per assay under the microscope. The migration cells in shRNA HMGB1 group was significantly less than those of control group. **P<0.01
Figure 4
Figure 4. The expression of HMGB1 and relative genes
(A) HMGB1, RAC1, and CDC42 protein and mRNA expression were detected in shRNA-NC and shRNA-HMGB1 in cervical cancer cell lines. Relative expression of HMGB1, RAC1, and CDC42 mRNA were detected by qRT-PCR. The data were normalized to the level of GAPDH mRNA. Error bars represent SD (n=3). (B) Immunoblot of HMGB1, Rac1, and Cdc42 in Siha/C33A cells after transfection with shRNA of HMGB1 compared with control group. Error bars represent SD (n=3). *P<0.05, **P<0.01.
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