Hexokinases 2 promoted cell motility and distant metastasis by elevating fibronectin through Akt1/p-Akt1 in cervical cancer cells

Qian Chen; Lu Li; Xian Liu; Qian Feng; Yanru Zhang; Pengsheng Zheng; Nan Cui

doi:10.1186/s12935-021-02312-0

Hexokinases 2 promoted cell motility and distant metastasis by elevating fibronectin through Akt1/p-Akt1 in cervical cancer cells

Cancer Cell Int. 2021 Nov 10;21(1):600. doi: 10.1186/s12935-021-02312-0.

Authors

Qian Chen^#^{1

2}, Lu Li^#^{3

4}, Xian Liu^{1

2}, Qian Feng^{1

2}, Yanru Zhang^{1

2}, Pengsheng Zheng^{5

6}, Nan Cui^{7

8}

Affiliations

¹ Department of Reproductive Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, 76 West Yanta Road, 710061, Xi'an, Shaanxi, People's Republic of China.
² Section of Cancer Stem Cell Research, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of the People's Republic of China, 710061, Xi'an, Shaanxi, People's Republic of China.
³ Department of Social Medicine and Health Care Management, School of Public Health, Hebei Medical University, 050017, Shijiazhuang, Hebei, People's Republic of China.
⁴ Hebei Key Laboratory of Environment and Human Health, Hebei Medical University, 050017, Shijiazhuang, Hebei, People's Republic of China.
⁵ Department of Reproductive Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, 76 West Yanta Road, 710061, Xi'an, Shaanxi, People's Republic of China. zpsheng@mail.xjtu.edu.cn.
⁶ Section of Cancer Stem Cell Research, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of the People's Republic of China, 710061, Xi'an, Shaanxi, People's Republic of China. zpsheng@mail.xjtu.edu.cn.
⁷ Department of Reproductive Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, 76 West Yanta Road, 710061, Xi'an, Shaanxi, People's Republic of China. cuin2003@xjtufh.edu.cn.
⁸ Section of Cancer Stem Cell Research, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of the People's Republic of China, 710061, Xi'an, Shaanxi, People's Republic of China. cuin2003@xjtufh.edu.cn.

^# Contributed equally.

Abstract

Background: Hexokinases 2 (HK2) is a member of the hexokinases, linking with malignant tumor growth and distant metastasis. However, evidence regarding the potential role of HK2 in regulating cell motility and tumor metastasis during the cervical cancer malignant progression remains limited.

Methods: In vitro migration and invasion assay, in vivo metastasis experiments were performed to detect the effective of HK2 on regulating cell motility and tumor metastasis in cervical cancer cells. RNA-Seq was performed to explore the potential molecules that participate in HK2-mediated cell motility and tumor metastasis in cervical cancer cells. The correlation between HK2 and Akt1, p-Akt1, FN1 expression in cervical cancer cells and human squamous cervical carcinoma (SCC) samples was verified in this study.

Results: In this study, cervical cancer cells with exogenous HK2 expression exhibited enhanced cell motility and distant metastasis. Transcriptome sequencing analysis revealed that fibronectin (FN1) was significantly increased in HK2-overexpressing HeLa cells, and the PI3K/Akt signaling pathway was identified by KEGG pathway enrichment analysis. Further studies demonstrated that this promotion of cell motility by HK2 was probably a result of it inducing FN1, MMP2 and MMP9 expression by activating Akt1 in cervical cancer cells. Additionally, HK2 expression was altered with the changing of Akt1/p-Akt1 expression, implying that HK2 expression is also modulated by Akt1/p-Akt1. Moreover, the positive correlation between HK2 and Akt1, p-Akt1, FN1 expression in human squamous cervical carcinoma (SCC) samples was verified by using Pearson correlation analysis.

Conclusions: This study demonstrated that HK2 could activate Akt1 in cervical cancer cells, subsequently enhancing cell motility and tumor metastasis by inducing FN1, MMP2 and MMP9 expression. There likely exists an interactive regulatory mechanism between HK2 and Akt1 during the malignant process of cervical cancer.

Keywords: Akt1; Cervical cancer; Fibronectin (FN1); HK2; Metastasis.

Abstract

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