Abstract
Hexokinase 2 (HK2) is a member of the hexokinases (HK) that has been reported to be a key regulator during glucose metabolism linked to malignant growth in many types of cancers. In this study, stimulation of HK2 expression was observed in squamous cervical cancer (SCC) tissues, and HK2 expression promoted the proliferation of cervical cancer cells in vitro and tumor formation in vivo by accelerating cell cycle progression, upregulating cyclin A1, and downregulating p27 expression. Moreover, transcriptome sequencing analysis revealed that MAPK3 (ERK1) was upregulated in HK2-overexpressing HeLa cells. Further experiments found that the protein levels of p-Raf, p-MEK1/2, ERK1/2, and p-ERK1/2 were increased in HK2 over-expressing SiHa and HeLa cells. When ERK1/2 and p-ERK1/2 expression was blocked by an inhibitor (FR180204), reduced cyclin A1 expression was observed in HK2 over-expressing cells, with induced p27 expression and inhibited cell growth. Therefore, our data demonstrated that HK2 promoted the proliferation of cervical cancer cells by upregulating cyclin A1 and down-regulating p27 expression through the Raf/MEK/ERK signaling pathway.
Highlights
Oncogenic types of human papillomaviruses (HPVs) are closely linked to almost 5% of the total incidence of human cancers
To investigate whether Hexokinase 2 (HK2) is involved in the development and progression of human cervical carcinoma, immunohistochemistry (IHC) was used to detect HK2 expression in the normal human cervix (NC), high-grade squamous intraepithelial lesions (HSILs), and squamous cervical cancer (SCC) tissues
The relative expression levels of HK2 in these cervical carcinoma samples were higher than that in the normal cervical samples (Figure 1E; p
Summary
Oncogenic types of human papillomaviruses (HPVs) are closely linked to almost 5% of the total incidence of human cancers. Cervical cancer has been reported to be one of the most prevalent HPV-induced malignancies. Human papillomavirus (HPV) can be detected in almost 99.7% of cervical carcinoma cases, and it accounts for more than 250,000 cancer deaths and more than 500,000 new cancer cases worldwide every year [1, 2]. HPV16 (55–60%) and HPV18 (10–15%) are high-risk HPV genotypes within cervical cancer [3], and these HPV sequences regularly continuously express the viral E6/E7 oncogenes, which are considered crucial for malignant cell transformation and the maintenance of cell growth [4]. Metabolic alteration is commonly present in cancer cells to support malignant growth by promoting cellular proliferation and cell survival [5].
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