Cervical cancer stem cell-associated genes: Prognostic implications in cervical cancer

Abstract

Cervical cancer is the fourth most common type of gynecological malignancy to affect females, worldwide. Although high-risk human papillomavirus (HR-HPV) infection is the primary etiologic agent associated with the development of cervical cancer, cancer stem cells (CSCs) also serve a prominent role in the development, metastasis, recurrence and prognosis of the disease. CSCs are a small subpopulation of cells that have the ability to self-renew and are present in the majority of tumors, including cervical cancer. Studies describing the phenotype of cervical CSCs (CCSCs) vary in their definition of the expression pattern of principal biomarkers, including Musashi-1, aldehyde dehydrogenase 1, Oct3/4, Sox2 and CD49f. However, these markers are not observed in all cancers, although several may be present in multiple tumor types. The present review describes the potential biomarkers of CSCs in cervical cancer. These CCSC biomarkers may serve as molecular targets to enhance the efficacy and reduce the side effects associated with chemotherapeutic treatment in HR-HPV-positive cervical cancer.

Keywords: biomarkers; cervical cancer stem cells; high-risk human papillomavirus; transformation zone.

Figure 1.

HR-HPV oncoprotein-mediated network regulation of CCSCs. HR-HPV targets stem cells of the cervical epithelium with the following surface markers: CD44, CD49f, CK17 and CD133. HR-HPV binds to receptors on the cell surface and the viral DNA is internalized and transported to the cell nucleus. Subsequently, the E6 and E7 oncogenes are transcribed and translated, giving rise to the oncoproteins E6 and E7. E6 and E7 have a number of molecular targets, including stemness-related genes Oct3/4, Nanog, Sox2 and Notch3; overexpression of these genes promotes the formation of tumors, inhibits cancer cell apoptosis, cell migration and sphere formation. Oct3/4, Nanog, Sox2 and Notch3 promote drug resistance via the upregulated expression of ABC transporters, ALDH1 and MSI1, which promotes the clonogenicity, proliferation, increased invasiveness and chemoresistance of CCSCs. HR-HPV, high risk-human papillomavirus; CCSCs, cervical cancer stem cells; ABC transporter, ATP-binding cassette transporter; ALDH1, aldehyde dehydrogenase 1; MSI1, Musashi-1.

Figure 2.

Model of the potential role of HR-HPV infection in CCSCs, and the implications for the treatment of cervical cancer. HR-HPV infects stem cells of the squamous epithelium, and HR-HPV oncoproteins HPV16 E6 and E7 are involved in the upregulation of Oct3/4, Sox2, Nanog and Fgf4 expression, which enhances the self-renewal and proliferation of cancer stem cells in cervical cancer. Current cancer treatments do not destroy CCSCs, leading to tumor recurrence and relapse. The combination of current cancer treatments with therapy directed at CCSC-associated genes may eradicate CCSCs, and tumor cells derived or transformed from CCSC. HR-HPV, high risk-human papillomavirus; CCSCs, cervical cancer stem cells.