Abstract
Previous studies have suggested that cancer stem cells (CSCs) resisted radiotherapy and chemotherapy. P16INK4A is a biomarker for cervical carcinogenesis and reduces proliferation of stem cells. We aimed to investigate the expression and clinical significance of cyclin-dependent kinase inhibitor 2A (P16INK4A), sex determining region Y-box 2 (SOX2), and Aldehyde dehydrogenase 1 family, member A1 (ALDH1A1) in cervical cancer treated with radiotherapy and cervical cell line models. The expressions of P16INK4A, SOX2, and ALDH1A1 were performed by immunohistochemical staining of tumor samples from 139 cervical cancer patients with International Federation of Gynecology and Obstetrics stages Ib to IV. The staining showed high expression in 100, 107, and 13 patients with P16INK4A (>80%), SOX2 (≥10%), and ALDH1A1 (50%), respectively. The high-P16INK4A group had a higher five-year overall survival (OS) rate and disease-free survival (DFS) than the low-P16INK4A group (OS: 62.0% and 35.2%, p = 0.016; DFS: 60.0% and 31.2%, p = 0.002). The low-P16INK4A/high-SOX2 and low-P16INK4A/high-ALDH1A1 groups had a worse five-year OS and DFS rate than the high-P16INK4A/low-SOX2 and high-P16INK4A/low-ALDH1A1 groups, respectively. Depletion of P16INK4A promoted chemoresistance and radioresistance of cervical cancer cells increased the expression of SOX2 and ALDH1A1 and exhibited higher self-renewal ability. These results suggest that lower P16INK4A expression associated with higher CSC markers predicts poor prognostic outcomes and is a promising target in patients with cervical cancer.
Highlights
Cervical carcinoma is the third most common malignancy diagnosed in women worldwide [1]
We describe the results of p16INK4A immunohistochemistry for 139 patients with FIGO 2009 stages Ib to IV, treated with radiotherapy, with/without chemotherapy
While we did not find that patients with a high expression of sex determining region Y-box 2 (SOX2) or ALDH1A1 tumors had poorer overall survival (OS) and disease-free survival (DFS), the patients with low P16INK4A/high SOX2 or low P16INK4A/high ALDH1A1 expression tumors had a significantly poor prognosis of OS and DFS
Summary
Cervical carcinoma is the third most common malignancy diagnosed in women worldwide [1]. Treatments of patients with early-stage (i.e., International Federation of Gynecology and Obstetrics (FIGO) stages IA–IB1) cervical cancer are radical hysterectomy and lymph node dissection. Most patients with advanced cervical cancer receive radiation therapy with or without cisplatin-containing chemotherapy as definitive treatments [2,3]. Resistance to radiotherapy is widely recognized as one of the major factors that limit therapeutic efficacy and influence patient outcomes. Ability of radiation resistance in cancer cells is acquired by intrinsic and extrinsic factors. The expression of vascular endothelial growth factor (VEGF), Galectin-1, Sphingosine kinase 1, SKP2, P16INK4A, hypoxia, and cancer stem cells (CSCs) may have a major influence on the survival of patients treated with definitive radiotherapy [4,5,6,7,8,9]. The detailed cellular or molecular mechanism of the contribution to radiation resistance is still largely unknown
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