Low P16INK4A Expression Associated with High Expression of Cancer Stem Cell Markers Predicts Poor Prognosis in Cervical Cancer after Radiotherapy

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.

Absence of Nuclear p16 Is a Diagnostic and Independent Prognostic Biomarker in Squamous Cell Carcinoma of the Cervix

“…To date, p16 expression pattern remains controversial, because there is no fundamental justification yet as to whether cytoplasmic/nuclear or only nuclear staining should be taken as positive [15]. As other authors have found [5,32], there was no association between p16 expression or location and pathological variables in our study, but we did find that the lack of nuclear p16 allowed SCCC to acquire aggressive features both in tumors and in vitro. This interesting finding goes some way to explaining the paradoxical p16 overexpression in SCCC.…”

“…The potential therapeutic value of p16 is also to be elucidated. On the one hand, depletion of p16 has been shown to promote chemo-and radioresistance in HeLa cells [32]. On the other hand, it has been suggested that p16 could be a therapeutic target in CC, since its knockdown inhibits cell proliferation, migration and invasion in SiHa and HeLa cell lines [43] and sensitizes SiHa cells to cisplatin [35].…”

Expression of P16 biomarker in squamous cell carcinoma of uterine cervix and its association with clinico-pathological parameters: A cross-sectional study

“…Normally, the expression of P16 increases with age which results in a decrease of the renewal activity of stem cells. In conditions of inhibition / low P16 expression, there will be high expression of cancer stem cells which results in increased ability of self-renewal of cancer stem cells 16 . The sensitivity, specificity and accuracy of P16 biomarker to diagnose SCC of cervix is 96.0%, 88.2% and 91.7%, respectively 17 .…”

Compromising the constitutive p16INK4a expression sensitizes human neuroblastoma cells to Hsp90 inhibition and promotes premature senescence

“…For this reason, we went ahead examining the downstream regulators such as CDK4 and CDK6. The kinase CDK6 is not only implicated in cancer for its oncogenic role, but for regulating the stem cell pool dynamics that facilitates recurrence . Altered stem cell marker expressions in response to KD and Hsp90 inhibition in matrix based manner (2D vs 3D) suggests their independent influence on regulating the stem cell pool dynamics.…”

“…The kinase CDK6 is not only implicated in cancer for its oncogenic role, but for regulating the stem cell pool dynamics that facilitates recurrence. 31,33,34 Altered stem cell marker expressions in response to KD and Hsp90 inhibition in matrix based manner (2D vs 3D) suggests their independent influence on regulating the stem cell pool dynamics. However, in KD combination with 17AAG, this regulation is found to be lost.…”