The Roles and Clinical Impacts of SKP2 and P16INK4A in Radioresistant Cervical Cancer

• Main Authors: Hung Chun Fu, 傅宏鈞
• Other Authors: H. Y. Kang
• Format: Others
• Language: zh-TW
• Published: 2019
• Online Access: http://ndltd.ncl.edu.tw/handle/ne4qzq

博士 === 長庚大學 === 臨床醫學研究所 === 107 === Cervical carcinoma is the third common malignancy in women worldwide. Radiation therapy (RT) with or without cisplatin-containing chemotherapy is the most commonly used treatment modality in patients with advanced cervical cancer. Loco-regional recurrences are frequently found in patients. The recurrent cervical cancer cell had higher radioresistance. The prognosis and response to irradiation were quite different in patients with a similar status of cervical cancer receiving RT or concurrent chemoradiotherapy (CCRT). Clearly, there remains a need for a better understanding of the molecular events involved the responses of cervical cancer to RT. We try to get a breakthrough in new therapeutic targets and new biomarkers to predict the prognosis of the patients. We aim to identify a molecular marker predicting the response of cervical cancer to radiotherapy. In the literature review, we found the radioresistance of cell was different at the different phase of cell-cycle (G1-S-G2-M). The cells in the S phase are the most radioresistant. S-phase kinase-associated protein 2 (SKP2) and cyclin-dependent kinase inhibitor 2A (CDKN2A, P16INK4A) are tow important proteins during G1-S phase of cell-cycle. SKP2 promotes cells into S-phase. In contrast to SKP2, P16INK4A decelerates the cell's progression from G1 phase to S phase. We suspected SKP2 and P16INK4A maight play an important role in radioresistant cervical cancer. SKP2 is an E3 ubiquitin ligase and a part of SKP1-Cul1-F-box (SCF) complexes. It has important roles in the ubiquitination of proteins involved in the cell cycle and also marks various other cellular proteins for destruction. Previous studies showed overexpression of SKP2 was frequent in human cancer progression and metastasis, and evidence suggested that SKP2 plays a protooncogenic role both in vitro and in vivo. It is still unclear whether SKP2 is a prognostic factor of cervical cancer treated with radiotherapy. We try to further study to answer the question. P16INK4A is encoded by the CDKN2A gene and is thought to be a tumor suppressor. P16INK4A is important in cell-cycle regulation by decelerating the progression of cycle from G1 to S phase. We used P16INK4A as a biomarker for cervical carcinogenesis. It is still unclear whether P16INK4A is a prognostic factor for cervical cancer receiving radiotherapy. We tried to investigate the expression and clinical significance of P16INK4A in cervical cancer. We included the patients (n = 149) with cervical cancer who had undergone radiotherapy from 2004 to 2006. Tumor samples were collected to examine the association between the expression of SKP2 and prognosis in cervical cancer. We found higher expression of SKP2 associated with recurrence (HRs: 2.52, p < 0.001), death (HRs: 2.01, p < 0.001) and higher locoregional recurrence rate (HRs: 3.76, p < 0.001). Cervical cancer cell lines with higher expression of SKP2 showed higher colony formation, cell survival rate and fewer DNA damages after irradiation. And, we proved the prognosis of the cervical cancer with higher expression of P16INK4A were better. In cell model, we knocked down expression of P16INK4A in HeLa and C33A cells and found they were more radioresistant and chemoresistat. P16INK4A is not only the gatekeeper of G1-S cell phase, but also an important factor of senescence of general or stem cells. Our data showed depletion of P16INK4A caused higher expression of sex determining region Y-box 2 (SOX2) and Aldehyde dehydrogenase 1 family, member A1 (ALDH1A1) in cervical cancer cells. And, higher self-renew ability was observed. So, we hypothesized P16INK4A inhibits stemness of cervical cancer cells and promotes radiosensitivity. In our clinical data showed the patients cervical whose cancer samples with lower P16INK4A and higher stem cell markers (SOX2 and ALDH1A1) had poorer prognosis and higher recurrent rate. Our data suggest that high SKP2 and P16 INK4A expression markers predict poor prognostic outcomes and are a promising target in patients with cervical cancer.