Increased expression of SKP2 is an independent predictor of locoregional recurrence in cervical cancer via promoting DNA-damage response after irradiation.
Although radiation therapy was known to be effective to cervical cancer, loco-regional recurrences are frequently found in patients. We aimed to identify a molecular marker predicting the response of cervical cancer to radiotherapy. 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 S-phase kinase-associated protein 2 (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. SKP2-C25, an inhibitor for SKP2 activity, dose-dependently decreased cell viability after irradiation and knockdown of SKP2 impaired DNA-damage response and sensitized the cervical cancer cells to irradiation. Our data showed the SKP2 represents a promising tool to identify patients with cervical cancer who have a higher risk of locoregional recurrence after radiotherapy. Targeting SKP2 may serve as a potential radiosensitizer for developing effective therapeutic strategies against cervical cancer.
Graduate Institute of Clinical Medical Sciences, Chang Gung University, College of Medicine, Kaohsiung, Taiwan.|Center for Menopause and Reproductive Medicine Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.|Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
Hung-Chun
HC
Fu
Graduate Institute of Clinical Medical Sciences, Chang Gung University, College of Medicine, Kaohsiung, Taiwan.|Center for Menopause and Reproductive Medicine Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.|Department of Dermatology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
Yi-Chien
YC
Yang
Graduate Institute of Clinical Medical Sciences, Chang Gung University, College of Medicine, Kaohsiung, Taiwan.|Center for Menopause and Reproductive Medicine Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
Yun-Ju
YJ
Chen
Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
Hao
H
Lin
Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
Yu-Che
YC
Ou
Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
Chan-Chao Chang
CC
Chien
Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
Eng-Yen
EY
Huang
Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
Hsuan-Ying
HY
Huang
Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
Jui
J
Lan
Medical Sciences Division, University of Oxford, Oxford, England, UK.
Hsi-Ping
HP
Chi
Center for Menopause and Reproductive Medicine Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.|Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
Ko-En
KE
Huang
Graduate Institute of Clinical Medical Sciences, Chang Gung University, College of Medicine, Kaohsiung, Taiwan.|Center for Menopause and Reproductive Medicine Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.|Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
Hong-Yo
HY
Kang
D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics / Q000528:radiation effects; D004249:DNA Damage; D004260:DNA Repair; D005260:Female; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D011379:Prognosis; D034622:RNA Interference; D044786:S-Phase Kinase-Associated Proteins / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000532:radiotherapy*
D044786:S-Phase Kinase-Associated Proteins
DNA damage; SKP2; cervical cancer; local recurrence; radioresistance