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Reduced Expression of DKK3 Is Associated With Adverse Clinical Outcomes of Uterine Cervical Squamous Cell Carcinoma
  1. Seok-Woo Ryu, PhD*,
  2. Jae Hyung Kim, MD,
  3. Mi Kyung Kim, MD, PhD,
  4. Youn-Jeong Lee, MD*,
  5. Jun-Soo Park, PhD§,
  6. Hyoung-Moo Park, MD, PhD*,
  7. Dong-Ho Kim, MD, PhD*,
  8. Sang-Hoon Lee, MD, PhD* and
  9. Eun-Ju Lee, MD, PhD*
  1. *Department of Obstetrics and Gynecology, Chung-Ang University School of Medicine, Seoul, Korea;
  2. Department of Radiology, Sanggye Paik Hospital, Inje University College of Medicine, Seoul, Korea;
  3. Department of Pathology, Chung-Ang University School of Medicine, Seoul, Korea; and
  4. §Division of Biological Science and Technology, Yonsei University, Wonju, Korea.
  1. Address correspondence and reprint requests to Eun-Ju Lee, MD, PhD, Department of Obstetrics and Gynecology, Chung-Ang University School of Medicine/Chung-Ang University Hospital, 224-1, Heuksuk-Dong, Dongjak-Gu, Seoul, 156-755, Korea. E-mail: ejlee{at}


Objective The aim of this study was to assess the expression of DKK3 protein and its target, beta-catenin, in uterine cervical squamous cell carcinoma and to determine potential clinical correlations.

Materials and Methods Six carcinoma in-situ (CIS) tissues and 88 invasive cervical cancer tissues were included in the study. Twenty-two normal cervical tissues and one gastric cancer tissue were used as controls. The expression of DKK3 and beta-catenin proteins was evaluated by immunohistochemical analysis. Clinical and pathological parameters were obtained from medical records. Survival data were estimated using Kaplan-Meier estimates and compared with a log-rank test. Multivariate analysis was performed using the Cox regression method.

Results DKK3 was predominantly present in the cytoplasm. Beta-catenin was observed only on the cellular membrane of both normal and cancer cells in contrast to earlier reports, in which beta-catenin was localized to the cytoplasm and nucleus of cancer cells. The expressions of beta-catenin and DKK3 were not correlated. Three of 6 CIS (50%) and 57 of 88 invasive cancer specimens (64.8%) had lower DKK3 expression than normal controls. DKK3 expression was decreased in a stage-dependent manner (P = 0.021). The patients with low expression of DKK3 were older than those with high expression of DKK3 (P < 0.01). Moreover, the patients with low DKK3 expression had a significantly lower 5-year disease-free survival rate than those with high DKK3 expression (P = 0.026). A multivariate analysis showed that International Federation of Gynecology and Obstetrics clinical stage and parametrial involvement were independent prognostic factors.

Conclusion Decreased DKK3 expression was associated with advanced International Federation of Gynecology and Obstetrics clinical stages and was predictive of lower disease-free survival in patients with cervical squamous cell carcinoma. DKK3 may be implicated in cervical carcinogenesis through a beta-catenin–independent mechanism.

  • Cervical cancer
  • DKK3
  • Beta-catenin

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  • This study was supported by a grant from the National R&D Program for Cancer Control, Ministry for Health and Welfare, Republic of Korea (1120280); and Korea Science and Engineering Foundation (KOSEF) grant funded by the Korea government (MEST) (2010-0005333).

  • Ryu SW and Kim JH contributed equally to this paper.