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Aberrant Nuclear Localization of aPKCλ/ι is Associated With Poorer Prognosis in Uterine Cervical Cancer

Tokinaga-Uchiyama, Aya, M.D.; Mizushima, Taichi, M.D., Ph.D.; Akimoto, Kazunori, Ph.D.; Nagashima, Yoji, M.D., Ph.D.; Sasaki, Kazunori, Ph.D.; Nakaya, Masa-aki, M.D., PhD; Ohashi, Kenichi, M.D., Ph.D.; Kubota, Kazumi, Ph.D.; Maruyama, Yasuyo, M.D.; Kato, Hisamori, M.D., Ph.D.; Hirahara, Fumiki, M.D., Ph.D.; Miyagi, Etsuko, M.D., Ph.D.; Ohno, Shigeo, Ph.D.; Asai-Sato, Mikiko, M.D., Ph.D.

International Journal of Gynecological Pathology: July 2019 - Volume 38 - Issue 4 - p 301–309
doi: 10.1097/PGP.0000000000000539

We previously reported that aberrant expression of atypical protein kinase C λ/ι (aPKCλ/ι) in low-grade squamous intraepithelial uterine cervix lesions was associated with an increased risk of progression to higher grade. This study aimed to investigate aPKCλ/ι expression patterns in cervical squamous cell carcinoma (SCC) and its association with disease progression. We immunohistochemically assessed aPKCλ/ι expression in 168 SCC samples and 13 normal uterine cervix samples. In 69.0% of SCC cases, aPKCλ/ι was expressed more abundantly than in normal epithelium, but there was no significant association between aPKCλ/ι intensity and disease progression (P=0.087, Cochran-Mantel-Haenszel test). aPKCλ/ι in normal cervical epithelium was confined to the cytoplasm or intercellular junctions. In contrast, aPKCλ/ι was predominantly localized within the nucleus in 36.9% of SCC samples (P<0.001, χ2 test), and the prevalence was significantly increased relative to advanced tumor stage (P<0.001, Cochran-Mantel-Haenszel test). Moreover, patients with SCC with aPKCλ/ι nuclear localization had worse prognoses than those with cytoplasmic localization (P<0.001, log-rank test). aPKCλ/ι localization differed between the intraepithelial lesion and adjacent invasive cancer in 40% of cases, while the expression pattern was similar between primary and matched metastatic tumors. In conclusion, aPKCλ/ι nuclear localization in cervical cancer is associated with tumor progression and worse prognosis. This is the first report to show aberrant nuclear aPKCλ/ι localization in a subgroup of cervical cancer patients and its association with worse prognosis.

Departments of Obstetrics and Gynecology and Molecular Reproductive Science (A.T.-U., T.M., Y.M., F.H., E.M., M.A.-S.)

Molecular Biology (A.T.-U., T.M., K.A., K.S., M.-A.N., S.O.)

Pathology (K.O.)

Biostatistics (K.K.), Yokohama City University Graduate School of Medicine

Department of Gynecology, Kanagawa Cancer Center (H.K.), Yokohama

Department of Medical and Life Science, Faculty of Pharmaceutical Sciences, Tokyo University of Science (K.A.)

Department of Surgical Pathology, Tokyo Women’s Medical University Hospital (Y.N.), Tokyo, Japan

A.T.-U.and T.M. contributed equally.

Supported in part by a Grant-in-Aid for Research from The Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan (#15K10725 to Y.M. and 26460456 to Y.N.), the MEXT-Supported Program for the Strategic Research Foundation at Private Universities (to K.A.), and funding from the Creation of Innovation Centers for Advanced Interdisciplinary Research Areas Program in the Project for Developing Innovation Systems from the MEXT of Japan (to S.O.).

The authors declare no conflict of interest.

Address correspondence and reprint requests to Mikiko Asai-Sato, MD, PhD, Department of Obstetrics and Gynecology and Molecular Reproductive Science, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-Ku, Yokohama 236-0004, Japan. E-mail:

©2019International Society of Gynecological Pathologists