Yuji Yaginuma

Alterations of UHRF Family Expression and UHRF1/ICBP90 Inhibits Phosphatase and Tensin Homolog Expression in Endometrial Cancer

Introduction: The altered protein expression of inverted CCAAT box-binding protein of 90 kDa/ubiquitin-like with PHD and RING finger domains 1 (ICBP90/UHRF1) and Np95-like ring finger protein (NIRF)/UHRF2, which belong to the ubiquitin-like with PHD and RING finger domains (UHRF) family, is linked to tumor malignancy and the progression of various cancers. To determine the role of NIRF and ICBP90 in endometrial tumorigenesis, we evaluated ICBP90 and NIRF expression levels in endometrial cancers. Also molecular alterations of phosphatase and tensin homolog (PTEN) expression are the important event for endometrial carcinogenesis; therefore, we investigated the involvement between ICBP90 and PTEN expression. Methods: We used Western blot for NIRF, ICBP90, and PTEN expression, mutation analysis of NIRF gene, and immunohistochemical staining for the expression of NIRF and ICBP90. For immunohistochemical staining, we examined atypical endometrial hyperplasia, endometrial cancers, and noncancerous samples. Results: Our data showed that the reduced expression of NIRF and overexpression of ICBP90 occurred in atypical endometrial hyperplasia and endometrial cancer compared to the normal endometrium. The decrease in NIRF expression was significantly correlated with histological grade. Expression of ICBP90 was high, especially in the peripheral margin of a cancer nest. Western blot analysis of endometrial cancer cell lines referred an opposite correlation between ICBP90 and PTEN expression. Conclusion: Our findings suggested that continually overexpressed ICBP90 may contribute to the inhibition of PTEN expression, which is a frequent and important event in endometrial carcinogenesis. We propose that the reduced NIRF expression and ICBP90 overexpression is an early event in endometrial carcinogenesis; thus ICBP90 may be useful as a therapeutic target in this disease.

Alterations of UHRF family Expression and was regulated by High Risk Type HPV16 in Uterine Cervical Cancer

The altered protein expression of inverted CCAAT box-binding protein of 90 kDa/ubiquitin-like with PHD and RING finger domains 1 (ICBP90/UHRF1), and Np95-like ring finger protein (NIRF)/UHRF2, which belong to the ubiquitin-like with PHD and RING finger domains (UHRF) family, is linked to tumor malignancy and the progression of various cancers. In this study, we analyzed the UHRF family expression in cervical cancers, and it's regulation by human papillomavirus (HPV). Western blotting was performed to analyze protein expression in cervical cancer cell lines. Immunohistochemical analysis were used to investigate the expression of UHRF family and MIB-1 in cervical cancer tissues. Transfection were done for analyze the relationship between UHRF family and HPVs. We showed that NIRF expression was decreased and ICBP90 expression was increased in cervical cancers compared to normal counterparts. Western blotting also showed that NIRF expression was quite low levels, but ICBP90 was high in human cervical cancer cell lines. Interestingly, ICBP90 was up regulated by high risk type HPV16 E6 and E7, but not low-risk type HPV11. On the other hand, NIRF was down regulated by high risk type HPV16 E6 but not by E7. Low risk type HPV11 E6 did not affect the NIRF expression at all. We propose that ICBP90 overexpression, and reduced NIRF expression, found in cervical cancers, is an important event of a cervical carcinogenesis, and especially ICBP90 may offer a proliferating marker and therapeutic target for treating uterine cervical cancers.