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Fluorescence-based Monitoring of PAD4 Activity via a Pro-fluorescence Substrate Analog
Published on: November 5, 2014
Expression of peptidylarginine deiminase type 4 in ovarian tumors
Lin Wang1, Xiaotian Chang, Guangying Yuan
1Research Center for Medicinal Biotechnology, Shandong Academy of Medicinal Sciences. Key Laboratory for Biotech-Drugs Ministry of Health & Provincial Laboratory for Modern Medicine and Technology of Shandong, Jinan, Shandong 250062, PR China.
Abstract:
Peptidylarginine deiminase type 4 (PADI4) converts arginine residues into citrulline. The current study focused on the expression of PADI4 in various subtypes of ovary cancers, and this study investigated the effects of estrogen on PADI4 expression in SKOV-3 cells that originated from ovary tumors. We utilized immunohistochemistry, real-time PCR and western blotting to analyze the expression of PADI4 in the tumor tissues and in the cell line that were cultured with estrodial-17β. PADI4 was detected in serious cystadenocarcinoma (n=39, positivity=100%), clear cell cancer (n=7, positivity= 100%), mucinous cystadenocarcinoma (n=6, positivity=100%), dysgerminoma (n=6, positivity=100%), squamous cell tumor (n=6, positivity=100%), sibnet-ring cell carcinoma (n=6, positivity=100%), endodermal sinus tumor (n=6, positivity=100%), germ cell tumors (n=6, positivity=100%) and immature teratoma (n=6, positivity=100%). However, PADI4 was either not detected or detected at low levels in granulosa cell tumor (n=6), malignant thecoma (n=6), ovarian cystadenoma (n=5) and normal ovarian tissue (n=11). For serious cystadenocarcinoma, all of the samples with high PADI4 expression belonged to the T1 and T2 stages of pTMN, whereas all of the samples that exhibited weak or moderate PADI4 expression belonged to the T3 and T4 stages. PADI4 was evenly distributed in the cytoplasm of tumor cells of serious cystadenocarcinoma that were classified as being grade II and III by histopathological scoring. However, PADI4 showed granular cellular distribution in the tumor tissues that were isolated from grade I cystadenocarcinoma. In addition, the PADI4 level was positively related with the ages of the patients that presented with serious adenocarcinoma (p=0.029). Real-time PCR and western blot analyses confirmed that PADI4 was expressed at higher levels in ovarian adenocarcinoma (n=8) compared to ovarian cystadenoma (n=5) (p< 0.05). The study also detected an increased level of PADI4 in SKOV-3 cells that were incubated with estrodial-17β in the range of 10(-12) to 10(-4)M. The results suggest an important role for PADI4 in the tumorigenesis of ovary cancers that are under the regulation of estrogen.
Insights
Peptidylarginine deiminase type 4 (PADI4) is highly expressed in most ovarian cancers but not in normal ovarian tissue. Estrogen increases PADI4 levels in ovarian cancer cells, suggesting a role in tumorigenesis.
Area of Science:
- Oncology
- Biochemistry
Background:
- Peptidylarginine deiminase type 4 (PADI4) catalyzes the conversion of arginine to citrulline.
- Ovarian cancer encompasses various histological subtypes with diverse clinical behaviors.
Purpose of the Study:
- To investigate the expression patterns of PADI4 across different ovarian cancer subtypes.
- To explore the influence of estrogen on PADI4 expression in ovarian cancer cells.
Main Methods:
- Immunohistochemistry was used to assess PADI4 protein expression in tumor tissues.
- Real-time PCR and Western blotting were employed to quantify PADI4 mRNA and protein levels.
- SKOV-3 ovarian cancer cells were treated with varying concentrations of estradiol-17β to evaluate estrogen's effect on PADI4 expression.
Main Results:
- PADI4 was highly expressed in serous cystadenocarcinoma, clear cell carcinoma, mucinous cystadenocarcinoma, dysgerminoma, squamous cell tumor, and germ cell tumors.
- PADI4 expression was low or undetectable in granulosa cell tumors, malignant thecomas, ovarian cystadenomas, and normal ovarian tissues.
- High PADI4 expression correlated with earlier stages (T1-T2) in serous cystadenocarcinoma and was positively associated with patient age.
- Estrogen treatment significantly increased PADI4 levels in SKOV-3 cells.
Conclusions:
- PADI4 is a potential biomarker for distinguishing ovarian cancers from benign ovarian tumors.
- PADI4 expression is linked to tumor stage and patient age in serous ovarian adenocarcinoma.
- Estrogen positively regulates PADI4 expression, implicating it in ovarian cancer development.
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