SERPINB3 in the Chicken Model of Ovarian Cancer: A Prognostic Factor for Platinum Resistance and Survival in Patients with Epithelial Ovarian Cancer

Abstract

Serine protease inhibitors (SERPINs) appear to be ubiquitously expressed in a variety of species and play important roles in pivotal physiological processes such as angiogenesis, immune responses, blood coagulation and fibronolysis. Of these, squamous cell carcinoma antigen 1 (SCCA1), also known as a SERPINB3, was first identified in squamous cell carcinoma tissue from the cervix of women. However, there is little known about the SERPINB3 expression in human epithelial ovarian cancer (EOC). Therefore, in the present study, we investigated the functional role of SERPINB3 gene in human EOC using chickens, the most relevant animal model. In 136 chickens, EOC was found in 10 (7.4%). SERPINB3 mRNA was induced in cancerous, but not normal ovaries of chickens (P<0.01), and it was abundant only in the glandular epithelium of cancerous ovaries of chickens. Further, several microRNAs, specifically miR-101, miR-1668 and miR-1681 were discovered to influence SERPINB3 expression via its 3′-UTR which suggests that post-transcriptional regulation influences SERPINB3 expression in chickens. SERPINB3 protein was localized predominantly to the glandular epithelium in cancerous ovaries of chickens, and it was abundant in the nucleus of both chicken and human ovarian cancer cell lines. In 109 human patients with EOC, 15 (13.8%), 66 (60.6%) and 28 (25.7%) patients showed weak, moderate and strong expression of SERPINB3 protein, respectively. Strong expression of SERPINB3 protein was a prognostic factor for platinum resistance (adjusted OR; odds ratio, 5.94; 95% Confidence Limits, 1.21–29.15), and for poor progression-free survival (PFS; adjusted HR; hazard ratio, 2.07; 95% CI; confidence interval, 1.03–4.41). Therefore, SERPINB3 may play an important role in ovarian carcinogenesis and be a novel biomarker for predicting platinum resistance and a poor prognosis for survival in patients with EOC.

Dynamic changes of tumor gene expression during repeated Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) in women with peritoneal cancer

“…The fact that CD44 drives inflammatory signaling in PC is also consistent with our finding of differential regulation of SERPINB3, associated with host-immune-response [31]. Furthermore, strong expression of SERPINB3 protein was characterized as a prognostic factor for platinum resistance and for poor progression-free survival [32], providing an alternative or additional explanation for the increased expression of SERPINB3 in our patients who all had undergone several systemic chemotherapies before recruitment for PIPAC.…”

SERPINB3 (Serpin Peptidase Inhibitor, Clade B (Ovalbumin), Member 3)

“…Indeed, SERPINB3 protects cells from exposure to radiation through an inhibitory effect either on the MAP family of c-Jun terminal kinase (JNK) [19] and the interaction between SERPINB3 and JNK1 was also supported by the crystallographic study [26]; or with a decreased phosphorylation of the proapoptotic p38 mitogen-activated protein kinase on p38 [27]. In epithelial ovarian cancer cells exposed to cisplatin, SERPINB3 expression is associated with drug resistance and poor progression-free survival [28,29], whereas it inhibits the release of mitochondrial cytochrome c in squamous cell carcinoma after treatment with TNF-α [30], or with DNA alkylating agents [28]. …”

“…Moreover, SERPINB3 expression is associated with poor survival in patients with breast cancer treated with anthracycline-based neoadjuvant chemotherapy [31] and in patients with epithelial ovarian cancer a high SERPINB3 expression is a prognostic factor for platinum resistance and shorter progression-free survival [32]. …”

Diethylstilbestrol regulates expression of avian apolipoprotein D during regression and recrudescence of the oviduct and epithelial-derived ovarian carcinogenesis

“…Moreover, an alternative theory for the origin of ovarian cancer has recently proposed that the source of ovarian cancer cells is the oviduct [37,38]. Indeed, about 40% of the up-regulated genes in EOC of laying hens include serpin peptidase inhibitor, clade B, member 3 (SERPINB3) [39], SERPINB11 [40], SERPINB12 [41], alpha 2 macroglobulin (A2M) [42], S-adenosylhomocysteine hydrolase-like protein 1 (AHCYL1) [43], pleiotrophin (PTN) [17], beta-defensin 11 (AvBD-11) [44], beta-catenin (CTNNB1) [45], prostaglandin D2 synthase (PTGDS2) [46], and vitelline membrane outer layer protein 1 (VMO1) [47] which are abundantly expressed during development and differentiation of the oviduct. In the present study, APOD mRNA and protein were abundantly and specifically detected in the GE of cancerous, but not normal ovaries of laying hens.…”