Epithelial ovarian cancer is an aggressive gynecological malignancy with a high mortality rate. Resistance against chemotherapeutic agents often develops in ovarian cancer patients, contributing to high recurrence rates. The multidrug resistance 1 (MDR1/ABCB1) gene encodes P‐glycoprotein, which affects the pharmacokinetic properties of anticancer agents. We previously reported that the Caudal‐related homeobox transcription factor CDX2 transcriptionally regulates MDR1 expression in colorectal cancer. CDX2 is a factor that influences cancer cell differentiation, malignancy, and cancer progression. We hypothesized that profiling of CDX2 and MDR1 expression could be an effective strategy for predicting anticancer drug resistance. We studied the expression of these factors in clinical samples from ovarian cancer patients. We found that endogenous MDR1 expression was positively associated with CDX2 expression in ovarian mucinous adenocarcinoma. Using ovarian mucinous adenocarcinoma cell lines, we also observed decreased MDR1 expression following inhibition of CDX2 by RNA interference. In addition, CDX2 overexpression in MN‐1 cells, which display low endogenous CDX2, resulted in upregulation of MDR1 expression. CDX2 induced MDR1‐dependent resistance to vincristine and paclitaxel, which was reversed by treatment with the MDR1‐specific inhibitor verapamil. Our findings show that CDX2 promotes upregulation of MDR1 expression, leading to drug resistance in ovarian mucinous adenocarcinoma. Therefore, our study demonstrates the potential of novel chemotherapy regimens based on CDX2 status and MDR1 expression in ovarian mucinous adenocarcinoma.

Background/Aim: The biological importance of the caudal-related homeobox transcription factor CDX2 in acquiring resistance to anticancer drugs has been studied in ovarian mucinous carcinoma. CDX2 promotes the expression of multidrug resistance 1 (MDR1) and confers resistance to paclitaxel. The regenerating islet-derived family member 4 (REG4) gene is a potential target gene of CDX2. In this study, we investigated the relationship between the expression of CDX2 and Reg IV and the regulation of Reg IV expression and examined novel chemotherapeutic regimens. Materials and Methods: The regulation of Reg IV expression by CDX2 and sensitivity of 5-fluorouracil (5-FU) were evaluated using ovarian mucinous cancer cell lines. Results: The correlation of CDX2 with Reg IV expression was demonstrated in ovarian mucinous carcinoma. Reg IV expression was enhanced by transfection of CDX2 and was suppressed by inhibition of CDX2 expression. OMC-3 cells with ectopically overexpressed CDX2 showed enhanced apoptosis and sensitivity to 5-FU. Conclusion: CDX2 promotes resistance to paclitaxel and sensitivity to 5-FU. Novel 5-FU-based chemotherapy based on CDX2 may be used in ovarian mucinous carcinoma.

Intravenous leiomyomatosis (IVL) is a rare benign neoplasm. Herein, we describe two cases of IVL at different levels of progression. The tumor in Case 1 was extensive, invading the right atrium after a hysterectomy for a uterine myoma. The tumor temporarily responded to hormonal treatment; however, tumor regrowth occurred. In contrast, the tumor in Case 2 extended only to the pelvic veins and was revealed preoperatively. Hysterectomy and bilateral salpingo-oophorectomy were performed, resulting in the complete surgical resection of the tumor. In Case 2, no recurrence has been observed. Tumor samples were evaluated for hyaluronan expression using Alcian blue staining (with and without hyaluronidase digestion). The tumor in Case 1 stained strongly positive for hyaluronan while the tumor in Case 2 stained weakly positive for hyaluronan. In contrast, a large non-IVL uterine leiomyoma (control) stained negative for hyaluronan. These results suggest a relationship between tumor hyaluronan expression and IVL progression, similar to that in other cancers.

Immunohistochemical localization of indoleamine 2,3-dioxygenase-1 and indoleamine 2,3-dioxygenase-2, the first and rate-limiting enzyme in tryptophan metabolism along the kynurenine pathway, has been studied in order to better understand the physiological significance of these enzymes at the maternal-fetal interface of human pregnancy with a gestational age of 7 weeks (n = 1) and term placentas (37-40 weeks of gestation, n = 5). Indoleamine 2,3-dioxygenase-1 protein immunoreactivity was found in glandular epithelium of the decidua and the endothelium of the fetal blood vessels in the villous stroma with some additional positive cells in the villous core and in the decidua. The syncytiotrophoblast stained strongly for indoleamine 2,3-dioxygenase-2. Immunoreactivity of kynurenine, the immediate downstream product of indoleamine 2,3-dioxygenase-mediated tryptophan metabolism, showed the same localization as that of indoleamine 2,3-dioxygenase-1 and indoleamine 2,3-dioxygenase-2, suggesting these are functional enzymes. Interferon-γ added to placental villous explant culture markedly stimulated expression level of both mRNA and immunoreactivity of indoleamine 2,3-dioxygenase-1. The different cellular expression and interferon-γ sensitivity of these enzymes at the maternal-fetal interface suggests distinct physiological roles for each enzyme in normal human viviparity.

Proper placental development relies on tightly regulated trophoblast differentiation and interaction with maternal cells. Human endogenous retroviruses (HERVs) play an integral role in modulating cell fusion events in the trophoblast cells of the developing placenta. Syncytin-1 (ERVW-1) and its receptor, solute-linked carrier family A member 5 (SLC1A5/ASCT2), promote fusion of cytotrophoblast (CTB) cells to generate the multi-nucleated syncytiotrophoblast (STB) layer which is in direct contact with maternal blood. Another HERV-derived protein known as Suppressyn (ERVH48-1/SUPYN) is implicated in anti-fusogenic events as it shares the common receptor with ERVW-1. Here, we explore primary tissue and publicly available datasets to determine the distribution of ERVW-1, ERVH48-1 and SLC1A5 expression at the maternal-fetal interface. While SLC1A5 is broadly expressed in placental and decidual cell types, ERVW-1 and ERVH48-1 are confined to trophoblast cell types. ERVH48-1 displays higher expression levels in CTB and extravillous trophoblast, than in STB, while ERVW-1 is generally highest in STB. We have demonstrated through gene targeting studies that suppressyn has the ability to prevent ERVW-1-induced fusion events in co-culture models of trophoblast cell/maternal endometrial cell interactions. These findings suggest that differential HERV expression is vital to control fusion and anti-fusogenic events in the placenta and consequently, any imbalance or dysregulation in HERV expression may contribute to adverse pregnancy outcomes.