Publications by authors named "Takiko Daikoku"

64 Publications

Brown adipocyte-specific knockout of Bmal1 causes mild but significant thermogenesis impairment in mice.

Mol Metab 2021 Mar 3;49:101202. Epub 2021 Mar 3.

Department of Cellular and Molecular Function Analysis, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan. Electronic address:

Objective: Impaired circadian clocks can cause obesity, but their pathophysiological role in brown adipose tissue (BAT), a major tissue regulating energy metabolism, remains unclear. To address this issue, we investigated the effects of complete disruption of the BAT clock on thermogenesis and energy expenditure.

Methods: Mice with brown adipocyte-specific knockout of the core clock gene Bmal1 (BA-Bmal1 KO) were generated and analyzed.

Results: The BA-Bmal1 KO mice maintained normal core body temperatures by increasing shivering and locomotor activity despite the elevated expression of thermogenic uncoupling protein 1 in BAT. BA-Bmal1 KO disrupted 24 h rhythmicity of fatty acid utilization in BAT and mildly reduced both BAT thermogenesis and whole-body energy expenditure. The impact of BA-Bmal1 KO on the development of obesity became obvious when the mice were fed a high-fat diet.

Conclusions: These results reveal the importance of the BAT clock for maintaining energy homeostasis and preventing obesity.
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http://dx.doi.org/10.1016/j.molmet.2021.101202DOI Listing
March 2021

Mucinous, endometrioid, and serous ovarian cancers with peritoneal dissemination are potent candidates for P-cadherin targeted therapy: a retrospective cohort study.

BMC Cancer 2021 Jan 7;21(1):32. Epub 2021 Jan 7.

Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kanazawa University, 13-1, Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan.

Background: Aberrant expression of P-cadherin has been reported in various cancers, and has been attracting attention as a target for cancer treatment. Ovarian cancer, the leading cause of death among gynecologic malignancies, is classified into four histological subtypes: serous, mucinous, endometrioid, and clear cell, and each has distinct biological behavior. Although a negative survival impact in serous ovarian cancer patients and some functional role in peritoneal dissemination have been reported, differences of P-cadherin expression in histological subtypes and the proportion and distribution of positive cells remain to be investigated. The aims of this study were to clarify the histological and distributional profiles of P-cadherin expression in ovarian cancer for development of target-therapy in near future.

Methods: A total of 162 primary, 60 metastatic, and 8 recurrent tumors (all cases from 162 ovarian cancer patients) were enrolled in the study. Immunohistochemistry was performed for P-cadherin expression. Associations with clinicopathological characteristics and survival were analyzed.

Results: P-cadherin expression showed a strong correlation with the FIGO stage, histological subtypes, positive peritoneal dissemination (P < 0.01), positive distant metastasis (P < 0.05), and trend toward negative overall survival probability (P = 0.050). P-cadherin was intensely and broadly expressed in mucinous, endometrioid, and serous subtypes (P < 0.01). Disseminated tumors demonstrated similar P-cadherin expression to primary tumors whereas metastatic lymph nodes demonstrated significantly decreased expression (P < 0.01).

Conclusions: Mucinous, endometrioid, and serous ovarian cancer patients accompanied with peritoneal disseminations are the most potent candidates for P-cadherin targeted drug delivery strategies. P-cadherin-targeted therapy may benefit and improve survival of poor-prognosis populations.
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http://dx.doi.org/10.1186/s12885-020-07737-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791827PMC
January 2021

The supression of DOCK family members by their specific inhibitors induces the cell fusion of human trophoblastic cells.

Biochem Biophys Res Commun 2020 09 3;529(4):1173-1179. Epub 2020 Aug 3.

Division of Transgenic Animal Science, Advanced Science Research Center, Kanazawa University, Kanazawa, Ishikawa, 920-8640, Japan.

Purpose: Among the members of the DOCK family, DOCK1-5 function as guanine-nucleotide exchange factors for small GTPase Rac1, which regulates the actin cytoskeleton. It has been reported that in model organisms the Dock-Rac axis is required for myoblast fusion. We examined the role of DOCK1-5 in trophoblast fusion herein.

Methods: We used a quantitative polymerase chain reaction (qPCR) to examine the mRNA expressions of DOCK1-5 and differentiation-related genes, i.e., fusogenic genes, in human trophoblastic cell lines, BeWo and JEG-3. We treated BeWo cells with TBOPP and C21 to inhibit DOCK1 and DOCK5. Cell dynamics and cell fusion were assessed by live imaging and immunostaining. The signaling pathways induced by DOCK1/5 inhibition were examined by western blotting.

Results: DOCK1 and DOCK5 were expressed in BeWo cells. The inhibition of DOCK1 or DOCK5 did not prevent the cell fusion induced by forskolin (a common reagent for cell fusion); it induced cell fusion. DOCK1 inhibition induced cell death, as did forskolin. DOCK1 and DOCK5 inhibition for 24 and 48 h increased the expression of the genes ASCT2 and SYNCYTIN2, which code responsive proteins of trophoblast cell fusion, respectively.

Conclusion: DOCK1 and DOCK5 inhibition participates in BeWo cell fusion, probably via pathways independent from forskolin-mediated pathways.
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http://dx.doi.org/10.1016/j.bbrc.2020.06.138DOI Listing
September 2020

Hypertensive disorders of pregnancy are associated with dysmenorrhea in early adulthood: A cohort study.

J Obstet Gynaecol Res 2020 Nov 18;46(11):2292-2297. Epub 2020 Aug 18.

Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kanazawa University, Ishikawa, Japan.

Aim: Hypertensive disorders of pregnancy (HDP) are serious conditions that occur in 5-10% of pregnancies. Maternal factors, such as maternal age, obesity, and renal disease, have been described as risk factors. In order to extract the background lifestyle and gynecological characteristics for HDP, we conducted a prospective cohort study.

Methods: Pregnant participants were administered a questionnaire on characteristics, menstrual abnormalities and lifestyle factors. The women were followed individually until 1-month postpartum. We used medical records to examine the relationship between menstrual abnormalities and the onset of HDP.

Results: We collected data from 193 pregnant women, and excluding 3 who had miscarriage, examined the records of 190. A total of 26 patients developed HDP, of which 10 had early-onset HDP and 16 had late-onset HDP. Although there was no significant association between HDP and dysmenorrhea just prior to pregnancy, there was a significant increase in the incidence of HDP in patients who experienced dysmenorrhea around the age of 20 years (odds ratio 4.362 [95% CI 1.61-11.81]).

Conclusion: We found that patients with a history of dysmenorrhea around the age of 20 years have a significantly higher risk of developing HDP. Although dysmenorrhea in young adulthood is ameliorated, it may become apparent as a perinatal disease when a physical load such as pregnancy is applied.
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http://dx.doi.org/10.1111/jog.14431DOI Listing
November 2020

The lack of terminal tubule cells in the submandibular gland of mice deficient in submandibular gland protein C.

Cell Tissue Res 2020 Aug 16;381(2):229-237. Epub 2020 May 16.

Department of Clinical Engineering, Faculty of Health Sciences, Komatsu University, Komatsu, Japan.

The submandibular gland (SMG) of newborn mice has no mature acini but has the rudiments of acini called terminal tubules (TT). The TT are composed of TT cells with dark secretory granules and proacinar cells with lighter secretory granules, the latter being considered the immediate precursor of mature acinar cells. TT cells contain a specific secretory protein, submandibular gland protein C (SMGC) and they decrease in number postnatally at a higher rate in males than in females. In the present study, in order to clarify the biological roles of TT cells and their secretory product SMGC, we generated a knockout (KO) mouse strain deficient in SMGC. The KO mice of both sexes grew normally, had normal reproductive capacity and had normal acinar and duct systems in the SMG in adult ages. However, through the neonatal and early postnatal stages, the KO mice were deficient not only in the production of SMGC but also in TT cells. With electron microscopy of the SMG of newborn KO mice, TT cells with characteristic granules were absent and replaced by undifferentiated ductal cells, whereas proacinar cells were normal. These results suggested that the absence of SMGC inhibits the development of TT cells and that the absence of SMGC and TT cells has no notable influence on the postnatal development of the acinar and duct systems in the SMG.
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http://dx.doi.org/10.1007/s00441-020-03205-wDOI Listing
August 2020

Adolescent Dietary Habit-induced Obstetric and Gynecologic Disease (ADHOGD) as a New Hypothesis-Possible Involvement of Clock System.

Nutrients 2020 May 2;12(5). Epub 2020 May 2.

Department of Obstetrics and Gynecology, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8640, Japan.

There are growing concerns that poor dietary behaviors at young ages will increase the future risk of chronic diseases in adulthood. We found that female college students who skipped breakfast had higher incidences of dysmenorrhea and irregular menstruation, suggesting that meal skipping affects ovarian and uterine functions. Since dysmenorrhea is more prevalent in those with a past history of dieting, we proposed a novel concept that inadequate dietary habits in adolescence become a trigger for the subsequent development of organic gynecologic diseases. Since inadequate feeding that was limited during the non-active phase impaired reproductive functions in post-adolescent female rats, we hypothesize that circadian rhythm disorders due to breakfast skipping disrupts the hypothalamic-pituitary-ovarian axis, impairs the reproductive rhythm, and leads to ovarian and uterine dysfunction. To explain how reproductive dysfunction is memorized from adolescence to adulthood, we hypothesize that the peripheral clock system also plays a critical role in the latent progression of reproductive diseases together with the central system, and propose naming this concept "adolescent dietary habit-induced obstetric and gynecologic disease (ADHOGD)". This theory will contribute to analyzing the etiologies of and developing prophylaxes for female reproductive diseases from novel aspects. In this article, we describe the precise outline of the above hypotheses with the supporting evidence in the literature.
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http://dx.doi.org/10.3390/nu12051294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282263PMC
May 2020

Promoting Roles of Embryonic Signals in Embryo Implantation and Placentation in Cooperation with Endocrine and Immune Systems.

Int J Mol Sci 2020 Mar 10;21(5). Epub 2020 Mar 10.

Institute for Environmental and Gender-specific Medicine, Juntendo University Graduate School of Medicine, Urayasu 279-0021, Japan.

Embryo implantation in the uterus is an essential process for successful pregnancy in mammals. In general, the endocrine system induces sufficient embryo receptivity in the endometrium, where adhesion-promoting molecules increase and adhesion-inhibitory molecules decrease. Although the precise mechanisms remain unknown, it is widely accepted that maternal-embryo communications, including embryonic signals, improve the receptive ability of the sex steroid hormone-primed endometrium. The embryo may utilize repulsive forces produced by an Eph-ephrin system for its timely attachment to and subsequent invasion through the endometrial epithelial layer. Importantly, the embryonic signals are considered to act on maternal immune cells to induce immune tolerance. They also elicit local inflammation that promotes endometrial differentiation and maternal tissue remodeling during embryo implantation and placentation. Additional clarification of the immune control mechanisms by embryonic signals, such as human chorionic gonadotropin, pre-implantation factor, zona pellucida degradation products, and laeverin, will aid in the further development of immunotherapy to minimize implantation failure in the future.
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http://dx.doi.org/10.3390/ijms21051885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084435PMC
March 2020

The Association and Significance of p53 in Gynecologic Cancers: The Potential of Targeted Therapy.

Int J Mol Sci 2019 Nov 4;20(21). Epub 2019 Nov 4.

Department of Obstetrics and Gynecology, Kanazawa University Graduate School of Medical Sciences, Kanazawa 920-8641, Japan.

Dysfunction of p53 is observed in the many malignant tumors. In cervical cancer, p53 is inactivated by degradation through the complex with human papilloma virus (HPV) oncoprotein E6 and E6-associated protein (E6AP), an E3 ubiquitin protein ligase. In endometrial cancer, overexpression of p53 in immunohistochemistry is a significant prognostic factor. A discrepancy between p53 overexpression and TP53 mutations is observed in endometrioid endometrial cancer, indicating that the accumulation of p53 protein can be explained by not only gene mutations but also dysregulation of the factors such as ERβ and MDM2. Furthermore, the double-positive expression of immunoreactive estrogen receptor (ER) β and p53 proteins is closely associated with the incidence of metastasis and/or recurrence. High-grade serous ovarian carcinoma (HGSC) arises from secretary cells in the fallopian tube. The secretary cell outgrowth (SCOUT) with TP53 mutations progresses to HGSC via the p53 signature, serous intraepithelial lesion (STIL), and serous intraepithelial carcinoma (STIC), indicating that TP53 mutation is associated with carcinogenesis of HGSC. Clinical application targeting p53 has been approved for some malignant tumors. Gene therapy by the adenovirus-mediated p53 gene transfer system is performed for head and neck cancer. A clinical phase III trial using MDM2/X inhibitors, idasanutlin (RG7388) combined with cytarabine, is being performed involving relapse/refractory acute myeloid leukemia patients. The use of adenoviruses as live vectors which encode wild-type p53 has given promising results in cervical cancer patients.
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http://dx.doi.org/10.3390/ijms20215482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6862296PMC
November 2019

IMP dehydrogenase-2 drives aberrant nucleolar activity and promotes tumorigenesis in glioblastoma.

Nat Cell Biol 2019 08 1;21(8):1003-1014. Epub 2019 Aug 1.

Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.

In many cancers, high proliferation rates correlate with elevation of rRNA and tRNA levels, and nucleolar hypertrophy. However, the underlying mechanisms linking increased nucleolar transcription and tumorigenesis are only minimally understood. Here we show that IMP dehydrogenase-2 (IMPDH2), the rate-limiting enzyme for de novo guanine nucleotide biosynthesis, is overexpressed in the highly lethal brain cancer glioblastoma. This leads to increased rRNA and tRNA synthesis, stabilization of the nucleolar GTP-binding protein nucleostemin, and enlarged, malformed nucleoli. Pharmacological or genetic inactivation of IMPDH2 in glioblastoma reverses these effects and inhibits cell proliferation, whereas untransformed glia cells are unaffected by similar IMPDH2 perturbations. Impairment of IMPDH2 activity triggers nucleolar stress and growth arrest of glioblastoma cells even in the absence of functional p53. Our results reveal that upregulation of IMPDH2 is a prerequisite for the occurance of aberrant nucleolar function and increased anabolic processes in glioblastoma, which constitutes a primary event in gliomagenesis.
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http://dx.doi.org/10.1038/s41556-019-0363-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686884PMC
August 2019

Novel strategy of ovarian cancer implantation: Pre-invasive growth of fibrin-anchored cells with neovascularization.

Cancer Sci 2019 Aug 9;110(8):2658-2666. Epub 2019 Jul 9.

Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.

Although direct adhesion of cancer cells to the mesothelial cell layer is considered to be a key step for peritoneal invasion of ovarian cancer cell masses (OCM), we recently identified a different strategy for the peritoneal invasion of OCM. In 6 out of 20 cases of ovarian carcinoma, extraperitoneal growth of the OCM was observed along with the neovascularization of feeding vessels, which connect the intraperitoneal host stroma and extraperitoneal lesions through the intact mesothelial cell layer. As an early step, the OCMs anchor in the extraperitoneal fibrin networks and then induce the migration of CD34-positive and vascular endothelial growth factor A (VEGF-A)-positive endothelial cells, constructing extraperitoneal vascular networks around the OCM. During the extraperitoneal growth of OCM, podoplanin-positive and α smooth muscle actin (αSMA)-positive cancer-associated fibroblasts (CAF) appears. In more advanced lesions, the boundary line of mesothelial cells disappears around the insertion areas of feeding vessels and then extraperitoneal and intraperitoneal stroma are integrated, enabling the OCM to invade the host stroma, being associated with CAF. In addition, tissue factors (TF) are strongly detected around these peritoneal implantation sites and their levels in ascites were higher than that in blood. These findings demonstrate the presence of neovascularization around fibrin net-anchored OCMs on the outer side of the intact peritoneal surface, suggesting a novel strategy for peritoneal invasion of ovarian cancer and TF-targeted intraperitoneal anti-cancer treatment. We observed and propose a novel strategy for peritoneal implantation of ovarian cancer. The strategy includes the preinvasive growth of fibrin-anchored cancer cells along with neovascularization on the outer side of the intact peritoneal surface.
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http://dx.doi.org/10.1111/cas.14098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6676109PMC
August 2019

Time Restriction of Food Intake During the Circadian Cycle Is a Possible Regulator of Reproductive Function in Postadolescent Female Rats.

Curr Dev Nutr 2019 Apr 26;3(4):nzy093. Epub 2018 Nov 26.

Department of Obstetrics and Gynecology, Kanazawa University, Kanazawa, Japan.

Background: We previously reported that skipping breakfast is associated with menstrual disorders of female college students during postadolescent maturation.

Objective: In this study, we investigated the effects of meal timing during circadian cycle on the ovarian function using young female rats.

Methods: Considering that rats are nocturnally active, 8-wk-old female Wistar rats were classified into 3 groups: fed during the daytime only (nonactive phase), night-time only (active phase), or control group I (without time or calorie restriction, free access to a standard caloric diet, 20.0% protein, 62.9% carbohydrate, and 7.0% fat, 3.95 kcal/g) for 4 wk. The changes in body weight and frequency of ovulation in each group were evaluated by a weight scale and a vaginal smear, respectively. At the end of the period of dietary restriction, ovaries were removed, and the numbers of growing follicles (mean diameter >250 µm) and corpora lutea (>600 µm) were examined using hematoxylin-eosin-stained tissue sections. In addition, 8-wk-old female rats were fed only during the night-time for 4 wk under a 20%-reduced food supply of the control group II (without any restriction).

Results: In the daytime-fed group, the frequency and number of ovulations were significantly decreased compared with those in the control group I ( < 0.05), with a reduced body weight gain concomitant with about 20% of reduction in the daily food intake. In contrast, in the night-time-fed group, even when a 20% reduction in the daily food intake was loaded, their estrus cyclicity did not change despite significant reductions in weight gain and food intake compared with control group II.

Conclusion: These findings indicate that restricting food intake to the inactive phase impairs ovarian function in postadolescent female rats, suggesting that the timing of food intake during circadian cycle is one of the crucial factors interfering with the reproductive function.
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http://dx.doi.org/10.1093/cdn/nzy093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446981PMC
April 2019

Development of a Highly Potent Analogue and a Long-Acting Analogue of Oxytocin for the Treatment of Social Impairment-Like Behaviors.

J Med Chem 2019 04 2;62(7):3297-3310. Epub 2019 Apr 2.

Faculty of Pharmaceutical Sciences, Tohoku University and Department of Pharmaceutical Sciences , Tohoku University Hospital , Sendai 980-8574 , Japan.

The nonapeptide hormone oxytocin (OT) has pivotal brain roles in social recognition and interaction and is thus a promising therapeutic drug for social deficits. Because of its peptide structure, however, OT is rapidly eliminated from the bloodstream, which decreases its potential therapeutic effects in the brain. We found that newly synthesized OT analogues in which the Pro of OT was replaced with N-( p-fluorobenzyl)glycine (2) or N-(3-hydroxypropyl)glycine (5) exhibited highly potent binding affinities for OT receptors and Ca mobilization effects by selectively activating OT receptors over vasopressin receptors in HEK cells, where 2 was identified as a superagonist ( E = 131%) for OT receptors. Furthermore, the two OT analogues had a remarkably long-acting effect, up to 16-24 h, on recovery from impaired social behaviors in two strains of CD38 knockout mice that exhibit autism spectrum disorder-like social behavioral deficits, whereas the effect of OT itself rapidly diminished.
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http://dx.doi.org/10.1021/acs.jmedchem.8b01691DOI Listing
April 2019

Ovarian insufficiency and CTNNB1 mutations drive malignant transformation of endometrial hyperplasia with altered PTEN/PI3K activities.

Proc Natl Acad Sci U S A 2019 03 19;116(10):4528-4537. Epub 2019 Feb 19.

Department of Cancer Biology and Genetics, Ohio State University, Columbus, OH 43210;

Endometrioid endometrial carcinomas (EECs) carry multiple driver mutations even when they are low grade. However, the biological significance of these concurrent mutations is unknown. We explored the interactions among three signature EEC mutations: loss-of-function (LOF) mutations in , gain-of-function (GOF) mutations of phosphoinositide 3-kinase (PI3K), and exon 3 mutations, utilizing in vivo mutagenesis of the mouse uterine epithelium. While epithelial cells with a monoallelic mutation in any one of three genes failed to propagate in the endometrium, any combination of two or more mutant alleles promoted the growth of epithelium, causing simple hyperplasia, in a dose-dependent manner. Notably, exon 3 deletion significantly increased the size of hyperplastic lesions by promoting the growth of PTEN LOF and/or PI3K GOF mutant cells through the activation of neoadenogenesis pathways. Although these three mutations were insufficient to cause EEC in intact female mice, castration triggered malignant transformation, leading to myometrial invasion and serosal metastasis. Treatment of castrated mice with progesterone or estradiol attenuated the neoplastic transformation. This study demonstrates that multiple driver mutations are required for premalignant cells to break the growth-repressing field effect of normal endometrium maintained by ovarian steroids and that exon 3 mutations play critical roles in the growth of preneoplastic cells within the endometrium of premenopausal women and in the myometrial invasion of EECs in menopausal women.
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http://dx.doi.org/10.1073/pnas.1814506116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6410785PMC
March 2019

Factors Regulating Human Extravillous Trophoblast Invasion: Chemokine-peptidase and CD9-integrin Systems.

Curr Pharm Biotechnol 2018 ;19(10):764-770

Institute for Environmental and Gender-specific Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.

The invasion of an extravillous trophoblast (EVT) into maternal decidual tissues, especially towards maternal spiral arteries, is an essential process in the human placental formation and subsequent normal fetal development. However, the precise regulatory mechanisms to induce EVT invasion towards arteries and/or to protect EVT from further invasion are not well understood. We found that a chemokine receptor, CCR1, was specifically expressed on EVT migrating towards maternal arteries. Using EVT isolated from a primary villous explant culture, RANTES, which is one of the ligands for CCR1, was shown to enhance EVT invasion. Furthermore, we observed that the platelets were deposited among intravascular EVT and platelet-derived soluble factors, which contained RANTES, enhanced EVT invasion. On the one hand, dipeptidyl peptidase IV (DPPIV), which can metabolize RANTES on the cell surface, was expressed on non-invading EVT and was demonstrated to suppress EVT invasion. In contrast, laeverin/aminopeptidase Q, which is specifically expressed on EVT, was shown to induce EVT invasion. Also, CD9 which is a cell surface marker of platelets and a regulator of integrin function was expressed on EVT and gene knockdown of the CD9 molecule enhanced EVT invasion. These findings suggest that the chemokine-chemokine receptor, chemokine-peptidase, and CD9-integrin systems play important roles in the regulation of EVT invasion during early human placental formation.
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http://dx.doi.org/10.2174/1389201019666181029164906DOI Listing
February 2019

The uterine epithelial loss of Pten is inefficient to induce endometrial cancer with intact stromal Pten.

PLoS Genet 2018 08 24;14(8):e1007630. Epub 2018 Aug 24.

Division of Reproductive Sciences, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.

Mutation of the tumor suppressor Pten often leads to tumorigenesis in various organs including the uterus. We previously showed that Pten deletion in the mouse uterus using a Pgr-Cre driver (Ptenf/fPgrCre/+) results in rapid development of endometrial carcinoma (EMC) with full penetration. We also reported that Pten deletion in the stroma and myometrium using Amhr2-Cre failed to initiate EMC. Since the Ptenf/fPgrCre/+ uterine epithelium was primarily affected by tumorigenesis despite its loss in both the epithelium and stroma, we wanted to know if Pten deletion in epithelia alone will induce tumorigenesis. We found that mice with uterine epithelial loss of Pten under a Ltf-iCre driver (Ptenf/f/LtfCre/+) develop uterine complex atypical hyperplasia (CAH), but rarely EMC even at 6 months of age. We observed that Ptenf/fPgrCre/+ uteri exhibit a unique population of cytokeratin 5 (CK5) and transformation related protein 63 (p63)-positive epithelial cells; these cells mark stratified epithelia and squamous differentiation. In contrast, Ptenf/fLtfCre/+ hyperplastic epithelia do not undergo stratification, but extensive epithelial cell apoptosis. This increased apoptosis is associated with elevation of TGFβ levels and activation of downstream effectors, SMAD2/3 in the uterine stroma. Our results suggest that stromal PTEN via TGFβ signaling restrains epithelial cell transformation from hyperplasia to carcinoma. In conclusion, this study, using tissue-specific deletion of Pten, highlights the epithelial-mesenchymal cross-talk in the genesis of endometrial carcinoma.
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http://dx.doi.org/10.1371/journal.pgen.1007630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6126871PMC
August 2018

Crosstalk between PKCα and PI3K/AKT Signaling Is Tumor Suppressive in the Endometrium.

Cell Rep 2018 07;24(3):655-669

Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA. Electronic address:

Protein kinase C (PKC) isozymes are commonly recognized as oncoproteins based on their activation by tumor-promoting phorbol esters. However, accumulating evidence indicates that PKCs can be inhibitory in some cancers, with recent findings propelling a shift in focus to understanding tumor suppressive functions of these enzymes. Here, we report that PKCα acts as a tumor suppressor in PI3K/AKT-driven endometrial cancer. Transcriptional suppression of PKCα is observed in human endometrial tumors in association with aggressive disease and poor prognosis. In murine models, loss of PKCα is rate limiting for endometrial tumor initiation. PKCα tumor suppression involves PP2A-family-dependent inactivation of AKT, which can occur even in the context of genetic hyperactivation of PI3K/AKT signaling by coincident mutations in PTEN, PIK3CA, and/or PIK3R1. Together, our data point to PKCα as a crucial tumor suppressor in the endometrium, with deregulation of a PKCα→PP2A/PP2A-like phosphatase signaling axis contributing to robust AKT activation and enhanced endometrial tumorigenesis.
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http://dx.doi.org/10.1016/j.celrep.2018.06.067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6118133PMC
July 2018

Dual expression of immunoreactive estrogen receptor β and p53 is a potential predictor of regional lymph node metastasis and postoperative recurrence in endometrial endometrioid carcinoma.

PLoS One 2017 30;12(11):e0188641. Epub 2017 Nov 30.

Department of Obstetrics and Gynecology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan.

Although histological grade and muscular invasion are related to the malignant behaviors of endometrial endometrioid carcinoma, lymphatic and/or distant metastases are unexpectedly encountered, even in patients in the low-risk group. To re-evaluate additional reliable parameters to predict the risk of progression, we examined the immunohistochemical expression profiles of p53 and estrogen receptor (ER) β proteins. Patients with endometrial endometrioid carcinoma who underwent surgical treatment at our hospital (n = 154) were recruited to this study, and the significance of the relationships between the incidence of regional lymph node metastasis and/or postoperative recurrence and clinical or experimental parameters was evaluated. By multivariate analysis, we found that histological grades, detection of immunoreactive p53 (positive rates more than 10%, p53-stained), and high expression of ERβ (high-ERβ) were independently associated with metastasis and/or recurrence. Among these parameters, the sensitivity and negative predictive values of high-ERβ were very high (up to 100%). In the population with high-ERβ, the positive rates of metastasis and/or recurrence were 61.1% in the p53-stained group and 21.9% in the p53-non-stained (negative) group. Furthermore, the positive rate in the group showing myometrial invasion of more than 1/2 and showing both p53-stained and high-ERβ was 80%. The disease-free survival of patients who were double-positive for p53-stained and high-ERβ was significantly shorter than that in other patients. In summary, our findings showed that increases in ERβ and p53 immunoreactivity were significantly correlated with the incidence of metastasis and/or recurrence in endometrial endometrioid carcinoma, suggesting that double-positivity for p53-stained and high-ERβ may provide a promising clinical indicator to predict the risk of progression.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0188641PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5708694PMC
December 2017

The Lipid Kinase PI5P4Kβ Is an Intracellular GTP Sensor for Metabolism and Tumorigenesis.

Mol Cell 2016 Jan 7;61(2):187-98. Epub 2016 Jan 7.

Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; Department of Cancer Biology and Department of Neurosurgery, University of Cincinnati College of Medicine, Brain Tumor Center at University of Cincinnati Neuroscience Institute, Cincinnati, OH 45267, USA. Electronic address:

While cellular GTP concentration dramatically changes in response to an organism's cellular status, whether it serves as a metabolic cue for biological signaling remains elusive due to the lack of molecular identification of GTP sensors. Here we report that PI5P4Kβ, a phosphoinositide kinase that regulates PI(5)P levels, detects GTP concentration and converts them into lipid second messenger signaling. Biochemical analyses show that PI5P4Kβ preferentially utilizes GTP, rather than ATP, for PI(5)P phosphorylation, and its activity reflects changes in direct proportion to the physiological GTP concentration. Structural and biological analyses reveal that the GTP-sensing activity of PI5P4Kβ is critical for metabolic adaptation and tumorigenesis. These results demonstrate that PI5P4Kβ is the missing GTP sensor and that GTP concentration functions as a metabolic cue via PI5P4Kβ. The critical role of the GTP-sensing activity of PI5P4Kβ in cancer signifies this lipid kinase as a cancer therapeutic target.
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http://dx.doi.org/10.1016/j.molcel.2015.12.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4747657PMC
January 2016

Dual Positive Regulation of Embryo Implantation by Endocrine and Immune Systems--Step-by-Step Maternal Recognition of the Developing Embryo.

Am J Reprod Immunol 2016 Mar 12;75(3):281-9. Epub 2016 Jan 12.

Academia for Repro-Regenerative Medicine, Tokyo, Japan.

In humans, HCG secreted from the implanting embryo stimulates progesterone production of the corpus luteum to maintain embryo implantation. Along with this endocrine system, current evidence suggests that the maternal immune system positively contributes to the embryo implantation. In mice, immune cells that have been sensitized with seminal fluid and then the developing embryo induce endometrial differentiation and promote embryo implantation. After hatching, HCG activates regulatory T and B cells through LH/HCG receptors and then stimulates uterine NK cells and monocytes through sugar chain receptors, to promote and maintain pregnancy. In accordance with the above, the intrauterine administration of HCG-treated PBMC was demonstrated to improve implantation rates in women with repeated implantation failures. These findings suggest that the maternal immune system undergoes functional changes by recognizing the developing embryos in a stepwise manner even from a pre-fertilization stage and facilitates embryo implantation in cooperation with the endocrine system.
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http://dx.doi.org/10.1111/aji.12478DOI Listing
March 2016

Neutrophils Oppose Uterine Epithelial Carcinogenesis via Debridement of Hypoxic Tumor Cells.

Cancer Cell 2015 Dec;28(6):785-799

Department of Pathology, NYU School of Medicine, New York, NY 10016, USA; NYU Cancer Institute, NYU Langone Medical Center, New York, NY 10016, USA. Electronic address:

Polymorphonuclear neutrophils (PMNs) are largely considered to foster cancer development despite wielding an arsenal of cytotoxic agents. Using a mouse model of PTEN-deficient uterine cancer, we describe a surprising inhibitory role for PMNs in epithelial carcinogenesis. By inducing tumor cell detachment from the basement membrane, PMNs impeded early-stage tumor growth and retarded malignant progression. Unexpectedly, PMN recruitment and tumor growth control occurred independently of lymphocytes and cellular senescence and instead ensued as part of the tumor's intrinsic inflammatory response to hypoxia. In humans, a PMN gene signature correlated with improved survival in several cancer subtypes, including PTEN-deficient uterine cancer. These findings provide insight into tumor-associated PMNs and reveal a context-specific capacity for PMNs to directly combat tumorigenesis.
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http://dx.doi.org/10.1016/j.ccell.2015.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4698345PMC
December 2015

Ovarian stimulation using human chorionic gonadotrophin impairs blastocyst implantation and decidualization by altering ovarian hormone levels and downstream signaling in mice.

Mol Hum Reprod 2014 Nov 13;20(11):1101-16. Epub 2014 Aug 13.

Kato Ladies Clinic, 7-20-3 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan

Ovarian stimulation induced by follicle-stimulating hormone and human chorionic gonadotrophin (hCG) is commonly used in assisted reproductive technology to increase embryo production. However, recent clinical and animal studies have shown that ovarian stimulation disrupts endometrial function and embryo development and adversely affects pregnancy outcomes. How ovarian stimulation impairs pregnancy establishment and the precise mechanisms by which this stimulation reduces the chances of conception remain unclear. In this study, we first demonstrated that ovarian stimulation using hCG alone impairs implantation, decidualization and fetal development of mice by generating abnormal ovarian hormone levels. We also showed that ovarian hormone levels were altered because of changes in the levels of the enzymes involved in their synthesis in the follicles and corpora lutea. Furthermore, we determined that anomalous ovarian hormone secretion induced by ovarian stimulation alters the spatiotemporal expression of progesterone receptors and their downstream genes, especially in the uterine epithelium. Epithelial estrogenic signaling and cell proliferation were promoted on the day of implantation in stimulated mice and these changes led to the failure of uterine transition from the prereceptive to the receptive state. Collectively, our findings indicate that ovarian stimulation using hCG induces an imbalance in steroid hormone secretion, which causes a failure of the development of uterine receptivity and subsequent implantation and decidualization by altering the expression of steroid receptors and their downstream signaling associated with embryo implantation.
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http://dx.doi.org/10.1093/molehr/gau065DOI Listing
November 2014

Mammalian target of rapamycin complex 1 and cyclooxygenase 2 pathways cooperatively exacerbate endometrial cancer.

Am J Pathol 2014 Sep 21;184(9):2390-402. Epub 2014 Jul 21.

Division of Reproductive Sciences, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. Electronic address:

The underlying causes of endometrial cancer (EMC) are poorly understood, and treatment options for patients with advanced stages of the disease are limited. Mutations in the phosphatase and tensin homologue gene are frequently detected in EMC. Cyclooxygenase 2 (Cox2) and mammalian target of rapamycin complex 1 (mTORC1) are known downstream targets of the phosphatase and tensin homologue protein, and their activities are up-regulated in EMC. However, it is not clear whether Cox2 and mTORC1 are crucial players in cancer progression or whether they work in parallel or cooperatively. In this study, we used a Cox2 inhibitor, celecoxib, and an mTORC1 inhibitor, rapamycin, in mouse models of EMC and in human EMC cell lines to explore the interactive roles of Cox2 and mTORC1 signaling. We found that a combined treatment with celecoxib and rapamycin markedly reduces EMC progression. We also observed that rapamycin reduces Cox2 expression, whereas celecoxib reduces mTORC1 activity. These results suggest that Cox2 and mTORC1 signaling is cross-regulated and cooperatively exacerbate EMC.
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http://dx.doi.org/10.1016/j.ajpath.2014.05.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4188174PMC
September 2014

Lactoferrin-iCre: a new mouse line to study uterine epithelial gene function.

Endocrinology 2014 Jul 13;155(7):2718-24. Epub 2014 May 13.

Division of Reproductive Sciences, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039.

Transgenic animal models are valuable for studying gene function in various tissue compartments. Mice with conditional deletion of genes in the uterus using the Cre-loxP system serve as powerful tools to study uterine biology. The uterus is comprised of 3 major tissue types: myometrium, stroma, and epithelium. Proliferation and differentiation in each uterine cell type are differentially regulated by ovarian hormones, resulting in spatiotemporal control of gene expression. Therefore, examining gene function in each uterine tissue type will provide more meaningful information regarding uterine biology during pregnancy and disease states. Although currently available Cre mouse lines have been very useful in exploring functions of specific genes in uterine biology, overlapping expression of these Cre lines in more than 1 tissue type and in other reproductive organs sometimes makes interpretation of results difficult. In this article, we report the generation of a new iCre knock-in mouse line, in which iCre is expressed from endogenous lactoferrin (Ltf) promoter. Ltf-iCre mice primarily direct recombination in the uterine epithelium in adult females and in immature females after estrogen treatment. These mice will allow for specific interrogation of gene function in the mature uterine epithelium, providing a helpful tool to uncover important aspects of uterine biology.
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http://dx.doi.org/10.1210/en.2014-1265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4060188PMC
July 2014

Possible roles of the cAMP-mediators EPAC and RAP1 in decidualization of rat uterus.

Reproduction 2014 Jun 28;147(6):897-906. Epub 2014 Feb 28.

Department of Endocrine and Neural PharmacologyTokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, JapanDivision of Reproductive SciencesPerinatal Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229-3026, USA.

The optimal decidualization of endometrial stromal cells (ESCs) following embryo implantation is one of the critical steps to establish pregnancy in rodents and humans. This step is intricately regulated by ovarian hormones. Using in vitro human ESCs model, we previously showed that activation of a cAMP mediator, exchange protein directly activated by cAMP (EPAC), promotes ovarian steroid- or cAMP analog-induced decidualization. However, expressions and functions of EPAC and RAP1 in the uterus during pregnancy have not yet been examined. In this study, we found that the expression of EPAC2 and RAP1 was markedly upregulated in the decidual cells at the implantation sites on days 7 and 9 of pregnancy in rats. Furthermore, both delayed-implantation and artificial decidualization models showed that EPAC2 and RAP1 expression was enhanced in decidual cells. Significant activation of cAMP-responsive element-binding protein (CREB), a central transcriptional factor of cAMP signaling, was observed in decidual cells. These spatiotemporal expressions of protein related EPAC pathway are overlapped by sites with activated cAMP signaling, indicating the association of EPAC signaling with decidualization. Strikingly, further studies in in vitro rat decidualization model showed that the cAMP analog and medroxyprogesterone stimulated the expression of decidual markers, while knockdown of EPAC1/2 and RAP1 attenuated the expressions of these markers. Together, these findings suggest that EPAC and RAP1 are the crucial factors for endometrial decidualization in rat pregnancy.
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http://dx.doi.org/10.1530/REP-13-0654DOI Listing
June 2014

Ovarian LGR5 is critical for successful pregnancy.

FASEB J 2014 May 27;28(5):2380-9. Epub 2014 Jan 27.

1Cincinnati Children's Hospital Medical Center, Division of Reproductive Sciences, MLC 7045, 3333 Burnet Ave., Cincinnati, OH 45229, USA.

Leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) is expressed in many organs, including female reproductive organs, and is a stem cell marker in the stomach and intestinal epithelium, hair follicles, and ovarian surface epithelium. Despite ongoing studies, the definitive physiological functions of Lgr5 remain unclear. We utilized mice with conditional deletion of Lgr5 (Lgr5(d/d)) in the female reproductive organs by progesterone receptor-Cre (Pgr(Cre)) to determine Lgr5's functions during pregnancy. Only 30% of plugged Lgr5(d/d) females delivered live pups, and their litter sizes were lower. We found that pregnancy failure in Lgr5(d/d) females was due to insufficient ovarian progesterone (P4) secretion that compromised decidualization, terminating pregnancy. The drop in P4 levels was reflected in elevated levels of P4-metabolizing enzyme 20α-hydroxysteroid dehydrogenase in corpora lutea (CL) inactivated of Lgr5. Of interest, P4 supplementation rescued decidualization failure and supported pregnancy to full term in Lgr5(d/d) females. These results provide strong evidence that Lgr5 is critical to normal CL function, unveiling a new role of LGR5 in the ovary.
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http://dx.doi.org/10.1096/fj.13-248344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3986831PMC
May 2014

CXCR2-expressing myeloid-derived suppressor cells are essential to promote colitis-associated tumorigenesis.

Cancer Cell 2013 Nov;24(5):631-44

Laboratory for Inflammation and Cancer, the Biodesign Institute at Arizona State University, Tempe, AZ 85287, USA.

A large body of evidence indicates that chronic inflammation is one of several key risk factors for cancer initiation, progression, and metastasis. However, the underlying mechanisms responsible for the contribution of inflammation and inflammatory mediators to cancer remain elusive. Here, we present genetic evidence that loss of CXCR2 dramatically suppresses chronic colonic inflammation and colitis-associated tumorigenesis through inhibiting infiltration of myeloid-derived suppressor cells (MDSCs) into colonic mucosa and tumors in a mouse model of colitis-associated cancer. CXCR2 ligands were elevated in inflamed colonic mucosa and tumors and induced MDSC chemotaxis. Adoptive transfer of wild-type MDSCs into Cxcr2(-/-) mice restored AOM/DSS-induced tumor progression. MDSCs accelerated tumor growth by inhibiting CD8(+) T cell cytotoxic activity.
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http://dx.doi.org/10.1016/j.ccr.2013.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3928012PMC
November 2013

A new role for muscle segment homeobox genes in mammalian embryonic diapause.

Open Biol 2013 Apr 24;3(4):130035. Epub 2013 Apr 24.

Division of Reproductive Sciences, Cincinnati Children's Research Foundation, Cincinnati, OH 45229, USA.

Mammalian embryonic diapause is a phenomenon defined by the temporary arrest in blastocyst growth and metabolic activity within the uterus which synchronously becomes quiescent to blastocyst activation and implantation. This reproductive strategy temporally uncouples conception from parturition until environmental or maternal conditions are favourable for the survival of the mother and newborn. The underlying molecular mechanism by which the uterus and embryo temporarily achieve quiescence, maintain blastocyst survival and then resume blastocyst activation with subsequent implantation remains unknown. Here, we show that uterine expression of Msx1 or Msx2, members of an ancient, highly conserved homeobox gene family, persists in three unrelated mammalian species during diapause, followed by rapid downregulation with blastocyst activation and implantation. Mice with uterine inactivation of Msx1 and Msx2 fail to achieve diapause and reactivation. Remarkably, the North American mink and Australian tammar wallaby share similar expression patterns of MSX1 or MSX2 as in mice-it persists during diapause and is rapidly downregulated upon blastocyst activation and implantation. Evidence from mouse studies suggests that the effects of Msx genes in diapause are mediated through Wnt5a, a known transcriptional target of uterine Msx. These studies provide strong evidence that the Msx gene family constitutes a common conserved molecular mediator in the uterus during embryonic diapause to improve female reproductive fitness.
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http://dx.doi.org/10.1098/rsob.130035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3718335PMC
April 2013

Conditional deletion of Tsc1 in the female reproductive tract impedes normal oviductal and uterine function by enhancing mTORC1 signaling in mice.

Mol Hum Reprod 2013 Jul 7;19(7):463-72. Epub 2013 Mar 7.

Division of Reproductive Sciences, The Perinatal Institute, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, MLC 7045, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.

Heightened mammalian target of rapamycin complex 1 (mTORC1) activity by genetic deletion of its direct inhibitor, Tsc1, is associated with aberrant development and dysfunction of the female reproductive tract in mice. Here, we compared the phenotypes of mice with conditional deletion of Tsc1 in the female reproductive tract by either progesterone receptor (PR)-Cre (Tsc1(PR(d/d))), which inactivates Tsc1 in all major cell types in the uterus (epithelium, stroma and myometrium), or anti-Mullerian hormone type 2 receptor (Amhr2)-Cre (Tsc1(Amhr2(d/d))), which inactivates stromal and myometrial Tsc1. Tsc1(PR(d/d)) and Tsc1(Amhr2(d/d)) females are infertile resulting from oviductal hyperplasia, retention of embryos in the oviduct and implantation failure. In contrast to the appropriate embryonic development after fertilization seen in Tsc1(Amhr2(d/d)) females, embryo development was disrupted in Tsc1(PR(d/d)) females. In addition, uteri in Tsc1(PR(d/d)) and Tsc1(Amhr2(d/d)) females showed epithelial hyperplasia but not endometrial cancer. In conclusion, Tsc1(PR(d/d)) and Tsc1(Amhr2(d/d)) have overlapping yet distinct phenotypes in the context of compartment-specific deletion of Tsc1.
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http://dx.doi.org/10.1093/molehr/gat016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3690805PMC
July 2013

Wakayama Symposium: Epithelial-mesenchymal interaction regulates tissue formation and characteristics: insights for corneal development.

Ocul Surf 2012 Oct 25;10(4):217-20. Epub 2012 Jul 25.

Department of Developmental Genetics Research, Institute of Advanced Medicine, Wakayama Medical University (WMU), Wakayama, Japan.

Epithelial-mesenchymal interactions and epithelial-to-mesenchymal transition (EMT) are essential during tissue formation and organ morphogenesis. The roles of Wnt/β-catenin signaling have been studied in many organ systems. In this review, we describe the importance of Wnt/β-catenin signaling by comparing skin and corneal development of Wnt/β-catenin gain of function (GOF) mutant mice. In the skin, Wnt/β-catenin signals have been suggested to play essential roles in regulating cell-cell interaction, cell proliferation and differentiation. Wnt signaling may be associated with basal cell carcinoma (BCC) of the skin. In the case of cornea, β-catenin GOF mutation leads to epithelial hyperplasia. Investigation of the mechanisms of growth factor signaling as a reference to general organogenesis could provide profound insights for understanding corneal development and pathogenesis.
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http://dx.doi.org/10.1016/j.jtos.2012.07.007DOI Listing
October 2012

Differential expression of the motin family in the peri-implantation mouse uterus and their hormonal regulation.

J Reprod Dev 2012 20;58(6):649-53. Epub 2012 Jul 20.

Laboratory of Animal Breeding and Reproduction, Division of Animal Science, Faculty of Agriculture, Utsunomiya University, Tochigi 321-8505, Japan.

Increased vascular permeability and angiogenesis are hallmarks of the implantation process in the uterus. Angiomotin (Amot), which is a vascular angiogenesis-related protein, belongs to the motin family. There are two other members of the motin family, angiomotin-like 1 and 2 (Amotl1 and 2), which are also thought to be involved with angiogenesis. In the present study, the distribution of motin mRNAs in the mouse uterus during the peri-implantation period was investigated by in situ hybridization. Amot and Amotl1 were expressed in the stromal cells on days 3 and 4; expressions of Amotl2 during the same period were low. During the postimplantation period, Amot and Amotl1 were expressed in secondary decidual cells, while Amotl2 expression fell to an undetectable level. We also examined hormonal regulation of motin expression by steroid hormone treatment in ovariectomized mice. We found that expression of Amot was induced by P(4) in stromal cells. Additionally, Amotl1 expression was upregulated by both P(4) and estrogen (E(2)) in stromal cells, whereas E(2) increased this gene expression for only a limited time; after 12 h, expression dissipated. In contrast, P(4) regulated the expression of Amotl2 in stromal cells, while E(2) regulated its expression in luminal epithelium cells. Our results demonstrated that Amot, Amotl1, and Amotl2 were differentially expressed in uterine cells during the peri-implantation period, and that their expressions were differentially regulated by P(4) and E(2).
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http://dx.doi.org/10.1262/jrd.2012-075DOI Listing
May 2013