Upregulation of miR-197 inhibits cell proliferation by directly targeting IGFBP5 in human uterine leiomyoma cells.

Uterine leiomyoma (ULM), one of the most common reproductive tract neoplasms in premenopausal women, is a kind of benign tumor with multigene involved. Finding and studying the key gene involved has been a long-needed factor for developing non-surgery therapy and prevention methods. The dysregulated microRNAs were reported to play important roles in ULM pathobiology by regulating tumor growth. Our investigations have revealed that miR-197 is at low expression in ULM. Characterization of the effects of miR-197 in ULM demonstrated that downregulation of miR-197 increased cell growth and induced cell cycle arrest in the G0/G1 phase in vitro, while upregulation of miR-197 expression had the opposite effect on ULM growth and progression. Further research on the mechanism of miR-197 on the proliferation of ULM cells, we showed that miR-197 inhibited cell proliferation of ULM by directly targeting IGFBP5, which was overexpressed in ULM and played an important role in the etiology of ULM. These findings obtained in this study deliver insights and further expand our understanding of the role of miR-197 and its target IGFBP5 in ULM development, which provides a potential novel therapeutic agent to target the proliferation of ULM cells.

Wide-ranging DNA methylation differences of primary trophoblast cell populations and derived cell lines: implications and opportunities for understanding trophoblast function.

Difficulties associated with long-term culture of primary trophoblasts have proven to be a major hurdle in their functional characterization. In order to circumvent this issue, several model cell lines have been established over many years using a variety of different approaches. Due to their differing origins, gene expression profiles and behaviour in vitro, different model lines have been utilized to investigate specific aspects of trophoblast biology. However, generally speaking, the molecular mechanisms underlying functional differences remain unclear. In this study, we profiled genome-scale DNA methylation in primary first trimester trophoblast cells and seven commonly used trophoblast-derived cell lines in an attempt to identify functional pathways differentially regulated by epigenetic modification in these cells. We identified a general increase in DNA promoter methylation levels in four choriocarcinoma (CCA)-derived lines and transformed HTR-8/SVneo cells, including hypermethylation of several genes regularly seen in human cancers, while other differences in methylation were noted in genes linked to immune responsiveness, cell morphology, development and migration across the different cell populations. Interestingly, CCA-derived lines show an overall methylation profile more similar to unrelated solid cancers than to untransformed trophoblasts, highlighting the role of aberrant DNA methylation in CCA development and/or long-term culturing. Comparison of DNA methylation and gene expression in CCA lines and cytotrophoblasts revealed a significant contribution of DNA methylation to overall expression profile. These data highlight the variability in epigenetic state between primary trophoblasts and cell models in pathways underpinning a wide range of cell functions, providing valuable candidate pathways for future functional investigation in different cell populations. This study also confirms the need for caution in the interpretation of data generated from manipulation of such pathways in vitro.

[Familial occurrence of a type 2 segmental manifestation of cutaneous leiomyomatosis]. / Familiäres Auftreten einer segmentalen Typ-2-Manifestation der kutanen Leiomyomatose.

BACKGROUND: There are several malignant or benign skin diseases which can be explained by the phenomenon of mosaicism or segmental manifestation, e. g. segmental neurofibromatosis 1 or cutaneous leiomyomatosis. Loss of heterozygosity is a crucial element for segmental manifestations. Two types of segmental manifestations can be defined in autosomal dominant skin diseases such as cutaneous leiomyomatosis. Type 1 is caused by a novel postzygotic segmental mutation; type 2 reflects an additional postzygotic loss of heterozygosity of the gene locus responsible for cutaneous leiomyomatosis in a initially heterozygous embryo. Loss of heterozygosity is a genetic process when a heterozygous cell becomes homozygous or hemizygous by loosing the corresponding wild-type allele. This phenomenon can be regarded as a precondition for tumor growth. In type-2 cases, the segmental manifestation is more distinctive with additional disseminated disease because of a germline mutation with heterozygosity of all somatic cells outside the strongly affected area. PATIENTS AND METHODS: A 74-year-old female patient and her 52-year-old son presented with segmental leiomyomas following the lines of Blaschko as well as disseminated skin tumors. The woman has undergone hysterectomy at the age of 29 because of multiple uterine leiomyomas, as had her mother and grandmother. RESULTS: Based on their typical clinical appearance, these cases represent the rare familial occurrence of type-2 manifestation of leiomyomas which indicates a postzygotic loss of the wild-type allele. CONCLUSION: Very unusual is the familial occurrence in mother and son of this type-2 manifestation of cutaneous leiomyomatosis. Apparently the gene locus is prone to a postzygotic loss of heterozygosity.

Female adnexal tumour of probable wolffian origin

We report a case of female adnexal tumour of probable wolffian origin, a rare tumour of the broad ligament, and discuss aspects of its origin, differential diagnosis and behaviour.(AU)

Female adnexal tumour of probable wolffian origin.

We report a case of female adnexal tumour of probable wolffian origin, a rare tumour of the broad ligament, and discuss aspects of its origin, differential diagnosis and behaviour.

Carcinogenic alterations in murine liver, lung, and uterine tumors induced by in utero exposure to ionizing radiation.

The atomic bombing of Hiroshima and Nagasaki and the nuclear accident at Chernobyl raised the question of prenatal sensitivity to ionizing radiation-induced cancer. In this study, mice were exposed to single doses of gamma-radiation (0.2-2.0 Gy) at different embryonic stages. The tumor incidence increased with dose from 15% in control mice to 35% in mice irradiated with 2.0 Gy on 18 d of prenatal life. Various oncogenic events were investigated in lymphoid, liver, lung, and uterine tumors. We observed threefold to fivefold increases in myc expression in 25% of the lymphomas, and the expression of Ha-ras and p53 genes decreased in 40% and 60% of the lung tumors by twofold to fivefold. Point mutations were tissue specific: Ha-ras codon 61 mutations were found in about 40% of the liver adenocarcinomas, Ki-ras codon 12 mutations in about 17% of lung tumors, and p53 mutations in about 15% of the lymphomas. Amplification and rearrangement of the p53, myc, and Ha-, Ki- and N-ras genes were not detected. Loss of heterozygosity on chromosome 4 at the multiple tumor suppressor 1 and 2 genes was observed in all types of malignancies. Allelic losses on chromosome 11 at the p53 locus were found in lymphoid, liver, and lung tumors, but they were absent from uterine tumors. Multiple oncogenic changes were often detected. The frequency of carcinogenic alterations was similar in spontaneous and radiation-induced lymphoid, liver, and uterine tumors. In radiation-induced lung adenocarcinomas, however, the incidences of many oncogenic changes were different from those found in their spontaneous counterparts. This suggests that different oncogenic pathways are activated during spontaneous and in utero gamma-radiation-induced murine lung carcinogenesis.

[Müllerian mixed tumors. Experience of the Rennes Regional University Hospital]. / Les tumeurs mixtes mullériennes. Expérience du C.H.R.U. de Rennes.

Seventeen cases of mixed Muller tumours (tumours of the uterus with malignant epithelial and mesenchymal components) are presented. These recently described tumours are rare and occur in menopaused women. Bloody discharge is the usual clinical manifestation, together with an increase of the volume of the uterus. Pathology examination of the surgical specimen is required for diagnosis using immunolabeling to distinguish between homologous tumours (the sarcomatous component occurs in the primary mesenchyma) and heterologous tumours (the mesenchymatous component results from a metastasis). Prognosis, usually poor, depends on the stage of the tumour. Overall survival at 5 years is about 30%. Survival in early stage I and state II tumours is no greater than 50% at 5 years. Treatment is based on radiosurgical techniques in less advanced tumours and requires radiochemotherapy in more advanced stage tumours. Recurrence is usually seen within 2 years, involving the pelvis alone in 10% of the cases and metastasis in most of the others. Because of their rapid development and poor prognosis, these tumours should be identified separately as a separate entity within a larger group of mixed mesodermic tumours.

[A classification of uterine tumors based on embryogenesis]. / Une classification des tumeurs de l'utérus basée sur l'embryogenèse.

On the basis of their results of studies of human embryos and foetuses, the authors believe that the myometrium is derived from the primitive mesenchyme, while the endometrium is derived from the coelomic mesothelium. The myometrium is the site of non-specific tumours common to all soft tissues (of other organs): leiomyoma, lipoleiomyoma, leiomyoblastoma, leiomyosarcoma; vascular tumours: angioma, haemangiopericytoma. The endometrium is the site of tumours derived either from the epithelial contingent (of glandular tubules): adenoma, adenocarcinoma; or from the epithelio-connective tissue contingents: mullerian dysplasia, carcinosarcoma (homologous mixed mesodermal tumour). The authors classify heterologous mixed mesodermal tumours in a separate group; they believe that they constitute true mixed mesodermal tumours derived from two cell clones: one of mullerian origin and the other derived from the primitive mesenchyme.

Hydatidiform moles and teratomas confirm the human identity of the preimplantation embryo.

Results of recent research on hydatidiform moles and teratomas show that during pregnancy the embryo does not receive any message or information from the mother able to control the mechanisms of development or to produce the type of cellular differentiation necessary for building the tissues of the new human adult. Thus, the biological identity of the new human being does not depend on the sojourn in the uterus; the preimplantation embryo is the same individual of the human species as the adult, into whom the embryo can in principle develop.

Hydatidiform mole: a vascular congenital anomaly.

The thesis is advanced that a critical time for development of embryonic blood vessels in the placenta is 13 to 21 days after conception, especially during days 18 to 21. Dietary requirements at this time are specific and demanding for nutritional precursors of thymidine which is an important constituent of DNA. Folic acid and histidine are specifically essential for thymidine synthesis. These are reviewed with respect to cultures and socioeconomon levels in societies where occurrence of hydatidiform mole is endemic. Specific nutritional deficiencies are discussed in relation to kinds of diets and ways of food preparation. When specific dietary requirements are lacking at a time of high need, embryo death, abnormality, and/or avascularity of trophoblastic placental villi may be the earliest pathogenic signs of hydatidiform mole.

[Clear cell carcinoma of the female genital tract]. / Les carcinomes à cellules claires du tractus génital féminin

Even though the existence of clear cell carcinomata is universally acknowledged at all levels of the female genital tract, the nomenclature and the pathogenesis are still controversial. Following the observation of several examples of these tumours, we have been tempted to define and state the origin of these tumours. In the light of urogenital embryogenesis we think that it is discretion that has led to purely descriptive terms to describe these carcinomata. A critical study of the hypotheses as to the pathogenesis that have been suggested about these tumours in the literature allows the summary of numerous arguments in favour of a müllerian origin or viewed in a broader aspect, coelomic origin for these tumours.