Anti-tumor effect of Wasabi component, 6-(methylsulfinyl) hexyl isothiocyanate, against endometrial carcinoma cells.

PURPOSE: Wasabi is a traditional plant seasoning with an anti-septic function. Recent studies revealed several functions of Wasabi, such as anti-inflammation; however, the anti-tumor effect against endometrial carcinoma (EMC) cells has not been examined. In the present study, we investigated the anti-tumor effect of 6-(methylsulfinyl) hexyl isothiocyanate (6-MITC), a major chemical compound of Wasabi, against various EMC cell lines in vitro and in vivo. METHODS: The effect of 6-MITC on cell viability was measured by the WST-1 assay in EMC and HUVEC cells. The impact of 6-MITC oral administration in nude mice was measured to assess the growth of the EMC xenograft and natural killer (NK) cell activity in the spleen. RESULTS: The addition of 6-MITC suppressed the proliferation of EMC cells (Ishikawa, HEC265, HEC108, KLE, and HEC1B) dose-dependently, but not HUVEC cells. 6-MITC (5 µM) enhanced the cisplatin sensitivity of EMC cells. 6-MITC induced apoptosis in a dose-dependent fashion in EMC cells other than HEC1B cells and was associated with increased expression of cleaved-caspase3 and decreased expression of BCL2. Oral administration of 6-MITC (2 and 4 µmol/kg) to Ishikawa and HEC1B xenografting mice resulted in a reduced tumor volume compared with the control (P < 0.05, 4 µmol/kg). Immunohistochemical staining of resected tumors revealed increased expression of Ki-67 and reduced cleaved-caspase3. Furthermore, 6-MITC treatment enhanced NK cell activity, especially when administered before tumor xenografting. CONCLUSION: These results indicate that 6-MITC has a marked anti-tumor effect against EMC cells and a novel effect to enhance NK cell activity. These effects suggest the therapeutic potential of 6-MITC.

Uterine Leiomyosarcoma Tumorigenesis in Lmp2-deficient Mice: Involvement of Impaired Anti-oncogenic Factor IRF1.

BACKGROUND/AIM: Uterine leiomyosarcoma (Ut-LMS) is a highly metastatic smooth muscle neoplasm. We have previously reported that low molecular mass protein2 Lmp2-deficient mice spontaneously developed Ut-LMS, which implicated this protein as an anti-oncogenic candidate. We also suggested that LMP2 may negatively regulate Ut-LMS independently of its role in the proteasome. Initially described as a transcription factor able to activate the expression of interferon-gamma (IFN-γ)-responsive genes, interferon regulatory factor-1 (IRF1) has been shown to play roles in the immune response, and tumor suppression. The aim of this study was to elucidate the molecular mechanism of sarcomagenesis of Ut-LMS using human and mouse uterine tissues. MATERIALS AND METHODS: The expression of the IFN-γ signal molecules, IRF1 and -2, STAT1, and LMP2, -3, -7 and -10 were examined by western blot analysis, electrophoretic mobility shift assay and immunohistochemistry in human and mouse uterine tissues. Physiological significance of IRF1 in sarcomagenesis of Ut-LMS was demonstrated by xenograft studies. RESULTS: In the present study, several lines of evidence indicated that although treatment with IFN-γ strongly induced the activation of STAT1 as a transcriptional activator, its target molecule, IRF1, was not clearly produced in Lmp2-deficient uterine smooth muscle cells (Ut-SMCs). CONCLUSION: Defective expression of IRF1 in the IFN-γ-induced signaling molecules may result in the malignant transformation of Ut-SMCs. The modulation of LMP2 may lead to new therapeutic approaches in human Ut-LMS.

Biological characterization of soft tissue sarcomas.

Soft tissue sarcomas are neoplastic malignancies that typically arise in tissues of mesenchymal origin. The identification of novel molecular mechanisms leading to mesenchymal transformation and the establishment of new therapies and diagnostic biomarker has been hampered by several critical factors. First, malignant soft tissue sarcomas are rarely observed in the clinic with fewer than 15,000 newly cases diagnosed each year in the United States. Another complicating factor is that soft tissue sarcomas are extremely heterogeneous as they arise in a multitude of tissues from many different cell lineages. The scarcity of clinical materials coupled with its inherent heterogeneity creates a challenging experimental environment for clinicians and scientists. Faced with these challenges, there has been extremely limited advancement in clinical treatment options available to patients as compared to other malignant tumours. In order to glean insight into the pathobiology of soft tissue sarcomas, scientists are now using mouse models whose genomes have been specifically tailored to carry gene deletions, gene amplifications, and somatic mutations commonly observed in human soft tissue sarcomas. The use of these model organisms has been successful in increasing our knowledge and understanding of how alterations in relevant oncogenic and/or tumour suppressive signal cascades, i.e., interferon-γ (IFN-γ), tumour protein 53 (TP53) and/or retinoblastoma (RB) pathway directly impact sarcomagenesis. It is the goal of many in the physiological community that the use of several mouse models will serve as powerful in vivo tools for further understanding of sarcomagenesis and potentially identify new diagnostic biomarker and therapeutic strategies against human soft tissue sarcomas.

Potential diagnostic biomarkers: differential expression of LMP2/ß1i and cyclin B1 in human uterine leiomyosarcoma.

AIMS AND BACKGROUND: Whilst most uterine smooth muscle neoplasms are benign, uterine leiomyosarcoma (Ut-LMS) is extremely malignant with a high incidence of metastasis and recurrence. Gynecological tumors are often associated with female hormone secretion, but no strong link has been detected between human Ut-LMS and the hormonal environment. In fact, the risk factors for Ut-LMS are poorly understood. In addition, no diagnostic biomarkers for differentiating between leiomyoma, a benign tumor, and malignant Ut-LMS have been found. Interestingly, mice that were homozygously deficient for LMP2/ß1i were found to spontaneously develop Ut-LMS and exhibited a Ut-LMS prevalence of ~40% by 14 months of age. Thus, analyzing potential risk factors for Ut-LMS (such as LMP2/ß1i) might aid the development of diagnostic biomarkers and clinical treatments for the condition. METHODS AND STUDY DESIGN: Fifty-seven patients (age range: 32-83 years) who had been diagnosed with uterine mesenchymal tumors were chosen from a pathological archive. Tissue samples from these patients were fixed in 10% buffered formalin, incubated in 4% paraformaldehyde for 8 hours, and embedded in paraffin. Tissue sections were stained with hematoxylin and eosin for standard histological examination or were subjected to further processing for immunohistochemical (IHC) examination. Serial Ut-LMS, bizarre leiomyoma, leiomyoma, and myometrium sections were subjected to IHC staining of ß-smooth muscle actin, estrogen receptor, cyclin B1, LMP2/ß1i, calponin h1, ki-67, tumor protein p53, and progesterone receptor. RESULTS: The Ut-LMS samples were positive for cyclin B1 and negative for LMP2/ß1i, while the opposite result was obtained for bizarre leiomyoma, leiomyoma, and myometrium samples. CONCLUSIONS: The expression pattern of LMP2/ß1i and cyclin B1 might be a diagnostic biomarker for human Ut-LMS. Studies of the biological roles of LMP2/ß1i and/or cyclin B1 could lead to the elucidation of new targets for therapies against Ut-LMS.

Polypoid endometriosis of the ovary mimicking ovarian carcinoma dissemination: a case report and literature review.

Polypoid endometriosis is a rare type of endometriosis. We report a case of polypoid endometriosis of the ovary mimicking ovarian carcinoma with peritoneal dissemination. Computed tomography and magnetic resonance imaging showed a left ovarian endometriotic cyst containing several nodules in the cystic wall that displayed enhancement, and pelvic nodules on the right ovary. A preoperative or intraoperative diagnosis to avoid the unnecessary extended operation is important for such disease. Retrospective magnetic resonance imaging analysis identified a peculiar finding for polypoid endometriosis: all solid nodules had a round and smooth shape and displayed a low-signal-intense marginal edge on T2-weighted images, suggesting that this is an important finding for differentiating polypoid endometriosis from ovarian carcinoma arising from endometriosis.

Clonality analysis suggests that STK11 gene mutations are involved in progression of lobular endocervical glandular hyperplasia (LEGH) to minimal deviation adenocarcinoma (MDA).

Lobular endocervical glandular hyperplasia (LEGH) is a benign proliferative disease of cervical glands. Although histological resemblance of minimal deviation adenocarcinoma (MDA) to LEGH and frequent association of LEGH with MDA have been reported, it still remains unclear whether LEGH is a precancerous lesion of MDA. The present study was undertaken to examine the pathogenetic relationship between LEGH and MDA using a clonality analysis and mutational analyses of the STK11 gene, of which mutations have been reported in MDA. Of nine cases of LEGH only, four were polyclonal and five were monoclonal in composition. Of six LEGH lesions associated with MDA or adenocarcinoma, two were polyclonal and four were monoclonal. In cases of MDA or adenocarcinoma coexisting with LEGH, the patterns of X chromosome inactivation in malignant lesions were identical to those in coexisting LEGH lesions. A mutation of STK11 was only identified in one MDA, but not in LEGH. These results indicate that a subset of LEGH may be a precursor to malignant tumors including MDA and that a mutation of STK11 may be involved in progression of LEGH to MDA.

Potential role of LMP2 as an anti-oncogenic factor in human uterine leiomyosarcoma: morphological significance of calponin h1.

Uterine leiomyosarcoma (LMS) is a highly metastatic smooth muscle neoplasm for which calponin h1 is suspected to have a biological role as a tumor-suppressor. We earlier reported that LMP2-null mice spontaneously develop uterine LMS through malignant transformation of the myometrium, thus implicating this protein as an anti-tumorigenic candidate as well. In the present study, we show that LMP2 may negatively regulate LMS independently of its role in the proteasome. Moreover, several lines of evidence indicate that although calponin h1 does not directly influence tumorigenesis, it clearly affects LMP2-induced cellular morphological changes. Modulation of LMP2 may lead to new therapeutic approaches in human uterine LMS.

Involvement of pelvic inflammation-related mismatch repair abnormalities and microsatellite instability in the malignant transformation of ovarian endometriosis.

Inflammation in the ovary, including ovulation and pelvic inflammatory disease, has been proposed to play a role in the pathogenesis of ovarian cancer. Endometriotic lesions trigger a local inflammatory reaction and have been reported to be associated with an increased risk of epithelial ovarian cancer. However, the precise molecular mechanisms of ovarian cancer arising from endometriosis are still to be elucidated. To clarify the involvement of mismatch repair (MMR) abnormalities in the inflammation-associated malignant transformation of endometriosis, the immunohistochemical expression of mismatch repair proteins (human mutL homolog 1 [hMLH1] and human mutS homolog 2 [hMSH2]) was examined in 27 cases of ovarian endometriosis, 25 cases of ovarian carcinoma accompanied by endometriosis, and 39 cases of solitary ovarian carcinoma. In addition, the relationship between mismatch repair abnormalities including the microsatellite instability, PTEN (phosphatase and tensin homolog) mutation, and clinicopathologic parameters was analyzed. The expression of mismatch repair proteins was stepwisely decreased in endometriosis, ovarian carcinoma accompanied by endometriosis, and ovarian carcinoma. Tumors harboring multiple microsatellite instability (high-frequency microsatellite instability [MSI-H]) were detected in 4 (14.8%) of 27 cases of endometriosis and 7 (30.4%) of 23 cases of ovarian carcinomas. The frequency of PTEN mutations was higher in MSI-H cases than in microsatellite instability-stable (MSI-S) cases. In 2 cases of ovarian carcinoma accompanied by endometriosis, the decreased expression of mismatch repair proteins and MSI-H was observed in both the endometriosis and carcinoma lesions. Clinicopathologically, the MSI-H cases were associated with elevated serum levels of C-reactive protein and higher white blood cell counts. These findings suggest that mismatch repair abnormalities might be involved in the malignant transformation of ovarian endometriosis and that inflammation induces mismatch repair abnormalities during ovarian carcinogenesis arising from endometriosis.

Prognostic significance of Notch signalling molecules and their involvement in the invasiveness of endometrial carcinoma cells.

AIMS: The aim of this study was to investigate the significance of the expression of Notch-related molecules in endometrial carcinoma. METHODS AND RESULTS: The expression of Notch receptors (Notch1 and 3) and Notch ligands [Jagged (JAG) 1 and Delta-like (DLL) 4] was examined immunohistochemically in 37 normal and 76 malignant endometrial tissue samples. For each section, immunohistochemical staining was scored using a positivity index (PI, full score; 200). The effects of a Notch inhibitor, DAPT, on cell proliferation, invasion and motility were investigated using endometrial carcinoma cell lines. The PIs for Notch1 (mean±SD 90.4±15.3), Notch3 (95.6 ± 20.4), JAG1 (95.5±10.0) and DLL4 (88.2±9.6), were significantly higher in endometrial carcinoma than normal endometrium. The PI for Notch1 was associated significantly with advanced International Federation of Gynecologists & Obstetricians (FIGO) stage. In addition, patients with tumours showing high expression of both Notch1 and JAG1 had a poor prognosis compared with those having double-negative carcinomas (P=0.015). DAPT suppressed invasiveness of cells derived from the endometrial carcinoma cell line KLE. CONCLUSIONS: The Notch1-JAG1 axis may enhance the invasive properties of endometrial carcinomas, which suggests the Notch pathway may be a promising target for the treatment of this malignancy.

Hypoxia upregulates ovarian cancer invasiveness via the binding of HIF-1α to a hypoxia-induced, methylation-free hypoxia response element of S100A4 gene.

Hypoxia is known to play important roles in the development and progression of tumors. We previously demonstrated that S100A4, a critical molecule for metastasis, was upregulated in ovarian cancer cells. Therefore, we examined the mechanisms of the upregulation of S100A4 expression in ovarian carcinoma cells, with particular attention paid to the effects of hypoxia. The expression levels of S100A4 were found to be correlated with the invasiveness of ovarian carcinoma cells in vitro and in vivo, and the upregulation of S100A4 expression was associated with hypomethylation of CpG sites in the first intron of S100A4 in ovarian carcinoma cell lines and tissues. The expression of S100A4 was increased under hypoxia and was associated with elevated invasiveness, which was inhibited by S100A4 small interfering RNA (siRNA). In addition, exposure to hypoxia reduced the methylation of hypoxia-response elements (HRE) of the S100A4 gene in a time-dependent fashion, in association with the increased binding of HIF-1α to a methylation-free HRE in ovarian carcinoma cells. These results indicate that hypoxia-induced hypomethylation plays an essential role in S100A4 overexpression and the epigenetic transformation of ovarian carcinoma cells into the "metastatic phenotype."

Molecular Approach to Uterine Leiomyosarcoma: LMP2-Deficient Mice as an Animal Model of Spontaneous Uterine Leiomyosarcoma.

Uterine leiomyosarcoma (LMS) develops more often in the muscle tissue layer of the uterine body than in the uterine cervix. The development of gynecologic tumors is often correlated with female hormone secretion; however, the development of uterine LMS is not substantially correlated with hormonal conditions, and the risk factors are not yet known. Importantly, a diagnostic-biomarker which distinguishes malignant LMS from benign tumor leiomyoma (LMA) is yet to be established. Accordingly, it is necessary to analyze risk factors associated with uterine LMS, in order to establish a treatment method. LMP2-deficient mice spontaneously develop uterine LMS, with a disease prevalence of ~40% by 14 months of age. We found LMP2 expression to be absent in human LMS, but present in human LMA. Therefore, defective LMP2 expression may be one of the risk factors for LMS. LMP2 is a potential diagnostic-biomarker for uterine LMS, and may be targeted-molecule for a new therapeutic approach.

Involvement of proteasome ß1i subunit, LMP2, on development of uterin leiomyosarcma.

BACKGROUND: Although the majority of smooth muscle neoplasms found in the uterus are benign, uterine leiomyosarcoma is extremely malignant, with high rates of recurrence and metastasis. The development of gynecologic tumors is often correlated with secretion of female hormone; however, the development of human uterine leiomyosarcoma is not substantially correlated with hormonal conditions, and the risk factors are unclearly understood. Importantly, a diagnostic-biomarker, which distinguishes malignant human uterine leiomyosarcoma from benign tumor leiomyoma is yet to be established. AIMS: It is necessary to analyze risk factors associated with human uterine leiomyosarcoma, in order to establish a diagnostic-biomarker and a clinical treatment method. PATIENTS AND METHODS: HISTOLOGY AND IMMUNOFLUORESCENCE STAINING: Uteri obtained from LMP2(-/-) mice or its parental mice (C57BL/6 mice) were fixed in 10% buffered formalin, incubated in 4% paraformaldehyde for 8 hours, and embedded in paraffin. Tissue sections (5 µm) were prepared and stained with H&E for routine histological examination or were processed further for immunofluorescence staining with appropriate antidodies. Furthermore, a total of 101 patients between 32 and 83 years of age and diagnosed as having smooth muscle tumors of the uterus were selected from pathological files. Immunohistochemistry staining for LMP2 was performed on serial human uterine leiomyosarcoma, leiomyoma and myometrium sections. RESULTS: Homozygous deficient mice for a proteasome ß1i subunit, LMP2 spontaneously develop uterine leiomyosarcoma, with a disease prevalence of ~40% by 14 months of age. Defective LMP2 expression in human uterine leiomyosarcoma was demonstrated, but present in human leiomyoma and myometrium. CONCLUSIONS: Loss in LMP2 expression may be one of the risk factors for human uterine leiomyosarcoma. LMP2 may be a potential diagnostic-biomarker and targeted-molecule for a new therapeutic approach.

Potential role of LMP2 as tumor-suppressor defines new targets for uterine leiomyosarcoma therapy.

Although the majority of smooth muscle neoplasms found in the uterus are benign, uterine leiomyosarcoma (LMS) is extremely malignant, with high rates of recurrence and metastasis. We earlier reported that mice with a homozygous deficiency for LMP2, an interferon (IFN)-γ-inducible factor, spontaneously develop uterine LMS. The IFN-γ pathway is important for control of tumor growth and invasion and has been implicated in several cancers. In this study, experiments with human and mouse uterine tissues revealed a defective LMP2 expression in human uterine LMS that was traced to the IFN-γ pathway and the specific effect of JAK-1 somatic mutations on the LMP2 transcriptional activation. Furthermore, analysis of a human uterine LMS cell line clarified the biological significance of LMP2 in malignant myometrium transformation and cell cycle, thus implicating LMP2 as an anti-tumorigenic candidate. This role of LMP2 as a tumor suppressor may lead to new therapeutic targets in human uterine LMS.

Distinguishing primary from secondary mucinous ovarian tumors: an algorithm using the novel marker DPEP1.

Distinguishing primary mucinous ovarian cancers from ovarian metastases of digestive organ cancers is often challenging. Dipeptidase 1 was selected as the candidate novel marker of colorectal cancer based on an analysis of a gene expression microarray. Immunohistochemical analysis indicated that 13/16 ovarian metastases of colorectal cancers, but only 1/58 primary mucinous ovarian cancers, were dipeptidase 1-positive (threshold; ≧25% expression, P<0.0001). Next, five immunohistochemical markers (dipeptidase 1, estrogen receptor-α, cytokeratin 7, cytokeratin 20, and caudal type homeobox 2) were analyzed in combination. In a hierarchical clustering analysis, the mutually exclusive expression of cytokeratin 7 and dipeptidase 1 specifically identified the ovarian metastases of colorectal cancers (P<0.0001). In a decision tree analysis, cytokeratin 7, caudal type homeobox 2, and dipeptidase 1 classified primary mucinous ovarian cancers and ovarian metastases of digestive organ cancers with 90% accuracy. Finally, the five immunohistochemical markers were combined with six preoperative factors (patient's age, tumor size, laterality, serum CEA, CA19-9, and CA125) and combinations were analyzed. Of the 11 factors, 4 (dipeptidase 1, cytokeratin 7, caudal type homeobox 2, and tumor size) were used to generate a decision tree to classify primary mucinous ovarian cancers and metastases of digestive organ cancers with 93% accuracy. In conclusion, we identified a novel immunohistochemical marker, dipeptidase 1, to distinguish primary mucinous ovarian cancers from ovarian metastasis of colorectal cancers. The algorithm using immunohistochemical and clinical factors to distinguish metastases of digestive organ cancers from primary mucinous ovarian cancers will be useful to establish a protocol for the diagnosis of ovarian metastasis.

Oct4 expression in immature teratoma of the ovary: relevance to histologic grade and degree of differentiation.

Immature teratoma of the ovary is an uncommon tumor comprising 1% of ovarian malignancies. The amount of immature neuroepithelium in the teratoma is an important prognostic factor. Although the current grading system based on this criterion is widely accepted, the biological significance of immature neuroepithelium is poorly understood. In this study, we used immunohistochemistry to evaluate the expression of Oct4 (also known as Oct3 or POU5F1), a transcription factor expressed in primordial germ cells and embryonic stem cells, along with that of PAX6, a transcription factor contributing to neurogenesis, and CD56, a known marker for tumors of neural origin, in 18 cases of pure immature teratoma of the ovary. Oct4 was expressed in the immature neuroepithelium of all 7 grade-3 cases and 2 grade-2 cases. It was not expressed in 4 grade-2 cases and all 5 grade-1 cases. These tumor cells lacked CD30 or α-fetoprotein expression, which supported the diagnosis of pure immature teratoma. PAX6 was expressed in the immature neuroepithelium of all immature teratomas, but not in Oct4-positive cells. CD56 was expressed in neural components of various maturities including PAX6-positive immature neuroepithelium, but not in Oct4-positive cells. These data suggest that the expression of these markers probably reflects the differentiation status of neural tissue in immature teratomas. The finding that Oct4 expression was exclusively detected in immature neuroepithelium of high-grade immature teratomas indicates that Oct4 might serve as a promising biomarker for the diagnosis of highly malignant cases of immature teratoma.

Immunohistochemical detection of steroid receptor cofactors in ovarian endometriosis: involvement of down-regulated SRC-1 expression in the limited growth activity of the endometriotic epithelium.

To study the steroid hormone-induced growth mechanisms of endometriosis, the immunohistochemical expression of steroid hormone receptor cofactors was investigated in 37 cases of endometriotic epithelia and was compared with that of eutopic endometria of identical patients. The expression of steroid receptor coactivators (p300/CBP and SRC-1) and corepressors (NCoR and SMRT) was examined in relation to the estrogen receptor (ER), the progesterone receptor (PR), and Ki-67. Results of immunostaining were indicated as a "positivity index" (PI, full score; 100). The expression of ER and PR in endometriotic epithelia largely resembled that in eutopic endometria, however, the expression of Ki-67 in the proliferative phase (PI 13.8 +/- 2.4, mean +/- SD) was significantly lower than that in eutopic endometria (32.6 +/- 10.6). The expression of SRC-1 in eutopic endometria was increased in the proliferative phase (56.5 +/- 16.8) and decreased in the secretory phase (14.8 +/- 6.9). In endometriosis, however, the PI for SRC-1 did not show apparent cyclic changes during the menstrual cycle. Moreover, the expression of SRC-1 in endometriotic epithelia in the proliferative phase was significantly lower than that in eutopic endometria. These findings suggested the reduced proliferative activity in endometriotic epithelia to be related to the reduced expression of SRC-1.

Type-specific roles of histone deacetylase (HDAC) overexpression in ovarian carcinoma: HDAC1 enhances cell proliferation and HDAC3 stimulates cell migration with downregulation of E-cadherin.

Histone acetylation/deacetylation controls chromatin activity and subsequent gene transcription. Recent studies demonstrated the activation of histone deacetylases (HDACs) in various human malignancies; however, the expression and function of HDACs in ovarian tumors are not fully understood. In this study, we examined the immunohistochemical expression of HDAC1, HDAC2 and HDAC3 using tissues obtained from 115 cases of ovarian tumors and compared it with that of Ki-67 (a growth marker), p21, and E-cadherin and clinicopathological parameters. In addition, we analyzed the effect of specific siRNA for HDAC1, HDAC2 and HDAC3 on the expression of cell cycle-related molecules and E-cadherin to clarify the functional difference among the 3 HDACs. The results indicated that the immunohistochemical expression of nuclear HDAC1, HDAC2 and HDAC3 proteins increased stepwise in benign, borderline and malignant tumors. The expression of HDAC1 and HDAC2 was correlated with Ki-67 expression and that of HDAC3 was inversely correlated with E-cadherin expression. Among the HDACs examined, only HDAC1 was associated with a poor outcome, when overexpressed. Treatment with HDAC inhibitors suppressed the proliferation of ovarian cancer cells in association with apoptosis. A specific siRNA for HDAC1 significantly reduced the proliferation of ovarian carcinoma cells via downregulation of cyclin A expression, but siRNA for HDAC3 reduced the cell migration with elevated E-cadherin expression. Our results suggested that HDAC1 plays an important role in the proliferation of ovarian cancer cells, whereas HDAC3 functions in cell adhesion and migration. Therefore, specific therapeutic approaches should be considered according to the HDAC subtypes.

Mice-lacking LMP2, immuno-proteasome subunit, as an animal model of spontaneous uterine leiomyosarcoma.

Uterine tumors are the most common type of gynecologic neoplasm. Uterine leiomyosarcoma (LMS) is rare, accounting for 2% to 5% of tumors of the uterine body. Uterine LMS develops more often in the muscle tissue layer of the uterine body than in the uterine cervix. The development of gynecologic tumors is often correlated with female hormone secretion; however, the development of uterine LMS is not substantially correlated with hormonal conditions, and the risk factors are not yet known. Radiographic evaluation combined with PET/CT can be useless in the diagnosis and surveillance of uterine LMS. Importantly, a diagnostic biomarker, which distinguishes malignant LMS and benign tumor leiomyoma (LMA) is yet to be established. Accordingly, it is necessary to analyze risk factors associated with uterine LMS in order to establish a method of treatment. LMP2-deficient mice spontaneously develop uterine LMS, with a disease prevalence of ∼40% by 14 months of age. It is therefore of interest whether human uterine LMS shows a loss of LMP2 expression. We found LMP2 expression is absent in human LMS, but present in human LMA. Therefore, defective LMP2 expression may be one of the risk factors for LMS. LMP2 is potentially a diagnostic biomarker for uterine LMS, and gene therapy with LMP2-encording DNA may be a new therapeutic approach.