The ubiquitin-proteasome pathway plays an important role in the regulation of cellular proteins. As an alternative to the proteasome itself, recent research has focused on methods to modulate the regulation of deubiquitinating enzymes (DUBs) upstream of the proteasome, identifying DUBs as novel therapeutic targets in breast, endometrial, and prostate cancers, along with multiple myeloma. bAP15, an inhibitor of the 19S proteasome DUBs UCHL5 and USP14, results in cell growth inhibition in several human cancers; however, the mechanism remains poorly understood in ovarian cancer. Here, we found that aberrant UCHL5 expression predicted shorter progression-free survival (PFS) in a cohort of 1435 patients with ovarian cancer described in the Gene Expression Omnibus and The Cancer Genome Atlas databases. The subgroup of patients with TP53 mutations was significantly more likely to exhibit poor PFS (p <0.001). Moreover, we found bAP15 could suppress TP53-mutant ovarian cancer cell survival by regulating TGF-β signaling through inhibiting UCHL5 expression and dephosphorylating Smad2, consequently inducing apoptosis. bAP15 (2.5 and 5.0 mg/kg) also exerted significant anti-tumor effect on nude mice bearing subcutaneous SKOV3 xenografts. As activated TGF-β signaling is involved in ovarian cancer progression, these findings suggest that UCHL5 inhibition offers potential opportunities for a novel targeted therapy against TGF-β-activated ovarian cancer.
Background: Recent Drosophila studies showed that Discs-large (Dlg) is critical for regulation of cell polarity and tissue architecture. We investigated the possibility that loss of the human homologue of Drosophila Dlg (DLG1) is involved in endometrial carcinogenesis.
Background: Loss of cellular polarity is a hallmark of cancer. E-cadherin, which localizes at the adherens junction, is a major cellular polarity determinant to control of tissue architecture. Loss of E-cadherin expression has been reported in many human cancers. Here, we investigated whether loss of E-cadherin expression is involved in endometrial cancer development. Methods and findings:We investigated the localization and expression of E-cadherin in 152 cases of endometrial cancer using immunohistochemical staining technique. E-cadherin localizes at the cellular membrane in the normal endometrial tissue. Loss of E-cadherin expression was observed significantly in endometrial cancer with high-grade histology. Our analysis revealed that patients with loss of E-cadherin show poorer overall and progression free survival. It was frequently observed in cases with advanced clinical stage, deep myometrial invasion, and p53 mutation, but the difference did not reached to the statistical significance. Loss of E-cadherin showed no obvious relationship with age at onset, lymph-nodal metastasis, vessel involvement, and estrogen and progesterone receptor expression. Conclusion:Our analysis revealed that disruption of tissue polarity due to loss of adherens junction protein E-cadherin provide more aggressive characters including high-grade histology and poor prognosis to endometrial cancer cells
Pegylated liposomal doxorubicin (PLD) has a good safety profile, but long-term use has been associated with development of squamous cell carcinoma of the tongue and oral cavity (SCCTO) in some patients. The study objective was to estimate the prevalence of oral leukoplakia, a known precursor of SCCTO, in patients with ovarian cancer and long-term PLD use.After approval of the institutional review board, medical record of 114 patients who were treated with PLD at our institution between January 2010 and December 2016 were retrospectively reviewed. All those patients have been referred for routine monitoring of oral mucositis every time before administration by a dentist. The patient characteristics included in the evaluation were age, smoking and drinking habits, the PLD dose and schedule, and presence or absence of oral leukoplakia and SCCTO at each oral examination. The relationships of the incidence of oral leukoplakia and patient characteristics were analyzed.The median total PLD dose was 160 (range 40–1550) mg/m2. Oral leukoplakia was seen in 6 (5.3%) patients. The median PLD dose, at the time of oral leukoplakia diagnosis, was 685 (range 400–800) mg/m2. SCCTO was not found. Univariate analysis revealed that age, Brinkman index, and habitual drinking were not considered as risk factors for oral leukoplakia, and only total PLD dose (OR, 1.470; 95% CI, 1.19–1.91; P < .001) remained as a significant independent risk factor for oral leukoplakia. The ROC curve analysis indicated that the optimal cutoff value of the total PLD dose to predict development of oral leukoplakia was 400 mg/m2. The sensitivity was 100% and the specificity was 88.8%. No patient discontinued PLD because of oral leukoplakia or SCCTO.The 2 most important clinical observations were the occurrence of oral leukoplakia in patients with long-term PLD use and that the development of oral leukoplakia was related to a total cumulative dose ≥400 mg/m2. Routine oral surveillance is recommended, particularly when the cumulative total dose exceeds 400 mg/m2.
Minimal deviation adenocarcinoma (MDA) is defined as an extremely well differentiated variant of endocervical adenocarcinoma. Several reports have stated that MDA associates with lobular endocervical glandular hyperplasia (LEGH). It is difficult to distinguish LEGH from MDA based on clinical and histologic similarities. There is no definite evidence proving that LEGH is a precursor lesion of MDA. A 45-year-old woman was admitted to our hospital for minute investigation of her neurological disorder. The multiple-cystic lesion at the uterine cervix was identified by magnetic resonance imaging. Based on her normal histological findings and severe underlying conditions, a careful follow-up strategy was adapted. Two years later, atypical glandular cells were observed and the multiple-cystic lesion had increased. Pathological diagnosis of a conization specimen was MDA. Radical hysterectomy was carried out. Pathological examination revealed coexistence of LEGH and MDA. Her clinical course and histological findings suggested the possibility that LEGH might be a precursor lesion of MDA.
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