Advanced ovarian cancer usually spreads to the visceral adipose tissue of the omentum. However, the omental stromal cell-derived molecular determinants that modulate ovarian cancer growth have not been characterized. Here, using next-generation sequencing technology, we identify significantly higher levels of microRNA-21 (miR21) isomiRNAs in exosomes and tissue lysates isolated from cancer-associated adipocytes (CAAs) and fibroblasts (CAFs) than in those from ovarian cancer cells. Functional studies reveal that miR21 is transferred from CAAs or CAFs to the cancer cells, where it suppresses ovarian cancer apoptosis and confers chemoresistance by binding to its direct novel target, APAF1. These data suggest that the malignant phenotype of metastatic ovarian cancer cells can be altered by miR21 delivered by exosomes derived from neighbouring stromal cells in the omental tumour microenvironment, and that inhibiting the transfer of stromal-derived miR21 is an alternative modality in the treatment of metastatic and recurrent ovarian cancer.

BACKGROUND: DBC1/KIAA1967 (deleted in breast cancer 1) is a putative tumour-suppressor gene cloned from a heterozygously deleted region in breast cancer specimens. Caspase-dependent processing of DBC1 promotes apoptosis, and depletion of endogenous DBC1 negatively regulates p53-dependent apoptosis through its specific inhibition of SIRT1. Hereditary breast and ovarian cancer susceptibility gene product BRCA1, by binding to the promoter region of SIRT1, is a positive regulator of SIRT1 expression. METHODS: A physical interaction between DBC1 and BRCA1 was investigated both in vivo and in vitro. To determine the pathophysiological significance of DBC1, its role as a transcriptional factor was studied. RESULTS: We found a physical interaction between the amino terminus of DBC1 and the carboxyl terminus of BRCA1, also known as the BRCT domain. Endogenous DBC1 and BRCA1 form a complex in the nucleus of intact cells, which is exported to the cytoplasm during ultraviolet-induced apoptosis. We also showed that the expression of DBC1 represses the transcriptional activation function of BRCT by a transient expression assay. The expression of DBC1 also inhibits the transactivation of the SIRT1 promoter mediated by full-length BRCA1. CONCLUSION: These results revealed that DBC1 may modulate the cellular functions of BRCA1 and have important implications in the understanding of carcinogenesis in breast tissue.

Background:The TFII-I is a multifunctional transcriptional factor known to bind specifically to several DNA sequence elements and to mediate growth factor signalling. A microdeletion at the chromosomal location 7q11.23 encoding TFII-I and the related family of transcription factors may result in the onset of Williams–Beuren syndrome, an autosomal dominant genetic disorder characterised by a unique cognitive profile, diabetes, hypertension, anxiety, and craniofacial defects. Hereditary breast and ovarian cancer susceptibility gene product BRCA1 has been shown to serve as a positive regulator of SIRT1 expression by binding to the promoter region of SIRT1, but cross talk between BRCA1 and TFII-I has not been investigated to date.Methods:A physical interaction between TFII-I and BRCA1 was explored. To determine pathophysiological function of TFII-I, its role as a transcriptional cofactor for BRCA1 was investigated.Results:We found a physical interaction between the carboxyl terminus of TFII-I and the carboxyl terminus of BRCA1, also known as the BRCT domain. Endogenous TFII-I and BRCA1 form a complex in nuclei of intact cells and formation of irradiation-induced nuclear foci was observed. We also showed that the expression of TFII-I stimulates the transcriptional activation function of BRCT by a transient expression assay. The expression of TFII-I also enhanced the transcriptional activation of the SIRT1 promoter mediated by full-length BRCA1.Conclusion:These results revealed the intrinsic mechanism that TFII-I may modulate the cellular functions of BRCA1, and provide important implications to understand the development of breast cancer.

Mutation of neoplastic tumor suppressor genes, scribble, discs large, and lethal giant larvae (lgl), causes disruption of cell polarity and overproliferation of Drosophila epithelial cells and neuroblasts. Reduced expression of human homologue of lgl, Hugl-1, has been reported to be involved in development and progression of human colon cancer and malignant melanoma. To explore the association between Hugl-1 expression and clinical character in endometrial cancer, we examined the expression of Hugl-1 in primary endometrial cancer tissues. The expression of Hugl-1 mRNA in 86 primary endometrial cancer tissues was examined using semiquantitative reverse transcription polymerase chain reaction (RT-PCR). All samples were categorized into two groups: Hugl-1 positive and Hugl-1 negative. Clinical data of each group were analyzed by Fisher's exact probability test and survival rates of each group were compared by Kaplan-Meier method and Log-rank test. Loss of Hugl-1 expression had correlation with the higher incidence of lymph node metastasis, but not to the patient's age at onset, distant metastasis, clinical stage, lymph or venous vessel invasion, or histopathological grade of differentiation. The Hugl-1-positive group had poorer prognosis compared with the Hugl-1-negative group. These results indicate that loss of Hugl-1 expression in endometrial cancer may contribute to lymph node metastasis and it can be a factor of poor prognosis.

Cervical intraepithelial neoplasia (CIN) has a natural history of bidirectional transition between different states. Therefore, conventional statistical models assuming a unidirectional disease progression may oversimplify CIN fate. We applied a continuous-time multistate Markov model to predict this CIN fate by addressing the probability of transitions between multiple states according to the genotypes of high-risk human papillomavirus (HPV). This retrospective cohort comprised 6022 observations in 737 patients (195 normal, 259 CIN1, and 283 CIN2 patients at the time of entry in the cohort). Patients were followed up or treated at the University of Tokyo Hospital between 2008 and 2015. Our model captured the prevalence trend satisfactory, particularly for up to two years. The estimated probabilities for 2-year transition to CIN3 or more were the highest in HPV 16-positive patients (13%, 30%, and 42% from normal, CIN1, and CIN2, respectively) compared with those in the other genotype-positive patients (3.1–9.6%, 7.6–16%, and 21–32% from normal, CIN1, and CIN2, respectively). Approximately 40% of HPV 52- or 58-related CINs remained at CIN1 and CIN2. The Markov model highlights the differences in transition and progression patterns between high-risk HPV-related CINs. HPV genotype-based management may be desirable for patients with cervical lesions.

Drosophila tumor suppressor Scribble has been identified as an apical-basolateral polarity determinant in epithelia. A human homolog of Drosophila Scribble, human Scribble (hScrib), has been identified as a protein targeted by human papillomavirus E6 for the ubiquitin-mediated degradation dependent on E6AP, a cellular ubiquitin-protein ligase. Human Scribble is classified as a LAP protein, having leucine-rich repeats (LRRs) and PDZ domains. We investigated whether hScrib, which is thought to have a role in polarity determination based on the data of its Drosophila homolog, is involved in cell-cycle regulation and proliferation control of epithelia. Transfection of hScrib inhibits cell-cycle progression from G1 to S phase, and it up-and down-regulates expression of adenomatous polyposis coli and cyclins A and D1, respectively. Knockdown of hScrib expression by siRNA leads to cell-cycle progression from G1 to S phase. We explored functional domain mapping to reveal which domains of hScrib are critical for its cellular proliferation control and localization at the basolateral membrane. We found that LRRs and PDZ domain 1 are indispensable for hScrib to inhibit cell growth by blocking cell-cycle progression and to keep its proper localization. These data indicate that basolateral membrane localization of hScrib is closely related to its proliferation control. Our findings suggest the possibility that hScrib is involved in signal transduction to negatively regulate cell proliferation by localizing at the basolateral membrane of epithelial cells through LRRs and PDZ domains. Loss of cell polarity due to aberrant expression and localization of junctional proteins causes overgrowth of epithelia.(2) Mutation of a tumor suppressor gene whose encoded protein regulates cell-cycle progression is also characteristic of cancer tissues. Maintenance of tissue polarity and regulation of cell cycle are tightly linked to keep normal growth control and differentiation in epithelia.(3) Loss of tissue architecture and disruption of the cell-cycle control system leads to uncontrolled proliferation of epithelial cells and subsequent tumor formation. Drosophila tumor suppressor Scribble has recently been identified as an apical-basal polarity determinant in epithelia.(5) Drosophila Scribble localizes at the septate junction, which is functionally identical to the vertebrate tight junction, and loss of scribble mutation causes mislocalization of adherens junction to the basolateral membrane.(5) Follicle cells homozygous for scribble mutation are rounded, rather than columnar, and are often multilayered, rather than sheet-like. (6) In Drosophila scribble mutant, disorganized epithelial tissue overproliferates and causes massive tumors in imaginal discs, brain, and follicles. (6) Recently, scribble has been identified as a novel regulator of S-phase entry in Drosophila by a genetic screen for dominant hypomorphic cyclin E mutation. The human homolog of Drosophila tumor suppressor Scribble, hScrib, has recently been identified as a target of...

Endometrial cancer is a ubiquitous gynecological disease with increasing global incidence. Therefore, despite the lack of an established screening technique to date, early diagnosis of endometrial cancer assumes critical importance. This paper presents an artificial-intelligence-based system to detect the regions affected by endometrial cancer automatically from hysteroscopic images. In this study, 177 patients (60 with normal endometrium, 21 with uterine myoma, 60 with endometrial polyp, 15 with atypical endometrial hyperplasia, and 21 with endometrial cancer) with a history of hysteroscopy were recruited. Machine-learning techniques based on three popular deep neural network models were employed, and a continuity-analysis method was developed to enhance the accuracy of cancer diagnosis. Finally, we investigated if the accuracy could be improved by combining all the trained models. The results reveal that the diagnosis accuracy was approximately 80% (78.91–80.93%) when using the standard method, and it increased to 89% (83.94–89.13%) and exceeded 90% (i.e., 90.29%) when employing the proposed continuity analysis and combining the three neural networks, respectively. The corresponding sensitivity and specificity equaled 91.66% and 89.36%, respectively. These findings demonstrate the proposed method to be sufficient to facilitate timely diagnosis of endometrial cancer in the near future.

Endometrial cancer is one of the most frequently diagnosed gynecological malignancies worldwide. However, its prognosis in advanced stages is poor, and there are only few available treatment options when it recurs. Epigenetic changes in gene function, such as DNA methylation, histone modification, and non-coding RNA, have been studied for the last two decades. Epigenetic dysregulation is often reported in the development and progression of various cancers. Recently, epigenetic changes in endometrial cancer have also been discussed. In this review, we give the main points of the role of DNA methylation and histone modification in endometrial cancer, the diagnostic tools to determine these modifications, and inhibitors targeting epigenetic regulators that are currently in preclinical studies and clinical trials.