HNRNPA1 (heterogeneous nuclear ribonucleoprotein A1)

Heterogeneous nuclear ribonucleoprotein (HNRNPA1) gene maps to chromosome 12, plus strand and has 13 exons and 12 introns. There are three reported transcripts due to the alternative splicing. HNRNPA1 is one of the most abundant and ubiquitously expressed nuclear proteins. HNRNPA1 is a member of RNA-binding protein family comprising of 20 members in humans (Dreyfuss, 1993; Pinol-Roma, Choi, Matunis, & Dreyfuss, 1988). HNRNPA1 has diverse roles in RNA splicing, telomere length maintenance, miRNA maturation and mRNA transport from nucleus to cytoplasm

ALCAM (Activated Leukocyte Cell Adhesion Molecule)

ALCAM (Activated Leukocyte Cell Adhesion Molecule), also known as CD166 (cluster of differentiation 166), is a member of a subfamily of immunoglobulin receptors with five immunoglobulin-like domains (VVC2C2C2) in the extracellular domain

Could MicroRNAs be Useful Tools to Improve the Diagnosis and Treatment of Rare Gynecological Cancers? A Brief Overview

Gynecological cancers pose an important public health issue, with a high incidence among women of all ages. Gynecological cancers such as malignant germ-cell tumors, sex-cord-stromal tumors, uterine sarcomas and carcinosarcomas, gestational trophoblastic neoplasia, vulvar carcinoma and melanoma of the female genital tract, are defined as rare with an annual incidence of <6 per 100,000 women. Rare gynecological cancers (RGCs) are associated with poor prognosis, and given the low incidence of each entity, there is the risk of delayed diagnosis due to clinical inexperience and limited therapeutic options. There has been a growing interest in the field of microRNAs (miRNAs), a class of small non-coding RNAs of 22 nucleotides in length, because of their potential to regulate diverse biological processes. miRNAs usually induce mRNA degradation and translational repression by interacting with the 30 untranslated region (30-UTR) of target mRNAs, as well as other regions and gene promoters, as well as activating translation or regulating transcription under certain conditions. Recent research has revealed the enormous promise of miRNAs for improving the diagnosis, therapy and prognosis of all major gynecological cancers. However, to date, only a few studies have been performed on RGCs. In this review, we summarize the data currently available regarding RGCs.peer-reviewe

GYNOCARE Update: Modern Strategies to Improve Diagnosis and Treatment of Rare Gynecologic Tumors—Current Challenges and Future Directions

More than 50% of all gynecologic tumors can be classified as rare (defined as an incidence of ≤6 per 100, 000 women) and usually have a poor prognosis owing to delayed diagnosis and treatment. In contrast to almost all other common solid tumors, the treatment of rare gynecologic tumors (RGT) is often based on retrospective studies, expert opinion, or extrapolation from other tumor sites with similar histology, leading to difficulty in developing guidelines for clinical practice. Currently, gynecologic cancer research, due to distinct scientific and technological challenges, is lagging behind. Moreover, the overall efforts for addressing these challenges are fragmented across different European countries and indeed, worldwide. The GYNOCARE, COST Action CA18117 (European Network for Gynecological Rare Cancer Research) programme aims to address these challenges by creating a unique network between key stakeholders covering distinct domains from concept to cure: basic research on RGT, biobanking, bridging with industry, and setting up the legal and regulatory requirements for international innovative clinical trials. On this basis, members of this COST Action, (Working Group 1, “Basic and Translational Research on Rare Gynecological Cancer”) have decided to focus their future efforts on the development of new approaches to improve the diagnosis and treatment of RGT. Here, we provide a brief overview of the current state of-the-art and describe the goals of this COST Action and its future challenges with the aim to stimulate discussion and promote synergy across scientists engaged in the fight against this rare cancer worldwide

The early G2 /M checkpoint and ubiquitination: Implications for breast tumorigenesis.

The ubiquitin/proteasome pathway is highly conserved in evolution and is essential for many diverse cellular functions. Many of the short-lived cell cycle regulatory proteins are targets of this proteasome pathway. Unregulated cell cycle proteins are important contributors to tumorigenesis. Efforts to identify and develop drugs that target the ubiquitin/proteasome pathway to treat malignancies have become an intense area of investigation. However, targeted drug design requires a better understanding of the many genes involved in the ubiquitin/proteasome pathway. The first aim of my thesis was to examine a ubiquitin ligase, CHFR (checkpoint with f&barbelow;orkhead-associated and r&barbelow;ing finger) that also functions as part of the early G2/M checkpoint, in breast cancer. This checkpoint delays chromosome condensation in response to microtubule poisons. We found that half of the 24 breast cancer cell lines studied had low CHFR expression. Following nocodazole treatment, breast cancer cells with low CHFR expression failed to arrest in prophase, whereas cells with higher CHFR expression arrested in prophase as expected. Further analysis revealed that some of the nocodazole treated cells may have progressed through mitosis due to lack of any functional mitotic checkpoints (i.e., early G2/M and spindle checkpoints). The second aim of my thesis was to identify novel oncogene candidates on the long arm of chromosome 17 through analysis of regions of amplifications. We detected two distinct amplicons on 17q23 that harbor putative oncogenes and several uncharacterized ESTs specifically expressed in breast tissue. Ubiquitin specific protease 6 (USP6), a gene that mapped more proximal to the 17q23 amplicons, was also significantly overexpressed in breast cancer cell lines. We demonstrated that overexpression of USP6 in NIH3T3 and 293 cells induced an increased growth rate but such overexpression alone could not induce neoplastic transformation in these cells. Overexpression of USP6 and other candidate oncogenes within identified amplicons may be functioning cooperatively during breast carcinogenesis. Additional studies to reveal the expression and function of genes in the ubiquitin/proteasome pathway will help us elucidate the complex interactions of cell-cycle regulation. A better understanding of how this pathway operates should then lead to the development of efficient therapeutical applications.Ph.D.Biological SciencesGeneticsHealth and Environmental SciencesOncologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/124053/2/3121924.pd

A parylene-based dual channel micro-electrophoresis system for rapid mutation detection via heteroduplex analysis

A new dual channel micro-electrophoresis system for rapid mutation detection based on heteroduplex analysis was designed and implemented. Mutation detection was successfully achieved in a total separation length of 250 μm in less than 3 min for a 590 bp DNA sample harboring a 3 bp mutation causing an amino acid change. Parylene-C was used as the structural material for fabricating the micro-channels as it provides conformal deposition, transparency, biocompatibility, and low background fluorescence without any surface treatment. A new dual channel architecture was derived from the traditional cross-channel layout by forming two identical channels with independent sample loading and waste reservoirs. The control of injected sample volume was accomplished by a new u-turn injection technique with pull-back method. The use of heteroduplex analysis as a mutation detection method on a cross-linked polyacrylamide medium provided accurate mutation detection in an extremely short length and time. The presence of two channels on the microchip offers the opportunity of comparing the sample to be tested with a desired control sample rapidly, which is very critical for the accuracy and reliability of the mutation analyses, especially for clinical and research purposes

Generating salt-tolerant Nicotiana tabacum and identification of stress-responsive miRNAs in transgenics

Identification of vacuolar Na+/H+ antiporters facilitates the basis of salt stress tolerance mechanisms. Na+ accumulation into the vacuole is crucial for the avoidance of cytoplasmic Na+ toxicity. In this study, we show that the introduction of AtNHX1 into tobacco generated more tolerant plants when compared to wild-type plants. Transgenic tobacco plants exhibited higher germination rates in the presence of increasing salt concentrations compared to wild-type plants. In addition, proline levels were higher under salt stress conditions in both the shoots and the roots of transgenics compared to wild-type plants. Increase in malondialdehyde production during lipid peroxidation by salinity was lower in transgenic plants compared to the controls. Being important and newly discovered determiners of plant stress responses, microRNAs (miRNAs) are noncoding small RNAs and essential indicators of plant stress response mechanisms. For further identification of stress responses, the expression levels of growth and abiotic stress-related miRNAs (miR319a, miR319b, miR159b, miR398a, and miR398b) were quantified. miR319a, miR319b, and miR159b expression levels were higher in wildtype plants, and miR319a and miR159b expression was restored in transgenic plants. There was a slight decrease in the expression levels of miR398a and miR398b of wild-type plants. However, the recovery of the miR398a and miR398b expressions was especially significant in transgenic plants. Furthermore, an investigation of miRNAs in transgenic plants can help to understand the stress tolerance mechanisms of the plants

Differential translation of mRNA isoforms underlies oncogenic activation of cell cycle kinase Aurora A.

Peer reviewed: TrueFunder: David James TrustAurora Kinase A (AURKA) is an oncogenic kinase with major roles in mitosis, but also exerts cell cycle- and kinase-independent functions linked to cancer. Therefore, control of its expression, as well as its activity, is crucial. A short and a long 3′UTR isoform exist for AURKA mRNA, resulting from alternative polyadenylation (APA). We initially observed that in triple-negative breast cancer, where AURKA is typically overexpressed, the short isoform is predominant and this correlates with faster relapse times of patients. The short isoform is characterized by higher translational efficiency since translation and decay rate of the long isoform are targeted by hsa-let-7a tumor-suppressor miRNA. Additionally, hsa-let-7a regulates the cell cycle periodicity of translation of the long isoform, whereas the short isoform is translated highly and constantly throughout interphase. Finally, disrupted production of the long isoform led to an increase in proliferation and migration rates of cells. In summary, we uncovered a new mechanism dependent on the cooperation between APA and miRNA targeting likely to be a route of oncogenic activation of human AURKA

Differential translation of mRNA isoforms underlies oncogenic activation of cell cycle kinase Aurora A

Aurora Kinase A (AURKA) is an oncogenic kinase with major roles in mitosis, but also exerts cell cycle- and kinase-independent functions linked to cancer. Therefore, control of its expression, as well as its activity, is crucial. A short and a long 3′UTR isoform exist for AURKA mRNA, resulting from alternative polyadenylation (APA). We initially observed that in triple-negative breast cancer, where AURKA is typically overexpressed, the short isoform is predominant and this correlates with faster relapse times of patients. The short isoform is characterized by higher translational efficiency since translation and decay rate of the long isoform are targeted by hsa-let-7a tumor-suppressor miRNA. Additionally, hsa-let-7a regulates the cell cycle periodicity of translation of the long isoform, whereas the short isoform is translated highly and constantly throughout interphase. Finally, disrupted production of the long isoform led to an increase in proliferation and migration rates of cells. In summary, we uncovered a new mechanism dependent on the cooperation between APA and miRNA targeting likely to be a route of oncogenic activation of human AURKA.</jats:p

ARID3B expression in primary breast cancers and breast cancer-derived cell lines

ARID3B (AT-rich interaction domain 3) is a member of the family of ARID proteins, which constitutes evolutionarily conserved transcription factors implicated in normal development, differentiation, cell cycle regulation and chromatin remodeling. In addition, ARID3B has been linked to cellular immortalization, epithelial-mesenchymal transition (EMT) and tumorigenesis. Given the emerging role of ARID3B in tumor development, we examined its expression in primary patient-derived breast cancer samples and breast cancer-derived cell lines