Nuclear Actin Polymerization Regulates Cell Epithelial-Mesenchymal Transition.

Current studies on actin function primarily rely on cytoplasmic actin due to the absence of cellular models specifically expressing nuclear actin. Here, cell models capable of expressing varying levels of nuclear F/G-actin are generated and a significant role of nuclear actin in the regulation of epithelial-mesenchymal transition (EMT) is uncovered. Through immunoprecipitation and mass spectrometry analyses, distinct binding partners for nuclear F-actin (ß-catenin, SMAD2, and SMAD3) and nuclear G-actin (MYBBP1A, NKRF, and MYPOP) are investigated, which respectively modulate EMT-promoting and EMT-repressing transcriptional events. While nuclear F-actin promotes EMT with enhanced cell migration, survival, and elongated mesenchymal morphology, nuclear G-actin represses EMT and related cell activities. Mechanistically, nuclear F-actin enhances ß-catenin, SMAD2, and SMAD3 expression and stability in the nuclei, while nuclear G-actin increases MYBBP1A, NKRF, and MYPOP expression and stability in the nuclei. The association between nuclear F/G-actin and N-cadherin/E-cadherin in the cell lines (in vitro), and increased nuclear actin polymerization in the wound healing cells (in vivo) affirm a significant role of nuclear actin in EMT regulation. With evidence of nuclear actin polymerization and EMT during development, and irregularities in disease states such as cancer and fibrosis, targeting nuclear actin dynamics to trigger dysregulated EMT warrants ongoing study.

Tracking miR-17-5p Levels following Expression of Seven Reported Target mRNAs.

As the most prominent member of the miR-17-92 cluster, miR-17-5p is well associated with tumorigenesis and cancer progression. It can exert both oncogenic and tumor-suppressive functions by inducing translational repression and/or mRNA decay. The complexity of the tissue-specific expression of the targeted transcripts seems to contribute to the differential functions of miR-17-5p in different types of cancers. In this study, we selected 12 reported miR-17-5p targeting genes with mRNA levels unaffected by miR-17-5p expression and analyzed their expression in 31 organ tissues in transgenic mice by real-time PCR. Surprisingly, miR-17-5p expressing transgenic mice showed a positive correlation in these tissues between miR-17-5p expression levels and the selected miR-17-5p targeted transcripts; with high expression of the miRNA in organs with high selected miRNA-targeted mRNA levels. In cancer cell lines, overexpression of 7 reported miR-17-5p targeted genes' 3'-UTRs promoted miR-17-5p expression; meanwhile, transfection of 3'-UTRs with mutations had no significant effect. Moreover, an increase in AGO2 mRNA was associated with 3'-UTR expression as confirmed by real-time PCR. Hence, miR-17-5p regulation by these target genes might be an alternative mechanism to maintain miR-17-5p expression at tissue-specific levels.

A Neuroligin Isoform Translated by circNlgn Contributes to Cardiac Remodeling.

[Figure: see text].

Incidence, clinical features, and outcomes of COVID-19 in Canada: impact of sex and age.

Male sex and older age have been reported to be associated with worse outcomes from COVID-19. It was postulated that estrogens may play a role in reducing the severity of the disease and may therefore offer a treatment option for COVID-19 patients. However, more female cases and deaths from COVID-19 have been recorded in Canada. To determine the potential role of estrogens, we analyzed COVID-19 data from Canada, focusing on the impact of sex and age. Although the overall incidence rate is higher in females than in males, when several high risk groups, including health care workers and long-term care residences, which are predominantly females, were excluded, we found that females had a lower incidence rate than males between the ages of 20s to 70s. Interestingly, this sex-based difference is more evident in females of the reproductive ages (20-49) than in postmenopausal patients (60s or older). Males have significantly higher hospitalization, ICU admission, and case fatality rates; however, a greater difference was observed in the older age groups. Finally, symptom manifestation varied between sexes. Some of the symptoms, which were more frequently observed in patients who recovered than patients who died, were more commonly observed in females of the reproductive age compared to their male counterparts. Since only females of the reproductive age have much higher circulating estrogens than males, these findings suggest that estrogens may play a role in reducing COVID-19 incidence and in the development of symptoms, especially those related to better survival.

The Role of microRNAs in Epithelial Ovarian Cancer Metastasis.

Epithelial ovarian cancer (EOC) is the deadliest gynecological cancer, and the major cause of death is mainly attributed to metastasis. MicroRNAs (miRNAs) are a group of small non-coding RNAs that exert important regulatory functions in many biological processes through their effects on regulating gene expression. In most cases, miRNAs interact with the 3' UTRs of target mRNAs to induce their degradation and suppress their translation. Aberrant expression of miRNAs has been detected in EOC tumors and/or the biological fluids of EOC patients. Such dysregulation occurs as the result of alterations in DNA copy numbers, epigenetic regulation, and miRNA biogenesis. Many studies have demonstrated that miRNAs can promote or suppress events related to EOC metastasis, such as cell migration, invasion, epithelial-to-mesenchymal transition, and interaction with the tumor microenvironment. In this review, we provide a brief overview of miRNA biogenesis and highlight some key events and regulations related to EOC metastasis. We summarize current knowledge on how miRNAs are dysregulated, focusing on those that have been reported to regulate metastasis. Furthermore, we discuss the role of miRNAs in promoting and inhibiting EOC metastasis. Finally, we point out some limitations of current findings and suggest future research directions in the field.

Translation of yes-associated protein (YAP) was antagonized by its circular RNA via suppressing the assembly of the translation initiation machinery.

Yap is the key component of Hippo pathway which plays crucial roles in tumorigenesis. Inhibition of Yap activity could promote apoptosis, suppress proliferation, and restrain metastasis of cancer cells. However, how Yap is regulated is not fully understood. Here, we reported Yap being negatively regulated by its circular RNA (circYap) through the suppression of the assembly of Yap translation initiation machinery. Overexpression of circYap in cancer cells significantly decreased Yap protein but did not affect its mRNA levels. As a consequence, it remarkably suppressed proliferation, migration and colony formation of the cells. We found that circYap could bind with Yap mRNA and the translation initiation associated proteins, eIF4G and PABP. The complex containing overexpressed circYap abolished the interaction of PABP on the poly(A) tail with eIF4G on the 5'-cap of the Yap mRNA, which functionally led to the suppression of Yap translation initiation. Individually blocking the binding sites of circYap on Yap mRNA or respectively mutating the binding sites for PABP and eIF4G derepressed Yap translation. Significantly, breast cancer tissue from patients in the study manifested dysregulation of circYap expression. Collectively, our study uncovered a novel molecular mechanism in the regulation of Yap and implicated a new function of circular RNA, supporting the pursuit of circYap as a potential tool for future cancer intervention.