Exosomopathies are a collection of rare diseases caused by mutations in genes that encode structural subunits of a ribonuclease complex termed the RNA exosome. The RNA exosome mediates both RNA processing and degradation of multiple classes of RNA. This complex is evolutionarily conserved and required for fundamental cellular functions, including rRNA processing. Recently, missense mutations in genes encoding structural subunits of the RNA exosome complex have been linked to a variety of distinct neurological diseases, many of them childhood neuronopathies with at least some cerebellar atrophy. Understanding how these missense mutations lead to the disparate clinical presentations that have been reported for this class of diseases necessitates investigation of how these specific changes alter cell-specific RNA exosome function. Although the RNA exosome complex is routinely referred to as ubiquitously expressed, little is known about the tissue- or cell-specific expression of the RNA exosome complex or any individual subunit. Here, we leverage publicly available RNA-sequencing data to analyze RNA exosome subunit transcript levels in healthy human tissues, focusing on those tissues that are impacted in exosomopathy patients described in clinical reports. This analysis provides evidence to support the characterization of the RNA exosome as ubiquitously expressed with transcript levels for the individual subunits that vary in different tissues. However, the cerebellar hemisphere and cerebellum have high levels of nearly all RNA exosome subunit transcripts. These findings could suggest that the cerebellum has a high requirement for RNA exosome function and potentially explain why cerebellar pathology is common in RNA exosomopathies.
Lung cancer, especially non-small cell lung cancer (NSCLC) is the most frequent cause of cancer-related mortality worldwide. MicroRNAs (miRNAs) represent a class of small non-coding RNA molecules. In recent years, many studies have confirmed that abnormal miRNAs expression in tumor can participate in many biological processes of NSCLC. However, whether miR-1294 is involved in the development of NSCLC remains unclear. In this study, miR-1294 was inhibited in NSCLC cell lines, and its expression was associated with tumor size and progression. MiR-1294 overexpression inhibited cell proliferation and cell cycle, conversely promoted cell apoptosis and senescence, and miR-1294 binding to MYH9 3’-UTR mediated suppression of it. Besides, three bioinformatics software were searched, and KLF4 was predicted as an upstream regulator of miR-1294. This study is the first to illuminate that miR-1294, mediated by KLF4, by targeting MYH9 to regulate NSCLC cell proliferation and apoptosis, and is a potential biomarker and therapeutic target for NSCLC.
Exosomopathies are a collection of rare diseases caused by mutations in genes that encode structural subunits of the RNA exosome complex (EXOSC). The RNA exosome is critical for both processing and degrading many RNA targets. Mutations in individual RNA exosome subunit genes (termed EXOSC genes) are linked to a variety of distinct diseases. These exosomopathies do not arise from homozygous loss-of-function or large deletions in the EXOSC genes likely because some level of RNA exosome activity is essential for viability. Thus, all patients described so far have at least one allele with a missense mutation encoding an RNA exosome subunit with a single pathogenic amino acid change linked to disease. Understanding how these changes lead to the disparate clinical presentations that have been reported for this class of diseases necessitates investigation of how individual pathogenic missense variants alter RNA exosome function. Such studies will require access to patient samples, a challenge for these very rare diseases, coupled with modeling the patient variants. Here, we highlight five recent studies that model pathogenic variants in EXOSC3, EXOSC2, and EXOSC5.
Increasing number of reports have shown the involvement of LncRNAs in the tumour progression in multiple cancers including colorectal and female reproductive cancers such as ovarian and breast. In particular, the profiling of lncRNAs in colorectal cancer (CRC), which is within the top three cancers in both female and male, have identified 556 upregulated and 1040 downregulated lncRNAs as compared to normal tissue. In this highlight, we looked at the mechanism in which some of these lncRNAs can act in CRC development and progression through promoting survival, proliferation and invasion and metastasis. Furthermore, we also look into the possibility of a cytoskeletal protein, gelsolin and its possible interaction with lncRNAs.
Patients with CRC (colorectal cancer) usually have a poor prognosis and the cure rate of CRC remained unsatisfied due to unfavorable curative effect. It is well known that microRNAs (miRNAs) and energy metabolism have pivotal roles in CRC progression. In a recent article in Cell Death & Disease by Xiaofeng Guo. et al. 2017, we have reported an oncogenic role of miR-181d in CRC by promoting glycolysis, and its underlying molecular mechanism about a new feedback loop among miR-181d/CRY2/FBXL3/c-myc signaling axis. Among these, we have identified the level of miR-181d was upregulated in CRC and the inhibition of miR-181d decreased glycolysis in CRC cells. We also found that c-myc played a central role in regulating cell glycolysis, which is required for the metabolic shift induced by miR-181d. Besides, we have demonstrated FBXL3 and CRY2 were direct targets of miR-181d and c-myc promoted miR-181d upregulation while inhibiting the expression of CRY2 and FBXL3 in CRC cells. The data from our recent article strongly suggest a new light onto the oncogenic function of the miR-181d in CRC. Furthermore, these findings represent a novel potential approach for silencing miR-181d/c-myc signaling pathway in CRC treatment.
