Short-Form Thymic Stromal Lymphopoietin (sfTSLP) Is the Predominant Isoform Expressed by Gynaecologic Cancers and Promotes Tumour Growth.

Thymic stromal lymphopoietin (TSLP) is an epithelial cell derived cytokine belonging to the IL-7 family and a key initiator of allergic inflammation. Two main isoforms of TSLP, classified as long- (lfTSLP) and short-form (sfTSLP), have been reported in human, but their expression patterns and role(s) in cancers are not yet clear. mRNA expression was examined by isoform-specific RT-PCR and RNA in situ hybridisation. Epigenetic regulation was investigated by chromatin immunoprecipitation-PCR and bisulfite sequencing. Tumour progression was investigated by gene overexpression, cell viability assay, cancer organoid culture and transwell invasion. Signals were investigated by proteome profiler protein array and RNA-sequencing. With the use of isoform-specific primers and probes, we uncovered that only sfTSLP was expressed in the cell lines and tumour tissues of human ovarian and endometrial cancers. We also showed the epigenetic regulation of sfTSLP: sfTSLP transcription was regulated by histone acetylation at promoters in ovarian cancer cells, whereas silencing of the sfTSLP transcripts was regulated by promoter DNA methylation in endometrial cancer cells. In vitro study showed that ectopically overexpressing sfTSLP promoted tumour growth but not invasion. Human phosphokinase array application demonstrated that the sfTSLP overexpression activated phosphorylation of multiple intracellular kinases (including GSK3α/ß, AMPKα1, p53, AKT1/2, ERK1/2 and Src) in ovarian cancer cells in a context-dependent manner. We further investigated the impact of sfTSLP overexpression on transcriptome by RNA-sequencing and found that EFNB2 and PBX1 were downregulated in ovarian and endometrial cancer cells, suggesting their role in sfTSLP-mediated tumour growth. In conclusion, sfTSLP is predominantly expressed in ovarian and endometrial cancers and promotes tumour growth.

Autophagy signals orchestrate chemoresistance of gynecological cancers.

Gynecological cancers are characterized by a high mortality rate when chemoresistance develops. Autophagy collaborates with apoptosis and participates in homeostasis of chemoresistance. Recent findings supported that crosstalk of necrotic, apoptotic and autophagic factors, and chemotherapy-driven hypoxia, oxidative stress and ER stress play critical roles in chemoresistance in gynecological cancers. Meanwhile, current studies have shown that autophagy could be regulated by and cooperate with metabolic regulator, survival factors, stemness factors and specific post-translation modification in chemoresistant tumor cells. Meanwhile, non-coding RNA and autophagy crosstalk also contribute to the chemoresistance. Until now, analysis of individual autophagy factors towards the clinical significance and chemoresistance in gynecological cancer is still lacking. We suggest comprehensive integrated analysis of cellular homeostasis and tumor microenvironment to clarify the role of autophagy and the associated factors in cancer progression and chemoresistance. Panel screening of pan-autophagic factors will pioneer the development of risk models for predicting efficacy of chemotherapy and guidelines for systematic treatment and precision medicine.

LncRNAs with miRNAs in regulation of gastric, liver, and colorectal cancers: updates in recent years.

Long noncoding RNA (lncRNA) is a kind of RNAi molecule composed of hundreds to thousands of nucleotides. There are several major types of functional lncRNAs which participate in some important cellular pathways. LncRNA-RNA interaction controls mRNA translation and degradation or serves as a microRNA (miRNA) sponge for silencing. LncRNA-protein interaction regulates protein activity in transcriptional activation and silencing. LncRNA guide, decoy, and scaffold regulate transcription regulators of enhancer or repressor region of the coding genes for alteration of expression. LncRNA plays a role in cellular responses including the following activities: regulation of chromatin structural modification and gene expression for epigenetic and cell function control, promotion of hematopoiesis and maturation of immunity, cell programming in stem cell and somatic cell development, modulation of pathogen infection, switching glycolysis and lipid metabolism, and initiation of autoimmune diseases. LncRNA, together with miRNA, are considered the critical elements in cancer development. It has been demonstrated that tumorigenesis could be driven by homeostatic imbalance of lncRNA/miRNA/cancer regulatory factors resulting in biochemical and physiological alterations inside the cells. Cancer-driven lncRNAs with other cellular RNAs, epigenetic modulators, or protein effectors may change gene expression level and affect the viability, immortality, and motility of the cells that facilitate cancer cell cycle rearrangement, angiogenesis, proliferation, and metastasis. Molecular medicine will be the future trend for development. LncRNA/miRNA could be one of the potential candidates in this category. Continuous studies in lncRNA functional discrepancy between cancer cells and normal cells and regional and rational genetic differences of lncRNA profiles are critical for clinical research which is beneficial for clinical practice.

Drugs for Targeted Therapies of Alzheimer's Disease.

Alzheimer's disease (AD) is one type of neurodegenerative diseases, which is prevalent in the elderly. Beta-amyloid (Aß) plaques and phosphorylated tau-induced neurofibrillary tangles are two pathological hallmarks of this disease and the corresponding pathological pathways of these hallmarks are considered as the therapeutic targets. There are many drugs scheduled for pre-clinical and clinical trial that target to inhibit the initiators of pathological Aß and tau aggregates as well as critical Aß secretases and kinases in tau hyperphosphorylation. In addition, studies in disease gene variations, and detection of key prognostic effectors in early development are also important for AD control. The discovery of potential drug targets contributed to targeted therapy in a stage-dependent manner, However, there are still some issues that cause concern such as the low bioavailability and low efficacy of candidate drugs from clinical trial reports. Therefore, modification of drug candidates and development of delivery agents are essential and critical. With other medical advancements like cell replacement therapy, there is hope for the cure of Alzheimer's disease in the foreseeable future.

Apoptosis and Anti-cancer Drug Discovery: The Power of Medicinal Fungi and Plants.

The purpose of this account is to review the compounds capable of eliciting mitochondria-mediated apoptosis in cancer cells produced by medicinal fungi and plants. The medicinal fungi discussed encompass Cordyceps, Ganoderma species, Coriolus versicolor and Hypsizygus marmoreus. The medicinal plants discussed comprise Astragalus complanatus, Dendrobium spp, Dioscorea spp, Glycyrrhiza spp, Panax notoginseng, Panax ginseng, and Momordica charantia. These compounds have the potential of development into anticancer drugs.

Therapeutic potentials of short interfering RNAs.

Short interfering RNA (siRNA) is one of the members of the family of RNA interference (RNAi). Coupled with the RNA-induced silencing complex (RISC), siRNA is able to trigger the cleavage of target RNAs which serve as a defensive system against pathogens. Meanwhile, siRNA in gene silencing opens a new avenue for the treatment of various diseases. SiRNA can effectively inhibit viral infection and replication and suppress tumorigenesis and various inflammation-associated diseases and cardiovascular diseases by inactivation of viral genes and downregulation of oncogene expression. Recently, endogenous siRNAs (endo-siRNAs) were discovered in the reproductive cells of animals which may be associated with regulation of cell division. Structural modification of siRNA enhances the delivery, specificity and efficacy and bioavailability to the target cells. There are at least five categories of siRNA delivery systems including viral vectors, lipid-based nanoparticles, peptide-based nanoparticles, polymer-based nanoparticles and inorganic small molecules like metal ions, silica and carbon. Sufficient preclinical and clinical studies supported that siRNA may be a potential medicine for targeted therapy of various diseases in the near future.