Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Accumulating investigations have identified the aberrant expression of miRNAs (microRNAs) in UM, such as miR-181, miR-20a, miR-144, miR-146a. The purpose of this study is to investigate the biological function of miR-224-5p in UM. The expression of miR-224-5p, PIK3R3, and AKT3 in 30 tumor tissues and paired adjacent noncancerous tissues were analyzed using Western blot analysis and quantitative real-time polymerase chain reaction (qRT-PCR) assays. Cell proliferation assay, transwell assay, and wound healing assay were used to measure the effects of miR-224-5p on the motility of UM in vitro. Western blot analysis and luciferase assays were used to detect the expression of PIK3R3 and AKT3 as miR-224-5p downstream targets. The results of Western blot analysis and qRT-PCR assays indicated that the expression of miR-224-5p was lower in UM tissues compared to normal tissue, while the expression of PIK3R3 and AKT3 were simultaneously increased. Upregulation of miR-224-5p significantly inhibited capacities of proliferation, invasion, and migration of OCM-1A cells and decreased expression of PIK3R3 and AKT3. Luciferase assay demonstrated PIK3R3 and AKT3 as downstream targets of miR-224-5p. Moreover, upregulating PIK3R3 and AKT3 restrained miR-224-5p-induced inhibition of the motility of OCM-1A cells. Thus, our study proved that miR-224-5p was involved in proliferation, invasion, and migration of UM cells via regulation the expression of PIK3R3 and AKT3. And the results also established a miR-224-5p/PIK3R3/PI3K/AKT axis in the regulation of UM progression, providing an experimental basis for further exploring the miR-224-5p as a therapeutic and diagnosis target for patients with UM.

miR-224-5p inhibits proliferation, migration, and invasion by targeting PIK3R3/AKT3 in uveal melanoma.

Purpose To explore the effects of PAK4/LIMK1/Cofilin-1 signaling pathway on the proliferation, invasion, and migration of human osteosarcoma cells. Methods The expression of PAK4/LIMK1/Cofilin-1 was detected by immunohistochemistry in osteosarcoma tissues. The osteosarcoma cell line MG63 was transfected and divided into Mock, Control siRNA, si-PAK4, LIMK1, and si-PAK4+LIMK1 groups. Then, the cellular biological features of MG63 cells were detected by CCK-8, wound-healing, Transwell, and flow cytometry methods. The relationship of PAK4 and LIMK1 was performed by co-immunoprecipitation test, and the protein expression of PAK4/LIMK1/Cofilin-1 was determined by Western blotting. Finally, the effect of PAK4 on the growth of osteosarcoma was verified by subcutaneous transplantation model of osteosarcoma in nude mice. Results The expression of PAK4/LIMK1/Cofilin-1 in both osteosarcoma tissues and cells was up-regulated. Positive PAK4, LIMK1, and Cofilin-1 expressions in osteosarcoma were associated with the clinical stage, distant metastasis, and tumor grade. The MG63 cell viability, migration, and invasion, as well as the expression of PAK4, p-LIMK/LIMK, and p-Cofilin-1/Cofilin-1, were restrained by the knock down of PAK4 while it promoted apoptosis. PAK4 silencing also suppressed the growth of subcutaneous transplanted tumor in nude mice. Co-immunocoprecipitation showed that LIMK and PAK4 protein can form complex in osteosarcoma cells. Besides, LIMK1 overexpression reversed the inhibition effect of PAK4 siRNA on the growth of osteosarcoma cells. Conclusion The expression of PAK4/LIMK1/Cofilin-1 pathway in osteosarcoma tissues was up-regulated. Thus, PAK4 inhibition may restrict the osteosarcoma cell proliferation, invasion, and migration but promote its apoptosis via decreasing the activity of LIMK1/Cofilin-1 pathway.

Effects of PAK4/LIMK1/Cofilin-1 signaling pathway on proliferation, invasion, and migration of human osteosarcoma cells.

Idiopathic pulmonary fibrosis (IPF) is a lethal fibrotic lung disease with an increasing global burden. It is hypothesized that fibroblasts have a number of functions that may affect the development and progression of IPF. However, the present understanding of cellular and molecular mechanisms associated with fibroblasts in IPF remains limited. The present study aimed to identify the dysregulated genes in IPF fibroblasts, elucidate their functions and explore potential microRNA (miRNA)‑mRNA interactions. mRNA and miRNA expression profiles were obtained from IPF fibroblasts and normal lung fibroblasts using a next‑generation sequencing platform, and bioinformatic analyses were performed in a step‑wise manner. A total of 42 dysregulated genes (>2 fold‑change of expression) were identified, of which 5 were verified in the Gene Expression Omnibus (GEO) database analysis, including the upregulation of neurotrimin (NTM), paired box 8 (PAX8) and mesoderm development LRP chaperone, and the downregulation of ITPR interacting domain containing 2 and Inka box actin regulator 2 (INKA2). Previous data indicated that PAX8 and INKA2 serve roles in cell growth, proliferation and survival. Gene Ontology analysis indicated that the most significant function of these 42 dysregulated genes was associated with the composition and function of the extracellular matrix (ECM). A total of 60 dysregulated miRNAs were also identified, and 1,908 targets were predicted by the miRmap database. The integrated analysis of mRNA and miRNA expression data, combined with GEO verification, finally identified Homo sapiens (hsa)‑miR‑1254‑INKA2 and hsa‑miR‑766‑3p‑INKA2 as the potential miRNA‑mRNA interactions in IPF fibroblasts. In summary, the results of the present study suggest that dysregulation of PAX8, hsa‑miR‑1254‑INKA2 and hsa‑miR‑766‑3p‑INKA2 may promote the proliferation and survival of IPF fibroblasts. In the functional analysis of the dysregulated genes, a marked association between fibroblasts and the ECM was identified. These data improve the current understanding of fibroblasts as key cells in the pathogenesis of IPF. As a screening study using bioinformatics approaches, the results of the present study require additional validation.

/pdf/bioinformatic-analysis-of-next-generation-sequencing-data-to-tz7zbqpxbo.pdf

Bioinformatic analysis of next‑generation sequencing data to identify dysregulated genes in fibroblasts of idiopathic pulmonary fibrosis.

Gastric cancer (GC) poses a serious threat worldwide with unfavorable prognosis mainly due to late diagnosis and limited therapies. Therefore, precise molecular classification and search for potential targets are required for diagnosis and treatment, as GC is complicated and heterogeneous in nature. Accumulating evidence indicates that epigenetics plays a vital role in gastric carcinogenesis and progression, including histone modifications, DNA methylation and non-coding RNAs. Epigenetic biomarkers and drugs are currently under intensive evaluations to ensure efficient clinical utility in GC. In this review, key epigenetic alterations and related functions and mechanisms are summarized in GC. We focus on integration of existing epigenetic findings in GC for the bench-to-bedside translation of some pivotal epigenetic alterations into clinical practice and also describe the vacant field waiting for investigation.

Gastric cancer: An epigenetic view

The strict regulation of HIF-1α by non-coding RNAs: new insight towards proliferation, metastasis, and therapeutic resistance strategies.

Although recent studies have shown the important role and overexpression of miR-224 in several tumors, its function in gastric cancer has not yet been defined. In the present study, we tried to confirm the result of microRNAs microarray and further investigated the functions of miR-224 in gastric cancer, and tried to find new downstream targets of miR-224. In this study, the level of miR-224 was measured in gastric cancer cells with the normal human gastric epithelial cell. The effects of miR-224 of on proliferation, migration, and target protein expression were evaluated by CCK8 assay, colony assay, transwell migration assay, western blotting. In addition, luciferase reporter plasmid was constructed to demonstrate the direct target of miR-224. Overexpression of miR-224 was detected in the gastric cancer cells, especially in SCG-7901. Exogenous miR-224 expression promoted the proliferation and migration of gastric cells and abrogating expression of miR-224 suppressed proliferation, and migration of SCG-7901 cells in vitro. Luciferase assays revealed that miR-224 directly targeted the 3'UTR of p21-activated kinase 4 (PAK4). The present study provides an experimental foundation for miR-224 as a potential tumor suppressor that may decrease PAK4 expression to inhibit gastric cancer cells and that in the future, targeting of this miRNA may provide a novel strategy for the diagnosis and treatment of patients with this lethal disease.

MiR-224 promotes proliferation and migration of gastric cancer cells through targeting PAK4.

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MiR-224 promotes proliferation and migration of gastric cancer cells through targeting PAK4.