RELA/NEAT1/miR-302a-3p/RELA feedback loop modulates pancreatic ductal adenocarcinoma cell proliferation and migration.

Pancreatic ductal adenocarcinoma (PDAC) remains a challenging malignancy due to distant metastasis. RELA, a major component of the NF-κB pathway, could serve as an oncogene through activating proliferation or migration-related gene expression, including NEAT1, a well-known oncogenic long noncoding RNA. In the current study, the expression and function of RELA and NEAT1 in PDAC were examined. The potential upstream regulatory microRNAs of RELA were screened and verified for their correlation with RELA and NEAT1. The expression and function of the selected miR-302a-3p were evaluated. RELA and NEAT1 expression were upregulated in PDAC tissues, particularly in PDAC tissues with lymph node metastasis, and their expression correlated with clinical parameters. RELA overexpression promoted PDAC cell proliferation and migration, which could be partially attenuated by the NEAT1 knockdown. By binding to RELA, miR-302a-3p inhibited RELA expression, as well as PDAC cell proliferation and migration. RELA downstream NEAT1 expression was negatively regulated by miR-302a-3p; the suppressive effect of NEAT1 knockdown on PDAC cell proliferation and migration was partially attenuated by miR-302a-3p inhibition. Moreover, through direct binding, the expression of miR-302a-3p was also negatively regulated by NEAT1. The expression of miR-302a-3p was downregulated and negatively correlated with RELA or NEAT1 in tissue samples, indicating that rescuing miR-302a-3p expression may inhibit PDAC cell proliferation and migration through RELA/NEAT1. In summary, RELA, NEAT1, and miR-302a-3p form a feedback loop in PDAC to modulate PDAC cell proliferation and migration.

MAPK inhibitors protect against early­stage osteoarthritis by activating autophagy.

Osteoarthritis (OA) is a chronic, age­related osteoarthropathy that causes a considerable decline in quality of life, as well as economic losses due to its high incidence and poor prognosis. Mitogen­activated protein kinases (MAPKs) regulate multiple cellular processes, including proliferation, differentiation and apoptosis, in certain diseases, such as cancer, diabetes and Alzheimer's disease. The present study aimed to investigate the regulatory role of the MAPK signaling pathway in early­stage OA. A rabbit model of early­stage OA was induced by treatment with the enzyme papain. U0126 [an extracellular signal­regulated kinase (ERK) inhibitor], SP600125 [a Jun NH2­terminal kinase (JNK) inhibitor] and SB203580 (a p38 inhibitor) were administered to the rabbits via intra­articular injection. The severity of OA was assessed by histological examination using H&E, toluidine blue and safranin­O/fast green staining, as well by analyzing the glycosaminoglycan (GAG) content and determining the OA Research Society International (OARSI) score. Western blotting was used to detect the protein expression levels of matrix metalloproteinase­3 (MMP3), ERK, phosphorylated (p)­ERK, p38, p­p38, JNK, p­JNK, Beclin1, UNC­51­like kinase 1 (ULK1) and microtubule­associated protein 1 light chain 3 (LC3)II/I. U0126, SP600125 or SB203580 treatment significantly decreased the OARSI scores and significantly increased the GAG levels in the cartilaginous tissues of OA model rabbits. These results indicated that the MAPK inhibitors reduced the severity of OA­induced injury at the early stage. Western blotting results demonstrated that MAPK inhibition significantly decreased the protein expression levels of MMP3 in OA cartilage. The protective effect of MAPK inhibitors in OA was mediated via the activation of autophagy, as demonstrated by the increased protein expression levels of LC3II/I, ULK1 and Beclin1. Overall, the data indicated that MAPK inhibitors may exert a protective effect against OA by restoring compromised autophagy. Furthermore, the present study suggested that MAPK inhibitors may represent a potential pharmacological strategy for treating OA in the future.

Endothelial cell-specific deficiency of the adenosine deaminase ADAR1 aggravates LPS-induced lung injury in mice via an MDA5-independent pathway.

Adenosine deaminase acting on RNA 1 (ADAR1) has been shown to participate in the regulation of endothelial cells (ECs), as well as local and systemic inflammatory responses. Here, we find that bacterial lipopolysaccharide (LPS)-induced upregulation of ADAR1 in lung ECs is impaired in aged mice, an animal model with high rates of sepsis and mortality. Endothelial cell-specific ADAR1 knockout (ADAR1ECKO ) mice suffer from higher mortality rates, aggravated lung injury, and increased vascular permeability under LPS challenge. In primary ADAR1 knockout ECs, expression of the melanoma differentiation-associated gene 5 (MDA5), a downstream effector of ADAR1, is significantly elevated. MDA5 knockout completely rescues the postnatal offspring death of ADAR1ECKO mice. However, there is no reduction in mortality or apoptosis in lung cells of ADAR1ECKO /MDA5-/- mice challenged with LPS, indicating the involvement of an MDA5-independent mechanism in this process.