LINC00483 promotes proliferation and metastasis through the miR-19a-3p/TBK1/MAPK axis in pancreatic ductal adenocarcinoma (PDAC).

Background: Long noncoding RNAs (lncRNAs) have been found to promote tumor progression. However, the role of lncRNAs in pancreatic ductal adenocarcinoma (PDAC) requires more investigation. Methods: In this study, microarray was used to measure lncRNA levels in 3 pairs of PDAC tissues. As the highest upregulated lncRNA, LINC00483 was selected for further investigation to determine its functions in PDAC. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) was used to confirm LINC00483 level in PDAC. PDAC cell lines were transfected with short hairpin RNA (shRNA) or microRNA (miRNA). 5-ethynyl-2'-deoxyuridine (EdU) assay, colony formation assay, wound healing assay, transwell assay, and xenograft mouse models were used to evaluate LINC00483 inhibition in vitro and in vivo. Luciferase reporter assay was performed to confirm binding sites of LINC00483 with miR-19a-3p, and miR-19a-3p with TANK-binding kinase 1 (TBK1). Immunohistochemistry (IHC) was performed to evaluate TBK1 and c-myc expression in PDAC tissues. Western blot was used to elucidate the LINC00483/miR-19a-3p/TBK1/mitogen-activated protein kinase (MAPK) axis. Results: Our data showed that LINC00483 was significantly upregulated in PDAC compared to normal tissue. High level of LINC00483 was correlated with advanced clinical stage, tumor invasion and metastasis, and adverse prognosis in PDAC patients. LINC00483 suppression inhibited proliferation and invasion in vitro and tumor development in vivo via modulation of miR-19a-3p expression. Subsequently, we found that miR-19a-3p binds to TBK1 in PDAC and LINC00483 could regulate PDAC cell progression by regulating miR-19a-3p via the TBK1/MAPK pathway. Conclusions: The results of our study suggested that the LINC00483/miR-19a-3p/TBK1/MAPK axis contributed to PDAC progression, which provides a potential therapeutic target for PDAC treatment.

Autophagy-Based Unconventional Secretory for AIM2 Inflammasome Drives DNA Damage Resistance During Intervertebral Disc Degeneration.

Intervertebral disc degeneration (IDD) is the primary cause of low back pain. Stress-induced DNA damage is closely relevant to the pathogenesis of IDD; however, the underlying mechanisms remain unclear. This study investigated the role of the absent in melanoma 2 (AIM2) inflammasome as a DNA damage sensor in nucleus pulposus (NP) cells. We found that the level of AIM2 increased in degenerated discs and was correlated to the degree of IDD. Knockdown of AIM2 ameliorated H2O2-induced DNA damage and apoptosis in NP cells in vitro, and retarded the progression of IDD in vivo. Furthermore, the induction of autophagy protected against cellular DNA damage via the unconventional secretion of AIM2. We further identified the Golgi re-assembly and stacking protein 55 (GRASP55) as mediator of the transport and secretion of AIM2 via an autophagic pathway. Taken together, our researches illustrate the role and regulatory mechanism of the AIM2 inflammasome during IDD. Targeting the AIM2 inflammasome may offer a promising therapeutic strategy for patients with IDD.

miR-515-5p suppresses HCC migration and invasion via targeting IL6/JAK/STAT3 pathway.

MicroRNAs (miRNAs) have been identified as critical modulators of cell migration and invasion, which are the major causes of cancer progression including hepatocellular carcinoma (HCC). However, the accurate role of miR-515-5p in HCC is still uncertain. Here, we report that miR-515-5p expression is down-regulated in HCC tissues and cell lines, and associated with absence of capsule formation (p = 0.015)﹑microvascular invasion(p = 0.003)﹑and advantange TNM stage (II-III) (p = 0.014) in HCC patients. Overexpression of miR-515-5p inhibited migration and invasion of HCC cells in vitro and in vivo, while miR-515-5p knockdown has the inverse effect. Moreover, using miRNA databases and dual-luciferase report assay, we find miR-515-5p directly binds to the 3'-untranslated region (3'-UTR) of interleukin 6 (IL6). In addition, the regulatory association between miR-515-5p and the IL-6/Janus kinase (JNK)/signal transducer and activator of transcription-3 (STAT3) signaling pathway was explored. Furthermore, overexpression of miR-515-5p inhibited the activation of the JAK/STAT3 signaling pathway, which was rescued by overexpression of IL-6. The results of the current study indicate that miR-515-5p overexpression may serve an important role in inhibiting migration and invasion of HCC cells via suppression of IL-6/JAK/STAT3 signaling pathway activation. MiR-515-5p may serve as a potential therapeutic target for HCC.

MicroRNA-520f-3p inhibits proliferation of gastric cancer cells via targeting SOX9 and thereby inactivating Wnt signaling.

MicroRNAs (miRNAs) are known to be important in a variety of cancer types. The specific expression and roles of miR-520f-3p in the context of gastric cancer (GC), however, remains unknown. Herein we determined miR-520f-3p expression to be significantly reduced in human GC cells compared to cells of the gastric epithelium, with comparable down-regulation also being evident in gastric cancer tissue samples and the low expression of this miRNA was positively correlated with features of more aggressive large tumor size (p = 0.019), depth of invasion (p = 0.008), and distant metastasis (p = 0.037). We further found that lower levels of miR-520f-3p corresponded with poorer GC patient overall (p = 0.003) and disease-free (p = 0.036) survival. When over-expressed in GC cells, miR-520f-3p was able to impair their growth, proliferation, and survival, instead leading to the induction of apoptosis. We further found that miR-520f-3p was able to bind the SOX9 3'-UTR, thereby negatively regulating its expression in GC cells. Consistent with this model, SOX9 and miR-520f-3p expression were negatively correlated with one another in GC tissues. When SOX9 was upregulated, this was also able to abrogate miR-520f-3p-mediated inactivation of Wnt/ß-catenin signaling. Together our findings thus suggest that miR-520f-3p can act to suppress GC progression, at least in part via suppressing SOX9 expression and thus disrupting Wnt/ß-catenin signaling. Our results thus highlight potential novel therapeutic targets in GC worthy of future investigation.

MicroRNA-212-3p inhibits the Proliferation and Invasion of Human Hepatocellular Carcinoma Cells by Suppressing CTGF expression.

MicroRNA-212-3p inhibits several human cancers but its effects on hepatocellular carcinoma (HCC) remain unclear. In this study, we show that miR-212-3p is down-regulated in HCC cell lines and tissues, and correlates with vascular invasion (p = 0.001), and the absence of capsule formation (p = 0.009). We found that miR-212-3p influenced the epithelial to mesenchymal transition (EMT) of HCCLM3 and Huh7 cells. Mechanistically, miR-212-3p repressed cell invasion through the suppression of connective tissue growth factor (CTGF). We therefore validate the anti-HCC effects of miR-212-3p through its ability to suppress CTGF and subsequent EMT.

MicroRNA-197-3p acts as a prognostic marker and inhibits cell invasion in hepatocellular carcinoma.

MicroRNAs (miRNAs) serve an important regulatory role in carcinogenesis and cancer progression. Aberrant expression of miR-197-3p has been reported in various human malignancies. However, the role of miR-197-3p in the progression and prognosis of hepatocellular carcinoma (HCC) remains unknown. The present study demonstrated that miR-197-3p was downregulated in HCC tissues and that the low level of miR-197-3p expression in HCC tumours correlated with aggressive clinicopathological characteristics; thus, miR-197-3p may serve as a predictor for poor prognosis in patients with HCC. Additionally, miR-197-3p markedly inhibited the metastasis of HCC cells in vitro and in vivo. Bioinformatics analysis further identified zinc finger protein interacted with K protein 1 (ZIK1) as a novel target of miR-197-3p in HCC cells. These findings suggest that miR-197-3p may regulate the survival of HCC cells, partially through the downregulation of ZIK1. Therefore, the miR-197-3p/ZIK1 axis may serve as a novel therapeutic target in patients with HCC.