CD146-dependent macrophage infiltration promotes epidural fibrosis via the Erdr1/ERK/CCR2 pathway.

Low back pain due to epidural fibrosis is a major complication after spine surgery. Macrophages infiltrate the wound area post laminectomy, but the role of macrophages in epidural fibrosis remains largely elusive. In a mouse model of laminectomy, macrophage depletion decreased epidural fibrosis. CD146, an adhesion molecule involved in cell migration, is expressed by macrophages. CD146-defective macrophages exhibited impaired migration, which was mediated by reduced expression of CCR2 and suppression of the MAPK/ERK signaling pathway. CD146-defective macrophages suppress the MAPK/ERK signaling pathway by increasing Erdr1. In vivo, CD146 deficiency decreased macrophage infiltration and reduced extracellular matrix deposition in wound tissues. Moreover, the anti-CD146 antibody AA98 suppressed macrophage infiltration and epidural fibrosis. Taken together, these findings demonstrated that CD146 deficiency alleviates epidural fibrosis by decreasing the migration of macrophages via the Erdr1/ERK/CCR2 pathway. Blocking CD146 and macrophage infiltration may help alleviate epidural fibrosis.

Construction of Prognostic Model and miRNA-mRNA Regulatory Network for Lung Squamous Cell Carcinoma.

The purpose of this paper was to construct a prognostic model, miRNA-mRNA regulatory network and protein-protein interaction (PPI) network for lung squamous cell carcinoma (LUSC) used data from the cancer genome atlas (TCGA) database. In this study, we first downloaded and sorted out the expression matrix containing 19962 mRNA transcripts (including 502 LUSC and 51 normal control (NC) samples) and the expression matrix containing 2205 miRNA transcripts (including 478 LUSC and 45 NC samples) from the TCGA database. We obtained 389 differentially expressed miRNAs (DE-miRNAs), of which 305 were upregulated and 84 down-regulated DE-miRNAs. Next, a total of 7 prognosis-related DE-miRNAs (PDE-miRNAs) were identified by Cox regression analysis, and the prognosis model consisting of three PDE-miRNAs (hsa-miR-4746-5p, hsa-miR-556-3p and hsa-miR-489-3p) was optimized. Then, we drew the survival curves and found that the survival rates of the three PDE-miRNA high and low expression groups and the survival rates of the high-risk and low-risk patients in the prognosis model had significant statistical differences. In addition, the receiver operating characteristics (ROC) curve analysis and independent prognostic analysis confirmed that the prognostic model we built has a relatively accurate ability to predict the grouping and prognosis of LUSC patients. Finally, Cox regression analysis were used to construct the miRNA-mRNA regulatory network, which showed the regulatory relationship between PDE-miRNAs and targeted mRNAs. Moreover, we constructed the PPI network composed of 145 targeted mRNAs and the subnetwork composed of 10 hub-targeted mRNAs (FCGR3A, IL13, CCR2, PPARGC1A, FCGR3B, ACSL1, PLXNA4, LPL, KAT2B and AOC3), which showed the interaction between targeted mRNAs. The above results indicated that the prognosis model we built can predict LUSC patients relatively accurately. The miRNA-mRNA regulatory network and the PPI network of targeted mRNAs illustrated the regulatory mechanisms and interactions between RNAs, which were of certain reference significance for us to further understand the molecular pathogenesis of LUSC and for clinical early diagnosis and treatment.

Downregulation of NEAT1 Suppresses Cell Proliferation, Migration, and Invasion in NSCLC Via Sponging miR-153-3p.

Background: Long noncoding RNA nuclear enriched abundant transcript 1 (NEAT1) has been reported to play a promotive role in nonsmall cell lung cancer (NSCLC) progression through microRNAs (miRNAs). However, the exact influence and mechanism of NEAT1 were unsatisfied. Methods: Quantitative real-time polymerase chain reaction was applied to examine the expression of NEAT1 and miR-153-3p. The cell proliferation ability, apoptosis rate, migration, and invasion were measured by Cell Counting Kit-8 (CCK8) assay, flow cytometry, and transwell assay, respectively. The epithelial-mesenchymal transition process and Wnt/ß-catenin signaling pathway were verified by Western blot. The interaction between NEAT1 and miR-153-3p was confirmed by dual-luciferase reporter assay and RNA immunoprecipitation assay. Results: These data showed that NEAT1 is highly expressed in NSCLC tissues and cell lines. Knockdown of NEAT1 suppresses cell proliferation, invasion, migration, and induces the cell apoptosis in NSCLC cell lines. At the same time, NEAT1 directly interacts with miR-153-3p in NSCLC. In addition, upregulation of miR-153-3p inhibits the cell progression, and miR-153-3p inhibitor recovers the inhibition effect of si-NEAT1 in NSCLC cell lines. Subsequently, si-NEAT1 inhibits Wnt/ß-catenin signaling pathway, which is reactivated by miR-153-3p inhibitor. Conclusions: Knockdown of NEAT1 could suppress cell proliferation, migration, and invasion of NSCLC while promoting cell apoptosis through sponging miR-153-3p.

Effect of inhibiting ACAT-1 expression on the growth and metastasis of Lewis lung carcinoma.

Accumulating evidence suggests that acetyl-CoA acetryltransferase 1 (ACAT-1) may mediate tumor development and metastasis. However, the specific function served by ACAT-1 in lung cancer is not well understood. Therefore, the present study initially verified that ACAT-1 was overexpressed in Lewis lung carcinoma (LLC) tissues compared with non-LLC mice and that this overexpression promoted the proliferation, invasion and metastasis of these LLC samples. Western blotting, immunofluorescence microscopy and flow cytometry allowed the present study to determine that the ACAT-1 inhibitor avasimibe significantly reduced the expression of ACAT-1 in LLC compared with LLC cells that are not treated with avasimibe (P<0.05). A combination of Cell Counting Kit-8 and wound healing assays demonstrated that downregulating ACAT-1 expression sufficiently inhibited the proliferation of LLC cells. Avasimibe promoted LLC cell apoptosis as assessed by a Annexin V/propidium iodide double staining assay. Furthermore, avasimibe inhibited tumor growth in vivo and improved immune responses, with tissue biopsies from LLC model mice exhibiting higher levels of ACAT-1 compared with in healthy controls. Altogether, the results of the present study reveal that avasimibe may inhibit the progression of LLC by downregulating the expression of ACAT-1, which may thus be a potential novel therapeutic target for lung cancer treatment.

Apatinib enhanced anti-tumor activity of cisplatin on triple-negative breast cancer through inhibition of VEGFR-2.

BACKGROUND: Triple-negative breast cancer (TNBC) was known as a fast-growing and an aggressive tumor. Cisplatin is the effective cytotoxic drug used for the treatment of TNBC. In addition, apatinib, a VEGFR2 inhibitor, exhibits antitumor activity in patients with TNBC. However, the effects of combination of apatinib with cisplatin on TNBC remain unclear. Thus, this study aimed to investigate the effects of apatinib in combination with cisplatin on MDA-MB-231 cells. METHODS: Immunohistochemistry was used to detect the expression of VEGFR2. In addition, CCK-8, flow cytometric, transwell assays were used to measure the cell proliferation, apoptosis, migration and invasion, respectively. Moreover, western blotting was used to detect the expressions of Bax, active caspase 3, p-VEGFR2, p-Akt and p-mTOR. RESULTS: VEGFR2 was significantly upreguated in patients with TNBC. In addition, the inhibitory effects of cisplatin on the proliferation, migration and invasion of MDA-MB-231 cells were enhanced by apatinib. Moreover, apatinib increased cisplatin-induced apoptosis on MDA-MB-231 cells via increasing the level of Bax and active caspase 3 and decreasing the expression of Bcl-2. Importantly, apatinib enhanced anti-tumor effect of cisplatin on MDA-MB-231 cells via inhibiting the levels of p-VEGFR2, p-Akt and p-mTOR. CONCLUSION: Our findings indicated that apatinib enhanced the anti-tumor effects of cisplatin on MDA-MB-231 cells via inhibition of VEGFR2. Thus, the combination of apatinib with cisplatin may serve as a potential approach in the treatment of patients with TNBC.

Successful treatment of metastatic colorectal cancer with apatinib: report of two cases and literature review.

Apatinib, a novel small molecule tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor-2, was approved for metastatic gastric adenocarcinoma in China in Oct 2014. This is the first report on its use for advanced colorectal cancer as a kind of third-line therapy to date. Here we report two Chinese patients who presented with metastatic colorectal cancer who received apatinib 850 mg daily as a third-line therapy. Both the patients achieved favorable benefits in outcomes after the administration of apatinib. Patient 1 benefited 4 months progression-free survival and 11 months overall survival, while patient 2's progression-free survival was over 10 months. Both the patients presented hand-foot syndrome, and one of them suffered a slight impairment of liver function, mild elevated blood pressure, and proteinuria. But these adverse events were manageable with symptomatic treatment and dose reduction or a short-time drug withdrawal.