MicroRNA-1224 Inhibits Tumor Metastasis in Intestinal-Type Gastric Cancer by Directly Targeting FAK

Intestinal-type gastric cancer (GC) of the Lauren classification system has specific epidemiological characteristics and carcinogenesis patterns. MicroRNAs (miRNAs) have prognostic significance, and some can be used as prognostic biomarkers in GC. In this study, we identified miR-1224 as a potential survival-related miRNA in intestinal-type GC patients by The Cancer Genome Atlas (TCGA) analysis. Using quantitative real-time PCR (qRT-PCR), we showed that the relative expression of miR-1224 was significantly decreased in intestinal-type GC tissues compared to matched adjacent normal mucosa tissues (p < 0.01). We found that high miR-1224 expression was associated with no lymph-node metastasis (p < 0.05) and good prognosis (p = 0.028) in 90 intestinal-type GC tissues. Transfection of intestinal-type GC cells with miR-1224 mimics showed that miR-1224 suppressed cell migration in vitro (wound healing assay and Transwell migration assay), whereas the transfection of cells with miR-1224 inhibitor promoted cell migration in vitro. miR-1224 also suppressed intestinal-type GC cell metastasis in a xenograft mouse model. Furthermore, bioinformatics, luciferase reporter, Western blotting, and immunohistochemistry (IHC) studies demonstrated that miR-1224 directly bound to the focal adhesion kinase (FAK) gene, and downregulated its expression, which decreased STAT3 and NF-κB signaling and subsequent the epithelial-to-mesenchymal transition (EMT). Repression of FAK is required for the miR-1224-mediated inhibition of cell migration in intestinal-type GC. The present study demonstrated that miR-1224 is downregulated in intestinal-type GC. miR-1224 inhibits the metastasis of intestinal-type GC by suppressing FAK-mediated activation of the STAT3 and NF-κB pathways, and subsequent EMT. miR-1224 could represent an important prognostic factor in intestinal-type GC

RANKL/RANK promotes the migration of gastric cancer cells by interacting with EGFR

BACKGROUND: The incidence and mortality rates of gastric cancer (GC) rank in top five among all malignant tumors. Chemokines and their receptor-signaling pathways reportedly play key roles in the metastasis of malignant tumor cells. Receptor activator of nuclear factor κB ligand (RANKL) is a member of the tumor necrosis factor family, with strong chemokine-like effects. Some studies have pointed out that the RANKL/RANK pathway is vital for the metastasis of cancer cells, but the specific mechanisms in GC remain poorly understood. RESULTS: This study reports original findings in cell culture models and in patients with GC. Flow cytometry and western blotting analyses showed that RANK was expressed in BGC-823 and SGC-7901 cells in particular. Chemotaxis experiments and wound healing assay suggested that RANKL spurred the migration of GC cells. This effect was offset by osteoprotegerin (OPG), a decoy receptor for RANKL. RANKL contributed to the activation of human epidermal growth factor receptor (HER) family pathways. The lipid raft core protein, caveolin 1 (Cav-1), interacted with both RANK and human epidermal growth factor receptor-1(EGFR). Knockdown of Cav-1 blocked the activation of EGFR and cell migration induced by RANKL. Moreover, RANK-positive GC patients who displayed higher levels of EGFR expression had poor overall survival. CONCLUSIONS: In summary, we confirmed that with the promotion of RANKL, RANK and EGFR can form complexes with the lipid raft core protein Cav-1, which together promote GC cell migration. The formation of the RANK-Cav-1-EGFR complex provides a novel mechanism for the metastasis of GC. These observations warrant confirmation in independent studies, in vitro and in vivo. They also inform future drug target discovery research and innovation in the treatment of GC progression

Elevated limb-bud and heart development (LBH) expression indicates poor prognosis and promotes gastric cancer cell proliferation and invasion via upregulating Integrin/FAK/Akt pathway

The limb-bud and heart development (LBH) gene is a highly conserved, tissue-specific transcription cofactor in vertebrates that regulates multiple key genes in embryonic development. The role of LBH in various cancer types is still controversial, and its specific role and molecular mechanism in the oncogenesis of gastric cancer (GC) remains largely unexplored. In the present study, the prognostic significance and clinicopathological characteristics of LBH in GC was determined. The LBH mRNA expression was first investigated in four independent public datasets (TCGA-STAD, GSE15459, GSE29272, and GSE62254) and then validated with our samples at the protein level. LBH was overexpressed at both the mRNA and protein levels in cancer compared with normal tissues. High LBH expression was correlated with advanced T, N, and M stages. Kaplan–Meier analysis and log-rank test indicated that higher LBH expression was statistically correlated with shorter overall survival (OS) in the public datasets and our study samples. Univariate and multivariate Cox regression analysis showed that LBH was an independent prognostic biomarker for survival in TCGA-STAD, GSE15459, GSE62254 cohorts, and our GC patients. In vitro experiments showed that knockdown of LBH can significantly inhibit the proliferation and invasion of HGC-27 cells, while overexpression of LBH can significantly enhance the proliferation and invasion of BGC-823 cells. Gene Set Enrichment Analysis (GSEA), Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomics (KEGG) indicated that high LBH expression is associated with the PI3K-Akt pathway, focal adhesion, and extracellular matrix (ECM)-receptor interaction. Western blot analysis showed that knockdown of LBH significantly inhibited the expression of integrin α5, integrin β1, p-FAK, and p-Akt. Therefore, results from the present study indicate that LBH is a potential independent prognostic biomarker and promotes proliferation and invasion of GC cells by activating the integrin/FAK/Akt pathway

Effect of an Albumin-Coated Mesoporous Silicon Nanoparticle Platform for Paclitaxel Delivery in Human Lung Cancer Cell Line A549

Albumin-coated paclitaxel-mesoporous silicon nanoparticles (APMSN) were prepared to improve the anticancer effect in lung cancer by means of regulating the dissolution rate of paclitaxel (PTX). PTX was absorbed into the mesoporous structure of mesoporous silicon nanoparticles (MSN), which was defined as PMSN. PTX was proved to exist in an amorphous state in PMSN, which increased the dissolution rate of PTX. Albumin was coated on the surface of MSN to form AMSN; AMSN and PTX were mixed to form APMSN in order to achieve sustained release of PTX. Then, it was found that APMSN had more significant antiproliferate effects and induced more apoptotic proportion in comparison with PTX in A549 cells. Furthermore, the absorption mechanism of APMSN into A549 cells was investigated. Transmission electron microscopy (TEM) and laser scanning confocal microscopy (LSCM) showed that APMSN could cross the cell membrane and was taken into the cytoplasm quickly. Taken together, our results demonstrate that AMSN carriers have potential as nanodrug delivery systems in the treatment of lung cancer

4-phenylbutyric acid promotes migration of gastric cancer cells by histone deacetylase inhibition-mediated IL-8 upregulation

Histone acetylation is regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). It is associated with gene transcription and expression. 4-Phenylbutyric acid (4-PBA), an HDAC inhibitor (HDACi), can inhibit cancer cell proliferation by increasing the level of histone acetylation. However, 4-PBA did not show any efficacy in clinical trials. In this study, we found that 4-PBA induced epithelial–mesenchymal transition (EMT) in gastric cancer cell lines MGC-803 and BGC-823 with ectopic E-cadherin expression. Based on the expression profile microarray, IL-8 was the most significantly up-regulated gene by 4-PBA, and was selected for further investigation. Knockdown of IL-8 partially prevented 4-PBA-induced-EMT by blocking the activation of the downstream Gab2-ERK pathway. Furthermore, CHIP assay confirmed that acetyl-H3 directly combined with the promoter region of IL-8 to promote its transcription. Therefore, the results of this study demonstrated that 4-PBA-mediated inhibition of HDAC activity could induce EMT in gastric cancer cells via acetyl-histone-mediated IL-8 upregulation, and the downstream Gab2/ERK activation. These data indicated the possible reason for the failure of 4-PBA in clinical trials

Hypoxia-induced ALDH3A1 promotes the proliferation of non-small-cell lung cancer by regulating energy metabolism reprogramming

Abstract Aldehyde dehydrogenase 3A1 (ALDH3A1) is an NAD+-dependent enzyme that is closely related to tumor development. However, its role in non-small-cell lung cancer (NSCLC) has not been elucidated. This study aimed to clarify the mechanism of ALDH3A1 and identify potential therapeutic targets for NSCLC. Here, for the first time, we found that ALDH3A1 expression could be induced by a hypoxic environment in NSCLC. ALDH3A1 was highly expressed in NSCLC tissue, especially in some late-stage patients, and was associated with a poor prognosis. In mechanistic terms, ALDH3A1 enhances glycolysis and suppresses oxidative phosphorylation (OXPHOS) to promote cell proliferation by activating the HIF-1α/LDHA pathway in NSCLC. In addition, the results showed that ALDH3A1 was a target of β-elemene. ALDH3A1 can be downregulated by β-elemene to inhibit glycolysis and enhance OXPHOS, thus suppressing NSCLC proliferation in vitro and in vivo. In conclusion, hypoxia-induced ALDH3A1 is related to the energy metabolic status of tumors and the efficacy of β-elemene, providing a new theoretical basis for better clinical applications in NSCLC

A Prognostic Model in Metastatic or Recurrent Gastric Cancer Patients with Good Performance Status Who Received First-Line Chemotherapy

AbstractPURPOSE: Good performance status is widely known as a superior prognostic predictor. However, some patients have large survival differences despite having good performance status that are influenced by certain prognostic factors. The purpose of this study was to explore baseline host- or tumor-related factors and to establish a prognostic model for metastatic or recurrent gastric cancer patients with good performance status who received first-line chemotherapy. METHODS: A total of 310 metastatic or recurrent gastric cancer patients with good performance status who received first-line chemotherapy were enrolled. Prognostic significance was determined using multivariate Cox regression analysis. Incorporating all pretreatment indicators, a prognostic model was established. Overall survival outcomes were compared with different risk groups using the Kaplan-Meier method and log-rank test. RESULTS: In multivariate analysis, no previous gastrectomy [hazard ratio (HR) = 1.42; 95% confidence interval (CI) = 1.08-1.85], number of distant metastatic sites (HR = 1.47; 95% CI = 1.11-1.96), bone metastasis (HR = 2.20; 95% CI = 1.16–4.18), liver metastasis (HR = 1.77; 95% CI = 1.31-2.39), and an elevated neutrophil lymphocyte ratio (HR = 1.37; 95% CI = 1.04-1.79) were independent prognostic factors of overall survival. Patients were categorized into three risk groups according to their risk scores. Median survival times for the low-risk (0 point), intermediate-risk (1-3 points), and high-risk (≥4 points) groups were 19.7, 10.7 and 5.1 months, respectively (P < .001). CONCLUSIONS: A prognostic model was developed that could facilitate risk stratification for metastatic or recurrent gastric cancer patients with good performance status who received first-line chemotherapy to help clinicians choose an applicable treatment based on the estimated prognosis