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FERMT1 promotes gastric cancer progression by activating the NF-κB pathway and predicts poor prognosis.

ABSTRACT: Recent studies have reported that FERMT1, a newly discovered adhesion protein, contributes to an aggressive phenotype in several solid malignancies. However, the function and regulatory mechanism of FERMT1 in gastric cancer remain unknown. We found that FERMT1 was overexpressed in gastric cancer tissues compared with normal tissues. Clinical data analysis indicated that the expression of FERMT1 correlated with the overall survival of gastric cancer patients. Patients with higher FERMT1 expression had lower survival rates than patients with lower FERMT1 expression. We established stable cell lines with FERMT1 knockdown and overexpression. In vitro and in vivo experiments indicated that knockdown of FERMT1 inhibited the proliferation, invasion, metastasis, and epithelial-mesenchymal transition of gastric cancer cells. Mechanistically, FERMT1 was found to activate NF-κB signaling by promoting the degradation of IκBα, thereby promoting gastric cancer. These results provide new evidence of the oncogenic effects of FERMT1 in gastric cancer and suggest that FERMT1 might be a promising target for gastric cancer treatment.

SUBMITTER: Fan H

PROVIDER: S-EPMC7515530 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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FERMT1 promotes gastric cancer progression by activating the NF-κB pathway and predicts poor prognosis.

Fan Hua H Zhang Shengjun S Zhang Yu Y Liang Wu W Cao Bo B

Cancer biology & therapy 20200729 9

Recent studies have reported that FERMT1, a newly discovered adhesion protein, contributes to an aggressive phenotype in several solid malignancies. However, the function and regulatory mechanism of FERMT1 in gastric cancer remain unknown. We found that FERMT1 was overexpressed in gastric cancer tissues compared with normal tissues. Clinical data analysis indicated that the expression of FERMT1 correlated with the overall survival of gastric cancer patients. Patients with higher FERMT1 expressio ...[more]

PMID: 32723205

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Project description:BackgroundRecently, increasing evidence has indicated that platelet-activating factor acetylhydrolase 1b catalytic subunit 3 (PAFAH1B3) plays an important role in several cancers. However, its role in lung adenocarcinoma (LUAD) has not been reported until now.MethodsThe expression of PAFAH1B3 in LUAD was determined by using the Gene Expression Profiling Interactive Analysis (GEPIA) database and real-time PCR (RT-PCR), western blot and immunohistochemical (IHC) analyses. A chi-square test was used to investigate the correlation between PAFAH1B3 expression and clinical parameters. Cox regression and Kaplan-Meier analysis were performed to analyze the prognostic value of PAFAH1B3. The CCK-8 assay, clone formation assay, transwell invasion assay and flow cytometry were conducted to detect cell proliferation, clone formation, invasion and the cell cycle. The xenograft tumor model was constructed to explore the function of PAFAH1B3 in vivo. Western blot and IHC analyses were performed to detect epithelial-to-mesenchymal transition (EMT)-related markers. Immune Cell Abundance Identifier (ImmuneCellAI) and IHC analyses were used to analyze the effect of PAFAH1B3 on immune cell infiltration.ResultsOur study showed that the expression of PAFAH1B3 was upregulated in LUAD tissues and cells compared with noncancerous tissues and cells. Additionally, the results indicated that the expression of PAFAH1B3 was positively correlated with distant metastasis, TNM stage and poor clinical outcome and it was an independent prognostic risk factor for LUAD. In addition, silencing PAFAH1B3 suppressed cell proliferation, colony formation, and invasion and increased the cell population in the G0-G1 phases in vitro. Furthermore, our results showed that knockdown of PAFAH1B3 increased the epithelial marker E-cadherin level and decreased the mesenchymal marker N-cadherin level in vitro and in vivo. We also proved that PAFAH1B3 downregulation inhibited tumorigenesis and neutrophil infiltration in the xenograft tumor model.ConclusionOur studies indicate that PAFAH1B3, a prognostic risk factor, promotes proliferation, invasion and EMT and affects immune infiltrates in LUAD.

Project description:MicroRNA‑301a (miRNA/miR‑301a) and nuclear factor (NF)‑κB signaling play important roles in tumor invasion, migration and progression. However, the role of miRNA‑301a‑3p in human gastric cancer (GC), and specifically in the activation of NF‑κB signaling, remains unclear. The aim of the present study was to investigate miRNA‑301a‑3p expression in GC progression and the molecular mechanisms as regards the regulation of NF‑κB signaling. Reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) was used to detect miRNA‑301a‑3p expression in GC and paired normal tissues. The association between the expression of miRNA‑301a‑3p and patient pathological parameters and the prognosis of GC was statistically analyzed using an in situ hybridization (ISH) assay. An MTS assay and a Transwell assay were performed to evaluate the effects of miRNA‑301a‑3p on the proliferation, invasion and migration of GC cells. RT‑qPCR and western blot analysis were used to analyze the association between miRNA‑301a‑3p and nuclear factor‑κB repressing factor (NKRF) expression and the corresponding downstream NF‑κB signaling molecules. A luciferase assay was used to verify the target effect of miRNA‑301a‑3p and NKRF. It was found that miRNA‑301a‑3p expression was significantly higher in 30 cases of primary GC compared with matched normal tissues. Additionally, the ISH assay indicated that the high expression of miRNA‑301a‑3p in GC was associated with tumor invasion depth, lymph node metastasis, lymph node invasion and tumor metastasis stage. Patients whose tumors had a higher miRNA‑301a‑3p expression level exhibited a poorer prognosis. The in vitro assay indicated that miRNA‑301a‑3p affected the proliferative and invasive ability of GC cells by targeting the expression of NKRF, which then affected NF‑κB signaling. Therefore, it was hypothesize that miRNA‑301a‑3p promotes GC progression and affects the prognosis of patients with GC by targeting NKRF, which in turn, directly influences NF‑κB activation.

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FERMT1 promotes gastric cancer progression by activating the NF-κB pathway and predicts poor prognosis.

Publications

FERMT1 promotes gastric cancer progression by activating the NF-κB pathway and predicts poor prognosis.

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