MEST promotes lung cancer invasion and metastasis by interacting with VCP to activate NF-κB signaling

Abstract

Background Cell invasion is a hallmark of metastatic cancer, leading to unfavorable clinical outcomes. In this study, we established two highly invasive lung cancer cell models (A549-i8 and H1299-i8) and identified mesoderm-specific transcript (MEST) as a novel invasive regulator of lung cancer. We aim to characterize its biological function and clinical significance in lung cancer metastasis. Methods Transwell invasion assay was performed to establish high-invasive lung cancer cell model. Immunohistochemistry (IHC) was used to detect MEST expression in tumor tissues. Mass spectrometry and bioinformatic analyses were used to identify MEST-regulated proteins and binding partners. Co-immunoprecipitation assay was performed to detect the interaction of MEST and VCP. The biological functions of MEST were investigated in vitro and in vivo. Immunofluorescence staining was conducted to explore the colocalization of MEST and VCP. Results MEST overexpression promoted metastasis of lung cancer cells in vivo and in vitro by activating NF-κB signaling. MEST increased the interaction between VCP and IκBα, which accelerated IκBα degradation and NF-κB activation. Such acceleration was abrogated by VCP silencing, indicating that MEST is an upstream activator of the VCP/IκBα/NF-κB signaling pathway. Furthermore, high expressions of MEST and VCP were associated with poor survival of lung cancer patients. Conclusion Collectively, these results demonstrate that MEST plays an important role in driving invasion and metastasis of lung cancer by interacting with VCP to coordinate the IκBα/NF-κB pathway. Targeting the MEST/VCP/IκBα/NF-κB signaling pathway may be a promising strategy to treat lung cancer.

A damage-associated molecular patterns-related gene signature for the prediction of prognosis and immune microenvironment in children stage III acute lymphoblastic leukemia

“…Among these genes, the partial control of human leucocyte antigen (HLA) genes like HLA-DQB2 on immune response to infection (45,46) could be used as a reasonable therapeutic target, which will be further explored to revive the antitumor immunity in ALL. Some studies have demonstrated that MEST promotes invasion and metastasis of solid tumors and by coordinating and activating the NF-κB and Wnt/β-catenin signaling pathways (47,48), which is consistent with our findings of MEST gene and its related signaling pathways in ALL. The functional and clinical significance of MEST and its potential target against ALL 10.3389/fped.2022.999684 could be considered.…”

Inhibition of nuclear deacetylase Sirtuin-1 induces mitochondrial acetylation and calcium overload leading to cell death

“…The tumor size and body weight were monitored every two days, and the tumor volume was calculated by the following equation: V = (length × width 2 )/2. At the end of the study, tumors were harvested for TUNEL assay, and several organs (liver, kidney, lung, and heart) were harvested for histologic analyses by Hematoxylin and Eosin (H&E) staining as previously described [ 22 ]. Briefly, the paraffin-embedded tissues fixed by paraformaldehyde were stained.…”

Studies on a novel mechanisms of VCP-mediated metastasis of osteosarcoma based on cell autophagy and EMT pathway

“…As a multifunctional protein, it participates in many cell biological processes, including protein degradation, membrane fusion, apoptosis, transcription activation and autophagy [9][10][11][12][13]. Studies have shown that VCP was over-expressed in many tumors and was associated with the occurrence, development and poor prognosis, including non-small cell lung cancer [14], colorectal cancer [15], prostate cancer [16], esophageal carcinomas [17], and breast cancer [18]. In previous studies, VCP was proved to be highly expressed and related to the metastasis of osteosarcoma.…”