PHB2 promotes tumorigenesis <i>via</i> RACK1 in non-small cell lung cancer

Wu, Bin; Chang, Ning; Xi, Hangtian; Xiong, Jie; Zhou, Ying; Wu, Yingtong; Wu, Shuo; Wang, Ning; Yi, Huang; Song, Yun; Chen, Lihua; Zhang, Jian

doi:10.7150/thno.52848

Cited by 35 publications

(35 citation statements)

References 56 publications

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“…However, the context-dependent role of RACK1 in lung cancer remains controversial [ 16 , 35 ]. In the current study, we found that loss of RACK1 inhibits the proliferation, migration and invasion abilities of NSCLC cells, consistent with most currently published papers [ 36 ]. Our research further validated the oncogenic role of RACK1 in NSCLC.…”

Section: Discussionsupporting

confidence: 92%

CPNE1 promotes non-small cell lung cancer progression by interacting with RACK1 via the MET signaling pathway

Wang

Yang

et al. 2022

Cell Commun Signal

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Background Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and the most lethal tumour worldwide. Copine 1 (CPNE1) was identified as a novel oncogene in NSCLC in our previous study. However, its specific function and relative mechanisms remain poorly understood. Methods The biological role of CPNE1 and RACK1 in NSCLC was investigated using gene expression knockdown and overexpression, cell proliferation assays, clonogenic assays, and Transwell assays. The expression levels of CPNE1, RACK1 and other proteins were determined by western blot analysis. The relationship between CPNE1 and RACK1 was predicted and investigated by mass spectrometry analysis, immunofluorescence staining, and coimmunoprecipitation. NSCLC cells were treated with a combination of a MET inhibitor and gefitinib in vitro and in vivo. Results We found that CPNE1 facilitates tumorigenesis in NSCLC by interacting with RACK1, which further induces activation of MET signaling. CPNE1 overexpression promoted cell proliferation, migration, invasion and MET signaling in NSCLC cells, whereas CPNE1 knockdown produced the opposite effects. In addition, the suppression of the enhancing effect of CPNE1 overexpression on tumorigenesis and MET signaling by knockdown of RACK1 was verified. Moreover, compared to single-agent treatment, dual blockade of MET and EGFR resulted in enhanced reductions in the tumour volume and downstream signaling in vivo. Conclusions Our findings show that CPNE1 promotes tumorigenesis by interacting with RACK1 and activating MET signaling. The combination of a MET inhibitor with an EGFR-TKI attenuated tumour growth more significantly than either single-drug treatment. These findings may provide new insights into the biological function of CPNE1 and the development of novel therapeutic strategies for NSCLC.

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Section: Discussionsupporting

confidence: 92%

CPNE1 promotes non-small cell lung cancer progression by interacting with RACK1 via the MET signaling pathway

Wang

Yang

et al. 2022

Cell Commun Signal

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“…In this study, R software package was used to analyze the coexpression genes of NPM1 in LUAD, and it was found that the expressions of RACK1, BTF3, RPL26L1 and NHP2 in LUAD had the strongest correlation with NPM1. Wu et al (40) found that PHB2 promotes tumorigenesis via RACK1 in non-small cell lung cancer. Jeon et al (41) found that kahweol inhibited the proliferation of NSCLC cells through ERK-mediated signaling pathways and the downregulation of BTF3, while the role of RPL26L1 and NHP2 in LUAD has not been reported.…”

Section: Discussionmentioning

confidence: 99%

NPM1 Is a Prognostic Biomarker Involved in Immune Infiltration of Lung Adenocarcinoma and Associated With m6A Modification and Glycolysis

et al. 2021

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BackgroundOverexpression of NPM1 can promote the growth and proliferation of various tumor cells. However, there are few studies on the comprehensive analysis of NPM1 in lung adenocarcinoma (LUAD).MethodsTCGA and GEO data sets were used to analyze the expression of NPM1 in LUAD and clinicopathological analysis. The GO/KEGG enrichment analysis of NPM1 co-expression and gene set enrichment analysis (GSEA) were performed using R software package. The relationship between NPM1 expression and LUAD immune infiltration was analyzed using TIMER, GEPIA database and TCGA data sets, and the relationship between NPM1 expression level and LUAD m6A modification and glycolysis was analyzed using TCGA and GEO data sets.ResultsNPM1 was overexpressed in a variety of tumors including LUAD, and the ROC curve showed that NPM1 had a certain accuracy in predicting the outcome of tumors and normal samples. The expression level of NPM1 in LUAD is significantly related to tumor stage and prognosis. The GO/KEGG enrichment analysis indicated that NPM1 was closely related to translational initiation, ribosome, structural constituent of ribosome, ribosome, Parkinson disease, and RNA transport. GSEA showed that the main enrichment pathway of NPM1-related differential genes was mainly related to mTORC1 mediated signaling, p53 hypoxia pathway, signaling by EGFR in cancer, antigen activates B cell receptor BCR leading to generation of second messengers, aerobic glycolysis and methylation pathways. The analysis of TIMER, GEPIA database and TCGA data sets showed that the expression level of NPM1 was negatively correlated with B cells and NK cells. The TCGA and GEO data sets analysis indicated that the NPM1 expression was significantly correlated with one m6A modifier related gene (YTHDF2) and five glycolysis related genes (ENO1, HK2, LDHA, LDHB and SLC2A1).ConclusionNPM1 is a prognostic biomarker involved in immune infiltration of LUAD and associated with m6A modification and glycolysis. NPM1 can be used as an effective target for diagnosis and treatment of LUAD.

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“…Rapid reduction of HDAC1 and RACK1 during FH induction was suggestive of ubiquitin-proteasome-dependent degradation. Recent studies suggested that RACK1 might also undergo ubiquitination under specific circumstances 48 - 50 . Our quantitative RT-PCR data also indicated that Hdac1 and Rack1 mRNA levels were unchanged under the same conditions (Figure 8 B).…”

Section: Resultsmentioning

confidence: 99%

Hepatic RACK1 deficiency protects against fulminant hepatitis through myeloid-derived suppressor cells

Liu¹,

Wang²,

Deng³

et al. 2022

Theranostics

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Fulminant hepatitis (FH) is a life-threatening disease with partially understood pathogenesis. It has been demonstrated that myeloid-derived suppressor cells (MDSCs) are recruited into the liver during this process, and their augmented accumulation by various strategies protects against liver injury. However, the underlying mechanism(s) remain elusive. Receptor for activated C kinase 1 (RACK1), a multi-functional scaffold protein, is highly expressed in normal liver and has been implicated in liver physiology and diseases, but the in vivo role of hepatic RACK1 in FH remains unknown. Methods: Survival curves and liver damage were monitored to investigate the in vivo role of hepatic RACK1 in FH. The liver microenvironment was explored by microarray-based transcriptome analysis, flow cytometry, immunoblotting, and immunohistochemistry. MDSCs were identified with phenotypic and functional characteristics. Functional antibodies were used to target MDSCs. Co-culture techniques were used to study the underlying mechanism(s) of protection. The interaction of RACK1 with histone deacetylase 1 (HDAC1) and the consequent effects on HDAC1 ubiquitination were analyzed. Ectopic expression of HDAC1 with recombinant adeno-associated virus serotype 8 was conducted to confirm the role of HDAC1 in the protective effects of hepatic RACK1 deficiency against FH. Post-translational modifications of RACK1 were also investigated during the induction of FH. Results: Liver-specific RACK1 deficiency rendered mice resistant to FH. RACK1-deficient livers exhibited high basal levels of chemokine (C-X-C motif) ligand 1 (CXCL1) and S100 calcium-binding protein A9 (S100A9), associated with MDSC accumulation under steady-state conditions. Targeting MDSCs with an antibody against either Gr1 or DR5 abrogated the protective effects of liver-specific RACK1 deficiency. Accumulated MDSCs inhibited inflammatory cytokine production from macrophages and enhanced IκB kinase (IKK)/NF-κB pathway activation in hepatocytes. Further investigation revealed that RACK1 maintained HDAC1 protein level in hepatocytes by direct binding, thereby controlling histone H3K9 and H3K27 acetylation at the Cxcl1 and S100a9 promoters. Ectopic expression of HDAC1 in livers with RACK1 deficiency partially reversed the augmented Cxcl1/S100a9 → MDSCs → IKK/NF-κB axis. During FH induction, RACK1 was phosphorylated at serine 110, enhancing its binding to ubiquitin-conjugating enzyme E2T and promoting its ubiquitination and degradation. Conclusion: Liver-specific RACK1 deficiency protects against FH through accelerated HDAC1 degradation and the consequent CXCL1/S100A9 upregulation and MDSC accumulation.

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PHB2 promotes tumorigenesis via RACK1 in non-small cell lung cancer

Cited by 35 publications

References 56 publications

CPNE1 promotes non-small cell lung cancer progression by interacting with RACK1 via the MET signaling pathway

CPNE1 promotes non-small cell lung cancer progression by interacting with RACK1 via the MET signaling pathway

NPM1 Is a Prognostic Biomarker Involved in Immune Infiltration of Lung Adenocarcinoma and Associated With m6A Modification and Glycolysis

Hepatic RACK1 deficiency protects against fulminant hepatitis through myeloid-derived suppressor cells

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