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MRPS17 Promotes Invasion and Metastasis Through PI3K/AKT Signal

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MRPS17 Promotes Invasion and Metastasis Through PI3K/AKT Signal Journal of Cancer 2021, Vol. 12 4849 Ivyspring International Publisher Journal of Cancer 2021; 12(16): 4849-4861. doi: 10.7150/jca.55719 Research Paper MRPS17 promotes invasion and metastasis through PI3K/AKT signal pathway and could be potential prognostic marker for gastric cancer Wenjie Zhou1,2*, Jun Ouyang1,2*, Junqing Li1,2*, Fangjie Liu4, Tailai An1, Lvjia Cheng1,2, Zi Chong Kuo1, Changhua Zhang1 and Yulong He1,2 1. Digestive Disease Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Zhenyuan Road 628, Guangming District, Shenzhen 518000, Guangdong, China. 2. Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Zhongshan 2nd Road 58, Yuexiu District, Guangzhou 510080, Guangdong, China. 3. Department of Pathology, The Seventh Affiliated Hospital, Sun Yat-sen University, Zhenyuan Road 628, Guangming District, Shenzhen 518000, Guangdong, China. 4. Department of Hematology, The Seventh Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan 2nd Road 58, Yuexiu District, Guangzhou 510080, Guangdong, China. 5. Scientific Research Centre, The Seventh Affiliated Hospital, Sun Yat-sen University, 628 Zhenyuan Road 628, Guangming District, Shenzhen 518000, Guangdong, China. *These authors contributed equally to this work. Corresponding authors: Changhua Zhang, E-mail: [email protected]; Yulong He, E-mail: [email protected]. © The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. Received: 2020.11.10; Accepted: 2021.05.29; Published: 2021.06.11 Abstract In this study, the molecular mechanisms through which Mitochondrial Ribosomal Protein S17 (MRPS17) contributes to gastric cancer (GC) and its prognostic significance in GC have been explored. As a protein encoding gene, MRPS17 encodes a 28s proteins belonging the ribosomal protein S17P family. The specific roles and molecular mechanisms of MRPS17 in cancers remain ambiguous. It was revealed by analyzing data from TCGA and GEO that elevated expression of MRPS17 was significantly associated with invasion of GC and poor survival of GC patients. Then through univariate and multivariate Cox regression analyses it was demonstrated that MRPS17 an independent prognostic factor for GC patients (P<0.001). It was demonstrated by differentially expressed gene analysis and functional enrichment analysis that MPRS17 is related to PI3K/AKT pathway and Cell adhesion molecules (CAMs), while its function is mediated by collagen-containing extracellular matrix and receptor ligand/regulator activity. Then it was proven by in-vitro experiments that knocking down of MRPS17 gene in AGS and SGC7901 cells would significantly inhibit proliferation and invasion capability of these cells. Furthermore, it was revealed by cell immunofluorescence assay that as a ribosomalprotein, MRPS17 was mainly distributed in the cytoplasmic surface of cell membrane. Additionally, activation of PI3K/AKT pathway is responsible for malignant progression of glioma that was promoted by MRPS17. In conclusion, it was revealed in the present study that MRPS17 promoted invasion and metastasis of GC and potential molecular mechanisms through which it exerted its influences on GC were explored, suggesting its potential as a novel prognostic biomarker for GC. Key words: gastric cancer, TCGA, PI3K/AKT signaling pathway, invasion and migration Introduction Gastric cancer (GC) is one of the most commonly curative surgery is not possible [3]. For patients with diagnosed malignant tumors and curative surgery advanced GC, radiotherapy, chemotherapy, targeted remains the treatment of choice for non-metastatic GC therapy and immunotherapy (one modality or more) [1]. With the application of multidisciplinary are usually applied. Thus, it is of significant teamwork mode, the 5-year survival rate of patients importance for us to develop novel treatment diagnosed with early gastric cancer can reach 95% [2]. alternatives and explore new prognostic markers to However, due to the elusive nature of GC and improve the prognosis of the patients that have been difficulties in diagnosing early GC, most patients are diagnosed with advanced GC [4, 5]. at an advanced stage when the diagnosis is made and http://www.jcancer.org Journal of Cancer 2021, Vol. 12 4850 Encoded by nuclear genes, mammalian Afterwards, we performed in-vitro experiments, mitochondrial ribosomal proteins are mainly involved demonstrating that knocking down of MRPS17 in in synthesis of mitochondrial proteins. Mitochondrial different GC cell lines could significantly inhibit ribosomes are comprised of a small subunit (28S) and proliferation and invasion of these cells. Additionally, a large subunit (39S) [6, 7]. The protein to rRNA ratio we verified the associations between MRPS17 and of mitochrondrial ribosomes is 3:4, which is 4:3 in PI3K/AKT signaling pathway, and cell adhesion prokaryotic ribosomes. Another aspect that molecules. Considering all these aforementioned distinguishes prokaryotic ribosomes from results, we could draw the conclusion that MRPS17 mammalian mitoribosomes is that the former ones could be utilized as a novel therapeutic and contain a 5S rRNA [8]. Amino acid sequences of prognostic biomarker for GC. mitoribosomal proteins and their biochemical properties vary significantly among different species, Materials and methods which makes it difficult for us to distinguish them Data processing easily [9]. As a protein encoding gene, MRPS17 encodes a protein (28s) belonging to the ribosomal Relevant RNA-sequencing and clinical data of protein S17P family, which was moderately conserved GC were extracted from the TCGA (https://portal. between human and prokaryotes [10]. MRPS17 has gdc.cancer.gov/) database. All the downloaded been reported to be involved in the pathogenesis of expression profiles were acquired as HT-seq read myxosarcoma and phosphoserine phosphatase counts and interpreted according to the Ensembl deficiency. MRPS17-related processes include reference database (http://www.ensembl.org/info/ biogenesis and maintenance of organelles and data/ftp/index.html). DEMs (differentially expressed translation of viral RNA. Varvagiannis et al. [11] mRNAs) between GC tissues and normal gastric reported that a 27-month-old boy showed tissues were identified using the “DESeq2” package of psychomotor delay and deformity features, mainly R software. mRNAs whose adjusted P-values were manifested as mild facial asymmetry. The case <0.05 and log2|fold change| values were >1 were discussed CHCHD2, GBAS, MRPS17, SEPT14 and defined as DEMs. The present study was performed PSPH may be related to the patient’s regarding in compliance with data access rules and publication phenotype, the unbalanced region of the patient’s guidelines of TCGA database. Heatmaps of this study chromosomes also contains three genes that are were made visualized using “pheatmap” and considered essential to mitochondrial function, “ggplot2” of R software. namely CHCHD2, GBAS and MRPS17. MRPS17 GO enrichment and KEGG pathway analysis encodes the mitochondrial ribosomal protein S17, which has an indirect role in the mitochondrial Genes were classified according to the projection translation system and the mrps17 is necessary for the at a specific level of GO terms or KEEG pathways by production of 13 proteins necessary for OxPhos [12]. “clusterProfiler” package of R software. Then GO According to Gene Ontology (GO) database, terms and KEGG pathways were performed through MRPS17-related annotations include rRNA binding a hypergeometric distribution with P < 0.05 as the and constitution of ribosome. ENSG00000249773 is significance threshold. one important paralog of MRPS17. To investigate the Immunohistochemistry prognostic value and biological function of RNA The formalin-fixed and paraffin-embedded binding proteins (RBPs) in stomach adenocarcinoma sections were deparaffinized with xylene and then (STAD), we conducted a prognosis of gastric cancer rehydrated. Antigen retrieval was performed with related RBP research [13]. Seven RBPs (PTBP1, PPIH, Tris/EDTA buffer pH 9.0 for 20 min at 95 ºC in SMAD5, MSI2, RBM15, MRPS17, and ADAT3) were paraffin-embedded tissue sections. The slides were identified to be prognosis-related and adopted to incubated with antibodies against MRPS17 (1:300, construct a prognostic model. In the study, we found Proteintech Group, USA) overnight at 4 °C. The that MRPS17 is strong correlation with prognosis, and reactivity was detected using Dako EnVision-HRP there is currently no research on this gene. (Dako). Two pathologists are responsible for In the present study, prognostic significance of reviewing each slide and score independently. MRPS17 and its potential roles in GC were explored. Based on results of analyzing the data from public Cell culture and siRNA transfection database, we further evaluated clinical and prognostic The gastric cancer cell lines used in our study significance of MRPS17. Then through KEGG and GO including AGS, SGC7901 were bought from the functional enrichment analysis, biological functions of Shanghai Institute of Cell Biology, Chinese Academy MRPS17 and molecular mechanisms were identified. of Sciences (Shanghai, China). After being rewarmed, http://www.jcancer.org Journal of Cancer 2021, Vol. 12 4851 SGC7901 cell line was cultured on dishes filled with FBS-supplemented medium. After being incubated RPMI-1640
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