Protein and Signaling Pathway Responses to rhIL-6 Intervention Before Lobaplatin Treatment in Osteosarcoma Cells

Zhang

et al. 2022

Front. Mol. Biosci.

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Despite increasing evidence to support the relationship between FUBP1 and tumorigenesis in some types of cancers, there have been no analyses from a pan-cancer perspective. Here, we are the first to investigate the putative oncogenic role of FUBP1 in 33 cancer types based on The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Dysregulated FUBP1 expression was observed in most cancer types, and high FUBP1 expression suggests poor prognosis in cancers such as ACC, KICH, LIHC, LUAD, LUSC, SARC, CESC, and SKCM. Missense mutation is the most common type of FUBP1 mutation, and R430 in KH_4 is a predominant mutation site. Enhanced phosphorylation of FUBP1 at the S120 site has been observed in clear cell RCC, lung adenocarcinoma, and pediatric brain cancer specimens from African-American and Asian individuals. The expression of FUBP1 was found to be negatively correlated with the infiltration of CD8+ T lymphocytes in GBM, HNSC-HPV- and UCEC but positively correlated with that of tumor-associated fibroblasts in CESC, ESCA, HNSC, LIHC, LUAD, PAAD, and THYM. Furthermore, RNA splicing and spliceosome signaling were predominantly enriched in both GO and KEGG analyses of the functional mechanism of FUBP1. Briefly, this pan-cancer analysis comprehensively revealed the multifaceted characteristics and oncogenic role of FUBP1 in different human cancers.

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pan-Cancer Transcriptome and Immune Infiltration Analyses Reveal the Oncogenic Role of Far Upstream Element-Binding Protein 1 (FUBP1)

Zhang

et al. 2022

Front. Mol. Biosci.

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“…These investigations highlight that FUBP1 could be used as a therapeutic candidate for patient‐tailored treatment alongside chemotherapy for different tumors. Our previous research found that FUBP1 could decrease the sensitivity of osteosarcoma cells to lobaplatin 19 . However, the specific mechanisms and signaling pathway remain unclear.…”

Section: Introductionmentioning

confidence: 98%

“…Our previous research found that FUBP1 could decrease the sensitivity of osteosarcoma cells to lobaplatin. 19 However, the specific mechanisms and signaling pathway remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Far upstream element‐binding protein 1 confers lobaplatin resistance by transcriptionally activating PTGES and facilitating the arachidonic acid metabolic pathway in osteosarcoma

Sun

et al. 2023

MedComm

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Drug resistance is a major obstacle in cancer treatment and recurrence prevention and leads to poor outcomes in patients suffering from osteosarcoma. Clarification of the mechanism of drug resistance and exploration of effective strategies to overcome this obstacle could lead to clinical benefits for these patients. The expression of far upstream element‐binding protein 1 (FUBP1) was found to be markedly elevated in osteosarcoma cell lines and clinical specimens compared with osteoblast cells and normal bone specimens. High expression of FUBP1 was correlated with a more aggressive phenotype and a poor prognosis in osteosarcoma patients. We found that overexpression of FUBP1 confers lobaplatin resistance, whereas the inhibition of FUBP1 sensitizes osteosarcoma cells to lobaplatin‐induced cytotoxicity both in vivo and in vitro. Chromatin immunoprecipitation‐seq and RNA‐seq were performed to explore the potential mechanism. It was revealed that FUBP1 could regulate the transcription of prostaglandin E synthase (PTGES) and subsequently activate the arachidonic acid (AA) metabolic pathway, which leads to resistance to lobaplatin. Our investigation provides evidence that FUBP1 is a potential therapeutic target for osteosarcoma patients. Targeting FUBP1, its downstream target PTGES and the AA metabolic pathway may be promising strategies for sensitizing chemoresistant osteosarcoma cells to lobaplatin.

“…Targeting IL-6 could be an effective strategy for overcoming stroma-induced chemotherapeutic resistance to tocilizumab in gastric cancer [ 5 ]. Additionally, according to previous studies, IL-6 is involved in resistance to chemotherapy in osteosarcoma cells in vitro [ 6 – 8 ]. However, to date, specific changes in phosphoproteins at the post-translational level have not been discovered.…”

Section: Introductionmentioning

confidence: 99%

Quantitative phosphoproteomic analysis reveals chemoresistance-related proteins and signaling pathways induced by rhIL-6 in human osteosarcoma cells

Zhang

et al. 2021

Cancer Cell Int

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Background IL-6 plays a pivotal role in resistance to chemotherapeutics, including lobaplatin. However, the underlying mechanisms are still unclear. This study was to investigate the changes in phosphoproteins and their related signaling pathways in the process of IL-6-induced chemoresistance to lobaplain in osteosarcoma cells. Methods We performed a quantitative phosphoproteomic analysis of the response of SaOS-2 osteosarcoma cells to recombinant human IL-6 (rhIL-6) intervention prior to lobaplatin treatment. The cells were divided into the control group (Con), the lobaplatin group (Lob), and the rhIL-6-and-lobaplatin group (IL-6). Three biological replicates of each group were included. The differentially expressed phosphoproteins were subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Netphos 3.1 was used for the prediction of kinases, and STRING was used for the visualization of protein–protein interactions. The conserved motifs surrounding the phosphorylated residues were analyzed using the motif-x algorithm. Western blot analysis was performed to verify the differential expression of p-FLNC, its predicted kinase and the related signaling pathway. The results of the bioinformatic analysis were validated by immunohistochemical staining of clinical specimens. Results In total, 3373 proteins and 12,183 peptides, including 3232 phosphorylated proteins and 11,358 phosphorylated peptides, were identified and quantified. Twenty-three significantly differentially expressed phosphoproteins were identified in the comparison between the IL-6 and Lob groups, and p-FLNC ranked second among these phosphoproteins. GO and KEGG analyses revealed the pivotal role of mitogen-activated protein kinase signaling in drug resistance induced by rhIL-6. Four motifs, namely, -SPxxK-, -RxxSP-, -SP-, and -SPK-, demonstrated higher expression in the IL-6 group than in the Lob group. The western blot analysis results verified the higher expression of p-FLNC, AKT1, and p-ERK and the lower expression of p-JNK in the IL-6 group than in the Con and Lob groups. The immunohistochemical staining results showed that p-FLNC, AKT1 and p-ERK1/2 were highly expressed in platinum-resistant clinical specimens but weakly expressed in platinum-sensitive specimens, and platinum-resistant osteosarcoma specimens demonstrated weak expression of p-JNK. Conclusions This phosphoproteomic study is the first to reveal the signature associated with rhIL-6 intervention before lobaplatin treatment in human osteosarcoma cells. p-FLNC, AKT1, and MAPK signaling contributes to resistance to lobaplatin in osteosarcoma SaOS-2 cells and may represent molecular targets to overcome osteosarcoma chemoresistance.