Next-Generation Sequencing Analysis of Gastric Cancer Identifies the Leukemia Inhibitory Factor Receptor as a Driving Factor in Gastric Cancer Progression and as a Predictor of Poor Prognosis
Gastric cancer (GC) is the third cause of cancer-related mortality worldwide. Nevertheless, because GC screening programs are not cost-effective, most patients receive diagnosis in the advanced stages, when surgical options are limited. Peritoneal dissemination occurs in approximately one-third of p...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-06-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.939969/full |
| _version_ | 1828807903631376384 |
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| author | Cristina Di Giorgio Silvia Marchianò Elisabetta Marino Michele Biagioli Rosalinda Roselli Martina Bordoni Rachele Bellini Ginevra Urbani Angela Zampella Eleonora Distrutti Annibale Donini Luigina Graziosi Stefano Fiorucci |
| author_facet | Cristina Di Giorgio Silvia Marchianò Elisabetta Marino Michele Biagioli Rosalinda Roselli Martina Bordoni Rachele Bellini Ginevra Urbani Angela Zampella Eleonora Distrutti Annibale Donini Luigina Graziosi Stefano Fiorucci |
| author_sort | Cristina Di Giorgio |
| collection | DOAJ |
| description | Gastric cancer (GC) is the third cause of cancer-related mortality worldwide. Nevertheless, because GC screening programs are not cost-effective, most patients receive diagnosis in the advanced stages, when surgical options are limited. Peritoneal dissemination occurs in approximately one-third of patients with GC at the diagnosis and is a strong predictor of poor outcome. Despite the clinical relevance, biological and molecular mechanisms underlying the development of peritoneal metastasis in GC remain poorly defined. Here, we report results of a high-throughput sequencing of transcriptome expression in paired samples of non-neoplastic and neoplastic gastric samples from 31 patients with GC with or without peritoneal carcinomatosis. The RNA-seq analysis led to the discovery of a group of highly upregulated or downregulated genes, including the leukemia inhibitory factor receptor (LIFR) and one cut domain family member 2 (ONECUT2) that were differentially modulated in patients with peritoneal disease in comparison with patients without peritoneal involvement. Both LIFR and ONECUT2 predicted survival at univariate statistical analysis. LIFR and its major ligand LIF belong to the interleukin-6 (IL-6) cytokine family and have a central role in immune system regulation, carcinogenesis, and dissemination in several human cancers. To confirm the mechanistic role of the LIF/LIFR pathway in promoting GC progression, GC cell lines were challenged in vitro with LIF and a LIFR inhibitor. Among several GC cell lines, MKN45 cells displayed the higher expression of the receptor, and their exposure to LIF promotes a concentration-dependent proliferation and epithelial–mesenchymal transition (EMT), as shown by modulation of relative expression of E-cadherin/vimentin along with JAK and STAT3 phosphorylation and acquisition of a migratory phenotype. Furthermore, exposure to LIF promoted the adhesion of MKN45 cells to the peritoneum in an ex vivo assay. These effects were reversed by the pharmacological blockade of LIFR signaling. Together, these data suggest that LIFR might have a major role in promoting disease progression and peritoneal dissemination in patients with GC and that development of LIF/LIFR inhibitors might have a role in the treatment of GC. |
| first_indexed | 2024-12-12T08:32:44Z |
| format | Article |
| id | doaj.art-e1a292506417492fa1c83108bae4988b |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-12T08:32:44Z |
| publishDate | 2022-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-e1a292506417492fa1c83108bae4988b2022-12-22T00:31:04ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-06-011210.3389/fonc.2022.939969939969Next-Generation Sequencing Analysis of Gastric Cancer Identifies the Leukemia Inhibitory Factor Receptor as a Driving Factor in Gastric Cancer Progression and as a Predictor of Poor PrognosisCristina Di Giorgio0Silvia Marchianò1Elisabetta Marino2Michele Biagioli3Rosalinda Roselli4Martina Bordoni5Rachele Bellini6Ginevra Urbani7Angela Zampella8Eleonora Distrutti9Annibale Donini10Luigina Graziosi11Stefano Fiorucci12Department of Medicine and Surgery, University of Perugia, Perugia, ItalyDepartment of Medicine and Surgery, University of Perugia, Perugia, ItalyAzienda Ospedaliera Santa Maria della Misericordia, Perugia, ItalyDepartment of Medicine and Surgery, University of Perugia, Perugia, ItalyDepartment of Pharmacy, University of Naples Federico II, Naples, ItalyDepartment of Medicine and Surgery, University of Perugia, Perugia, ItalyDepartment of Medicine and Surgery, University of Perugia, Perugia, ItalyDepartment of Medicine and Surgery, University of Perugia, Perugia, ItalyDepartment of Pharmacy, University of Naples Federico II, Naples, ItalyAzienda Ospedaliera Santa Maria della Misericordia, Perugia, ItalyDepartment of Medicine and Surgery, University of Perugia, Perugia, ItalyAzienda Ospedaliera Santa Maria della Misericordia, Perugia, ItalyDepartment of Medicine and Surgery, University of Perugia, Perugia, ItalyGastric cancer (GC) is the third cause of cancer-related mortality worldwide. Nevertheless, because GC screening programs are not cost-effective, most patients receive diagnosis in the advanced stages, when surgical options are limited. Peritoneal dissemination occurs in approximately one-third of patients with GC at the diagnosis and is a strong predictor of poor outcome. Despite the clinical relevance, biological and molecular mechanisms underlying the development of peritoneal metastasis in GC remain poorly defined. Here, we report results of a high-throughput sequencing of transcriptome expression in paired samples of non-neoplastic and neoplastic gastric samples from 31 patients with GC with or without peritoneal carcinomatosis. The RNA-seq analysis led to the discovery of a group of highly upregulated or downregulated genes, including the leukemia inhibitory factor receptor (LIFR) and one cut domain family member 2 (ONECUT2) that were differentially modulated in patients with peritoneal disease in comparison with patients without peritoneal involvement. Both LIFR and ONECUT2 predicted survival at univariate statistical analysis. LIFR and its major ligand LIF belong to the interleukin-6 (IL-6) cytokine family and have a central role in immune system regulation, carcinogenesis, and dissemination in several human cancers. To confirm the mechanistic role of the LIF/LIFR pathway in promoting GC progression, GC cell lines were challenged in vitro with LIF and a LIFR inhibitor. Among several GC cell lines, MKN45 cells displayed the higher expression of the receptor, and their exposure to LIF promotes a concentration-dependent proliferation and epithelial–mesenchymal transition (EMT), as shown by modulation of relative expression of E-cadherin/vimentin along with JAK and STAT3 phosphorylation and acquisition of a migratory phenotype. Furthermore, exposure to LIF promoted the adhesion of MKN45 cells to the peritoneum in an ex vivo assay. These effects were reversed by the pharmacological blockade of LIFR signaling. Together, these data suggest that LIFR might have a major role in promoting disease progression and peritoneal dissemination in patients with GC and that development of LIF/LIFR inhibitors might have a role in the treatment of GC.https://www.frontiersin.org/articles/10.3389/fonc.2022.939969/fullgastric cancer (GC)metastasesperitoneal carcinomatosis (PC)trascriptome analysisbiomarkerLIF/LIFR axis |
| spellingShingle | Cristina Di Giorgio Silvia Marchianò Elisabetta Marino Michele Biagioli Rosalinda Roselli Martina Bordoni Rachele Bellini Ginevra Urbani Angela Zampella Eleonora Distrutti Annibale Donini Luigina Graziosi Stefano Fiorucci Next-Generation Sequencing Analysis of Gastric Cancer Identifies the Leukemia Inhibitory Factor Receptor as a Driving Factor in Gastric Cancer Progression and as a Predictor of Poor Prognosis Frontiers in Oncology gastric cancer (GC) metastases peritoneal carcinomatosis (PC) trascriptome analysis biomarker LIF/LIFR axis |
| title | Next-Generation Sequencing Analysis of Gastric Cancer Identifies the Leukemia Inhibitory Factor Receptor as a Driving Factor in Gastric Cancer Progression and as a Predictor of Poor Prognosis |
| title_full | Next-Generation Sequencing Analysis of Gastric Cancer Identifies the Leukemia Inhibitory Factor Receptor as a Driving Factor in Gastric Cancer Progression and as a Predictor of Poor Prognosis |
| title_fullStr | Next-Generation Sequencing Analysis of Gastric Cancer Identifies the Leukemia Inhibitory Factor Receptor as a Driving Factor in Gastric Cancer Progression and as a Predictor of Poor Prognosis |
| title_full_unstemmed | Next-Generation Sequencing Analysis of Gastric Cancer Identifies the Leukemia Inhibitory Factor Receptor as a Driving Factor in Gastric Cancer Progression and as a Predictor of Poor Prognosis |
| title_short | Next-Generation Sequencing Analysis of Gastric Cancer Identifies the Leukemia Inhibitory Factor Receptor as a Driving Factor in Gastric Cancer Progression and as a Predictor of Poor Prognosis |
| title_sort | next generation sequencing analysis of gastric cancer identifies the leukemia inhibitory factor receptor as a driving factor in gastric cancer progression and as a predictor of poor prognosis |
| topic | gastric cancer (GC) metastases peritoneal carcinomatosis (PC) trascriptome analysis biomarker LIF/LIFR axis |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.939969/full |
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