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LIM1 contributes to the malignant potential of endometrial cancer

INTRODUCTION: The incidence of endometrial cancer (EC) has been increasing worldwide. However, because there are limited chemotherapeutic options for the treatment of EC, the prognosis of advanced-stage EC is poor. METHODS: Gene expression profile datasets for EC cases registered in The Cancer Genom...

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Autores principales: Kato, Hiroaki, Saeki, Noritaka, Imai, Matome, Onji, Hiroshi, Yano, Akiko, Yoshida, Shuhei, Sakaue, Tomohisa, Fujioka, Toru, Sugiyama, Takashi, Imai, Yuuki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10036843/
https://www.ncbi.nlm.nih.gov/pubmed/36969081
http://dx.doi.org/10.3389/fonc.2023.1082441
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author Kato, Hiroaki
Saeki, Noritaka
Imai, Matome
Onji, Hiroshi
Yano, Akiko
Yoshida, Shuhei
Sakaue, Tomohisa
Fujioka, Toru
Sugiyama, Takashi
Imai, Yuuki
author_facet Kato, Hiroaki
Saeki, Noritaka
Imai, Matome
Onji, Hiroshi
Yano, Akiko
Yoshida, Shuhei
Sakaue, Tomohisa
Fujioka, Toru
Sugiyama, Takashi
Imai, Yuuki
author_sort Kato, Hiroaki
collection PubMed
description INTRODUCTION: The incidence of endometrial cancer (EC) has been increasing worldwide. However, because there are limited chemotherapeutic options for the treatment of EC, the prognosis of advanced-stage EC is poor. METHODS: Gene expression profile datasets for EC cases registered in The Cancer Genome Atlas (TCGA) was reanalyzed. Highly expressed genes in advanced-stage EC (110 cases) compared with early-stage EC (255 cases) were extracted and Gene Ontology (GO) enrichment analysis was performed. Among the enriched genes, Kaplan-Meier (KM) plotter analysis was performed. Candidate genes expression was analyzed in HEC50B cells and Ishikawa cells by RT-qPCR. In HEC50B cells, LIM homeobox1 (LIM1) was knocked down (KD) and cell proliferation, migration, and invasion ability of the cells were evaluated. Xenografts were generated using LIM1-KD cells and tumor growth was evaluated. Ingenuity Pathway Analysis (IPA) of RNA-seq data using LIM-KD cells was performed. Expression of phospho-CREB and CREB-related proteins were evaluated in LIM1-KD cells by western blotting and in xenograft tissue by immunofluorescent staining. Two different CREB inhibitors were treated in HEC50B and cell proliferation was evaluated by MTT assay. RESULTS: Reanalysis of TCGA followed by GO enrichment analysis revealed that homeobox genes were highly expressed in advanced-stage EC. Among the identified genes, KM plotter analysis showed that high LIM1 expression was associated with a significantly poorer prognosis in EC. Additionally, LIM1 expression was significantly higher in high-grade EC cell lines, HEC50B cells than Ishikawa cells. Knockdown of LIM1 showed reduced cell proliferation, migration and invasion in HEC50B cells. Xenograft experiments revealed that tumor growth was significantly suppressed in LIM1-KD cells. IPA of RNA-seq data using LIM-KD cells predicted that the mRNA expression of CREB signaling-related genes was suppressed. Indeed, phosphorylation of CREB was decreased in LIM1-KD cells and LIM1-KD cells derived tumors. HEC50B cells treated by CREB inhibitors showed suppression of cell proliferation. CONCLUSION AND DISCUSSION: Collectively, these results suggested that high LIM1 expression contributed to tumor growth via CREB signaling in EC. Inhibition of LIM1 or its downstream molecules would be new therapeutic strategies for EC.
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spelling pubmed-100368432023-03-25 LIM1 contributes to the malignant potential of endometrial cancer Kato, Hiroaki Saeki, Noritaka Imai, Matome Onji, Hiroshi Yano, Akiko Yoshida, Shuhei Sakaue, Tomohisa Fujioka, Toru Sugiyama, Takashi Imai, Yuuki Front Oncol Oncology INTRODUCTION: The incidence of endometrial cancer (EC) has been increasing worldwide. However, because there are limited chemotherapeutic options for the treatment of EC, the prognosis of advanced-stage EC is poor. METHODS: Gene expression profile datasets for EC cases registered in The Cancer Genome Atlas (TCGA) was reanalyzed. Highly expressed genes in advanced-stage EC (110 cases) compared with early-stage EC (255 cases) were extracted and Gene Ontology (GO) enrichment analysis was performed. Among the enriched genes, Kaplan-Meier (KM) plotter analysis was performed. Candidate genes expression was analyzed in HEC50B cells and Ishikawa cells by RT-qPCR. In HEC50B cells, LIM homeobox1 (LIM1) was knocked down (KD) and cell proliferation, migration, and invasion ability of the cells were evaluated. Xenografts were generated using LIM1-KD cells and tumor growth was evaluated. Ingenuity Pathway Analysis (IPA) of RNA-seq data using LIM-KD cells was performed. Expression of phospho-CREB and CREB-related proteins were evaluated in LIM1-KD cells by western blotting and in xenograft tissue by immunofluorescent staining. Two different CREB inhibitors were treated in HEC50B and cell proliferation was evaluated by MTT assay. RESULTS: Reanalysis of TCGA followed by GO enrichment analysis revealed that homeobox genes were highly expressed in advanced-stage EC. Among the identified genes, KM plotter analysis showed that high LIM1 expression was associated with a significantly poorer prognosis in EC. Additionally, LIM1 expression was significantly higher in high-grade EC cell lines, HEC50B cells than Ishikawa cells. Knockdown of LIM1 showed reduced cell proliferation, migration and invasion in HEC50B cells. Xenograft experiments revealed that tumor growth was significantly suppressed in LIM1-KD cells. IPA of RNA-seq data using LIM-KD cells predicted that the mRNA expression of CREB signaling-related genes was suppressed. Indeed, phosphorylation of CREB was decreased in LIM1-KD cells and LIM1-KD cells derived tumors. HEC50B cells treated by CREB inhibitors showed suppression of cell proliferation. CONCLUSION AND DISCUSSION: Collectively, these results suggested that high LIM1 expression contributed to tumor growth via CREB signaling in EC. Inhibition of LIM1 or its downstream molecules would be new therapeutic strategies for EC. Frontiers Media S.A. 2023-03-10 /pmc/articles/PMC10036843/ /pubmed/36969081 http://dx.doi.org/10.3389/fonc.2023.1082441 Text en Copyright © 2023 Kato, Saeki, Imai, Onji, Yano, Yoshida, Sakaue, Fujioka, Sugiyama and Imai https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Kato, Hiroaki
Saeki, Noritaka
Imai, Matome
Onji, Hiroshi
Yano, Akiko
Yoshida, Shuhei
Sakaue, Tomohisa
Fujioka, Toru
Sugiyama, Takashi
Imai, Yuuki
LIM1 contributes to the malignant potential of endometrial cancer
title LIM1 contributes to the malignant potential of endometrial cancer
title_full LIM1 contributes to the malignant potential of endometrial cancer
title_fullStr LIM1 contributes to the malignant potential of endometrial cancer
title_full_unstemmed LIM1 contributes to the malignant potential of endometrial cancer
title_short LIM1 contributes to the malignant potential of endometrial cancer
title_sort lim1 contributes to the malignant potential of endometrial cancer
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10036843/
https://www.ncbi.nlm.nih.gov/pubmed/36969081
http://dx.doi.org/10.3389/fonc.2023.1082441
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