NF-κB Activates Transcription of the RNA-Binding Factor HuR, via PI3K-AKT Signaling, to Promote Gastric Tumorigenesis

Min Ju Kang, Byung Kyu Ryu, Min Goo Lee, Jikhyon Han, Jin Hee Lee, Tae Kyu Ha, Do Sun Byun, Kwon Seok Chae, Bong Hee Lee, Hyang Sook Chun, Kil Yeon Lee, Hyo Jong Kim, Sung-Gil Chi

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Abstract

Background & Aims: HuR is a RNA-binding factor whose expression is commonly upregulated in some human tumor types. We explored the molecular mechanism underlying HuR elevation and its role in gastric cancer tumorigenesis. Methods: HuR expression and subcellular localization were determined by polymerase chain reaction, immunoblot, and immunohistochemical analyses. Its effect on tumor growth was characterized using flow cytometry, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling, and soft agar analyses. Luciferase reporter, chromatin immunoprecipitation, and electrophoretic mobility shift assays were used to measure transcriptional activation by nuclear factor κB (NF-κB) signaling. Results: Compared with normal gastric tissues, HuR was expressed at higher levels in gastric tumors, particularly in advanced versus early tumors; this increase was associated with enhanced cytoplasmic translocation of HuR. HuR overexpression increased proliferation of tumor cells, activating the G1 to S transition of the cell cycle, DNA synthesis, and anchorage-independent growth. Small interfering RNA-mediated knockdown of HuR expression reduced tumor cell proliferation and response to apoptotic stimuli. No genetic or epigenetic alterations of HuR were observed in gastric tumor cell lines or primary tumors; overexpression depended on phosphatidylinositol 3-kinase/AKT signaling and NF-κB activity. AKT activation increased p65/RelA binding to a putative NF-κB binding site in the HuR promoter, the stability of HuR target transcripts, and the cytoplasmic import of HuR. Conclusions: HuR is a direct transcription target of NF-κB; its activation in gastric cancer cell lines depends on phosphatidylinositol 3-kinase/AKT signaling. HuR activation by this pathway has proliferative and antiapoptotic effects on gastric cancer cells.

Original languageEnglish
JournalGastroenterology
Volume135
Issue number6
DOIs
Publication statusPublished - 2008 Dec 1

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Phosphatidylinositol 3-Kinases
Stomach
Carcinogenesis
RNA
Neoplasms
Phosphatidylinositol 3-Kinase
Stomach Neoplasms
Cell Proliferation
DNA Nucleotidylexotransferase
Chromatin Immunoprecipitation
Electrophoretic Mobility Shift Assay
Growth
Tumor Cell Line
Luciferases
Epigenomics
Small Interfering RNA
Transcriptional Activation
Agar
Cell Cycle
Flow Cytometry

ASJC Scopus subject areas

  • Gastroenterology

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NF-κB Activates Transcription of the RNA-Binding Factor HuR, via PI3K-AKT Signaling, to Promote Gastric Tumorigenesis. / Kang, Min Ju; Ryu, Byung Kyu; Lee, Min Goo; Han, Jikhyon; Lee, Jin Hee; Ha, Tae Kyu; Byun, Do Sun; Chae, Kwon Seok; Lee, Bong Hee; Chun, Hyang Sook; Lee, Kil Yeon; Kim, Hyo Jong; Chi, Sung-Gil.

In: Gastroenterology, Vol. 135, No. 6, 01.12.2008.

Research output: Contribution to journalArticle

Kang, MJ, Ryu, BK, Lee, MG, Han, J, Lee, JH, Ha, TK, Byun, DS, Chae, KS, Lee, BH, Chun, HS, Lee, KY, Kim, HJ & Chi, S-G 2008, 'NF-κB Activates Transcription of the RNA-Binding Factor HuR, via PI3K-AKT Signaling, to Promote Gastric Tumorigenesis', Gastroenterology, vol. 135, no. 6. https://doi.org/10.1053/j.gastro.2008.08.009
Kang, Min Ju ; Ryu, Byung Kyu ; Lee, Min Goo ; Han, Jikhyon ; Lee, Jin Hee ; Ha, Tae Kyu ; Byun, Do Sun ; Chae, Kwon Seok ; Lee, Bong Hee ; Chun, Hyang Sook ; Lee, Kil Yeon ; Kim, Hyo Jong ; Chi, Sung-Gil. / NF-κB Activates Transcription of the RNA-Binding Factor HuR, via PI3K-AKT Signaling, to Promote Gastric Tumorigenesis. In: Gastroenterology. 2008 ; Vol. 135, No. 6.
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abstract = "Background & Aims: HuR is a RNA-binding factor whose expression is commonly upregulated in some human tumor types. We explored the molecular mechanism underlying HuR elevation and its role in gastric cancer tumorigenesis. Methods: HuR expression and subcellular localization were determined by polymerase chain reaction, immunoblot, and immunohistochemical analyses. Its effect on tumor growth was characterized using flow cytometry, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling, and soft agar analyses. Luciferase reporter, chromatin immunoprecipitation, and electrophoretic mobility shift assays were used to measure transcriptional activation by nuclear factor κB (NF-κB) signaling. Results: Compared with normal gastric tissues, HuR was expressed at higher levels in gastric tumors, particularly in advanced versus early tumors; this increase was associated with enhanced cytoplasmic translocation of HuR. HuR overexpression increased proliferation of tumor cells, activating the G1 to S transition of the cell cycle, DNA synthesis, and anchorage-independent growth. Small interfering RNA-mediated knockdown of HuR expression reduced tumor cell proliferation and response to apoptotic stimuli. No genetic or epigenetic alterations of HuR were observed in gastric tumor cell lines or primary tumors; overexpression depended on phosphatidylinositol 3-kinase/AKT signaling and NF-κB activity. AKT activation increased p65/RelA binding to a putative NF-κB binding site in the HuR promoter, the stability of HuR target transcripts, and the cytoplasmic import of HuR. Conclusions: HuR is a direct transcription target of NF-κB; its activation in gastric cancer cell lines depends on phosphatidylinositol 3-kinase/AKT signaling. HuR activation by this pathway has proliferative and antiapoptotic effects on gastric cancer cells.",
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T1 - NF-κB Activates Transcription of the RNA-Binding Factor HuR, via PI3K-AKT Signaling, to Promote Gastric Tumorigenesis

AU - Kang, Min Ju

AU - Ryu, Byung Kyu

AU - Lee, Min Goo

AU - Han, Jikhyon

AU - Lee, Jin Hee

AU - Ha, Tae Kyu

AU - Byun, Do Sun

AU - Chae, Kwon Seok

AU - Lee, Bong Hee

AU - Chun, Hyang Sook

AU - Lee, Kil Yeon

AU - Kim, Hyo Jong

AU - Chi, Sung-Gil

PY - 2008/12/1

Y1 - 2008/12/1

N2 - Background & Aims: HuR is a RNA-binding factor whose expression is commonly upregulated in some human tumor types. We explored the molecular mechanism underlying HuR elevation and its role in gastric cancer tumorigenesis. Methods: HuR expression and subcellular localization were determined by polymerase chain reaction, immunoblot, and immunohistochemical analyses. Its effect on tumor growth was characterized using flow cytometry, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling, and soft agar analyses. Luciferase reporter, chromatin immunoprecipitation, and electrophoretic mobility shift assays were used to measure transcriptional activation by nuclear factor κB (NF-κB) signaling. Results: Compared with normal gastric tissues, HuR was expressed at higher levels in gastric tumors, particularly in advanced versus early tumors; this increase was associated with enhanced cytoplasmic translocation of HuR. HuR overexpression increased proliferation of tumor cells, activating the G1 to S transition of the cell cycle, DNA synthesis, and anchorage-independent growth. Small interfering RNA-mediated knockdown of HuR expression reduced tumor cell proliferation and response to apoptotic stimuli. No genetic or epigenetic alterations of HuR were observed in gastric tumor cell lines or primary tumors; overexpression depended on phosphatidylinositol 3-kinase/AKT signaling and NF-κB activity. AKT activation increased p65/RelA binding to a putative NF-κB binding site in the HuR promoter, the stability of HuR target transcripts, and the cytoplasmic import of HuR. Conclusions: HuR is a direct transcription target of NF-κB; its activation in gastric cancer cell lines depends on phosphatidylinositol 3-kinase/AKT signaling. HuR activation by this pathway has proliferative and antiapoptotic effects on gastric cancer cells.

AB - Background & Aims: HuR is a RNA-binding factor whose expression is commonly upregulated in some human tumor types. We explored the molecular mechanism underlying HuR elevation and its role in gastric cancer tumorigenesis. Methods: HuR expression and subcellular localization were determined by polymerase chain reaction, immunoblot, and immunohistochemical analyses. Its effect on tumor growth was characterized using flow cytometry, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling, and soft agar analyses. Luciferase reporter, chromatin immunoprecipitation, and electrophoretic mobility shift assays were used to measure transcriptional activation by nuclear factor κB (NF-κB) signaling. Results: Compared with normal gastric tissues, HuR was expressed at higher levels in gastric tumors, particularly in advanced versus early tumors; this increase was associated with enhanced cytoplasmic translocation of HuR. HuR overexpression increased proliferation of tumor cells, activating the G1 to S transition of the cell cycle, DNA synthesis, and anchorage-independent growth. Small interfering RNA-mediated knockdown of HuR expression reduced tumor cell proliferation and response to apoptotic stimuli. No genetic or epigenetic alterations of HuR were observed in gastric tumor cell lines or primary tumors; overexpression depended on phosphatidylinositol 3-kinase/AKT signaling and NF-κB activity. AKT activation increased p65/RelA binding to a putative NF-κB binding site in the HuR promoter, the stability of HuR target transcripts, and the cytoplasmic import of HuR. Conclusions: HuR is a direct transcription target of NF-κB; its activation in gastric cancer cell lines depends on phosphatidylinositol 3-kinase/AKT signaling. HuR activation by this pathway has proliferative and antiapoptotic effects on gastric cancer cells.

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U2 - 10.1053/j.gastro.2008.08.009

DO - 10.1053/j.gastro.2008.08.009

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JO - Gastroenterology

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SN - 0016-5085

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