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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ASJC Scopus subject areas

  • Gastroenterology

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Kang, M. J., Ryu, B. K., Lee, M. G., Han, J., Lee, J. H., Ha, T. K., Byun, D. S., Chae, K. S., Lee, B. H., Chun, H. S., Lee, K. Y., Kim, H. J., & Chi, S-G. (2008). NF-κB Activates Transcription of the RNA-Binding Factor HuR, via PI3K-AKT Signaling, to Promote Gastric Tumorigenesis. Gastroenterology, 135(6). https://doi.org/10.1053/j.gastro.2008.08.009