Significance of Autologous Interleukin-6 Production in the HA22T/VGH Cell Model of Hepatocellular Carcinoma

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Abstract

Cancer cells may often support their own growth, survival,and drug resistance by autocrine/paracrine loops based on the production of different factors; results from us and others have shown that similar interleukin-6 (IL-6)-related loops are operative in multiple myelomaand prostate or renal cancer. Because this aspect has not been investigated in detail for hepatocellular carcinoma (HCC), we have examined it in HA22T/VGH cells. These differ from other primary livercancer cell lines (that is, HepG2, HuH-6, and HuH-7) in that enzymelinked immunosorbent assay (ELISA) showed the HA22T/VGH cells tosecrete remarkable amounts of IL-6 (16.8 ng /106 cells/24 h); this production, due to constitutive activation of NF-B, is inhibited by agentslike curcumin and dehydroxymethylepoxyquinomicin (DHMEQ), whichinterfere with the transcription factor. Flow cytometry, ELISA, mRNA,and Western blotting analyses were performed to characterize the status of the IL-6 receptor in HA22T/VGH cells. Two transmembraneglycoproteins that form the functional IL-6 receptor have beenidentified: the ligand-binding gp80 and the signal-transducer gp130. Soluble forms of gp80 also trigger membrane gp130 signaling when complexed with IL-6, while soluble forms of gp130 inhibit the same process. Our results showed that HA22T/VGH cells express gp130 at theirsurface, but release only traces of its soluble form. For gp80, the cellsproduced the mRNAs of both its membrane and soluble form. However, in immunoblotting they exhibited a very faint content of the samesubunit, which, in addition, was neither expressed at the cell surfacenor secreted. In MTT assays, incubation with a neutralizing anti-IL-6 antibody for up to 7 days did not affect the growth of HA22T/VGH cells.Also, other specific anti-IL-6 approaches (siRNA or AODN) failed to produce this result. In conclusion, autostimulatory loops mediated by IL-6are less likely to occur in HCC than in other kinds of cancer. However,since release of IL-6 is frequent in HCC, especially in its more advancedstages, the use of agents like curcumin or DHMEQ might be beneficialto counteract its adverse systemic effects (e.g., cachexia).
Lingua originaleEnglish
Numero di pagine8
RivistaAnnals of the New York Academy of Sciences
Stato di pubblicazionePublished - 2006

All Science Journal Classification (ASJC) codes

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  • ???subjectarea.asjc.1300.1300???
  • ???subjectarea.asjc.1200.1207???

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