Relationship between interleukin‐6 and proliferation and differentiation in cholangiocarcinoma

Sugawara, Hiroshi; Yasoshima, Mitsue; Kawakami, Kazuyoshi; Kono, Naoko; Watanabe, Yoh; Harada, Kenichi; Nakanuma, Yasuni

doi:10.1046/j.1365-2559.1998.00445.x

Cited by 90 publications

(83 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nevertheless, constitutive activation of IL-6/gp130 and HGF/met autocrine growth control circuits in vitro are likely relevant to cholangiocarcinogenesis in vivo given that evidence of both IL-6 and HGF production were detected after inoculation of the cell line into scid mice. In addition, as alluded to earlier, there is evidence of IL-6 production 17,25 and met overexpression in the majority of patients with cholangiocarcinoma. 26 In conclusion, this study has further defined nonneoplastic BEC growth control mechanisms and highlighted some differences between BECs and CCs that might be associated with neoplastic transformation.…”

Section: Discussionmentioning

confidence: 56%

Growth control of human biliary epithelial cells by interleukin 6, hepatocyte growth factor, transforming growth factor β1, and activin a: Comparison of a cholangiocarcinoma cell line with primary cultures of non-neoplastic biliary epithelial cells

et al. 2000

View full text Add to dashboard Cite

A well characterized human cholangiocarcinoma (CC) cell line, SG231, was compared with primary cultures of normal human biliary epithelial cells (BECs) for alterations in interleukin 6 (IL-6) and hepatocyte growth factor (HGF)-mediated stimulation and transforming growth factor ␤1 (TGF-␤1) and activin A-mediated inhibition of growth. Results were compared with immunolabeling of the original tumor and after injection of SG231 into the liver of BALB/cByJ-scid mice. In vitro, both BECs and CCs expressed met, gp80, and gp130 messenger RNA (mRNA) and protein, but the levels of expression were higher in the CCs than in the BECs. In both the CCs and BECs, exogenous HGF or IL-6 induced phosphorylation of met or gp130, respectively, and a concentration-dependent increase in DNA synthesis. However, the CCs but not BECs, continued to grow in basal serum-free medium (SFM) and spontaneously produced both IL-6 and HGF under these conditions, which resulted in auto-phosphorylation of gp130 and met, respectively; and neutralizing anti-HGF or anti-IL-6 alone inhibited CC growth, indicative of autocrine growth control circuits. Conversely, activin A inhibits the growth of both BECs and CCs, but does not significantly increase apoptosis. Activin-A-induced growth inhibition of both CCs and BECs can be reversed by 100 ng/mL exogenous IL-6, but not by 10 to 100 ng/mL HGF. TGF-␤1 inhibited the growth of BECs but had no mitoinhibitory or proapoptotic effects on CCs. Immunolabeling of the original tumor and after inoculation into scid mice showed positive staining for met, gp130, gp80, and IL-6. This study contributes to a further understanding of BEC growth control and derangements that can occur during cholangiocarcinogenesis. (HEPATOL-OGY 2000;32:26-35.)

show abstract

Section: Discussionmentioning

confidence: 56%

Growth control of human biliary epithelial cells by interleukin 6, hepatocyte growth factor, transforming growth factor β1, and activin a: Comparison of a cholangiocarcinoma cell line with primary cultures of non-neoplastic biliary epithelial cells

et al. 2000

View full text Add to dashboard Cite

show abstract

“…27 Thus, information regarding the regulation of Mcl-1 expression by these cells is germane to cancer therapy for this neoplasm. Because of the importance of IL-6 in the biology of cholangiocarcinoma, [6][7][8][9] there is good reason to explore the potential regulation of Mcl-1 by IL-6. In a prior study, we demonstrated that IL-6 via an Akt pathway prolongs the half-life of Mcl-1 protein, The cells were also transfected with a mutant construct in which residues Ϫ92 and Ϫ91 were changed from TT to CC and prepared cell lysates were subjected to the reporter gene assay.…”

Section: Discussionmentioning

confidence: 99%

“…The inflammatory mediator interleukin-6 (IL-6) has been implicated in the biology of cholangiocarcinoma [6][7][8][9] and is capable of serving both as a mitogen and a survival factor for cholangiocytes and cholangiocarcinoma cells. [7][8][9] IL-6 can inhibit cell death programs in a variety of tumor cell types, in part, by upregulating the potent antiapoptotic Bcl-2 family member myeloid cell leukemia-1 (Mcl-1).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Interleukin 6 upregulates myeloid cell leukemia‐1 expression through a STAT3 pathway in cholangiocarcinoma cells†

et al. 2005

View full text Add to dashboard Cite

“…Neoplastic human biliary epithelial cells can acquire the ability to produce HGF and IL-6 constitutively, and these growth factors can stimulate mitogenesis in an autocrine and paracrine fash-ion. 1,[4][5][6][7] Accordingly, patients with cholangiocarcinoma show increased serum levels of IL-6 production, 8,9 and Met is overexpressed on the tumor cells. 10 In animal models of cholangiocarcinoma, HGF and IL-6 are detected after inoculation of the cholangiocarcinoma cell line into SCID mice and in furan-induced rat cholangiocarcinomas.…”

mentioning

confidence: 99%

Involvement of 85-kd cytosolic phospholipase A2 and cyclooxygenase-2 in the proliferation of human cholangiocarcinoma cells

Wu¹,

Han²,

Lunz³

et al. 2002

Hepatology

View full text Add to dashboard Cite

Cyclooxygenase 2 (COX-2) and cytosolic phospholipase A 2 (cPLA 2 ) are the crucial ratelimiting enzymes in prostaglandin (PG) metabolism that show increased expression in a number of human cancers, including cholangiocarcinomas; and treatment of cholangiocarcinoma cell lines with COX-2 inhibitors can decrease proliferation. Cholangiocarcinomas also produce and proliferate in response to nonneoplastic biliary epithelial cell mitogens, such as interleukin 6 (IL-6) and hepatocyte growth factor (HGF). This study was designed to determine whether there is any relationship between eicosanoid metabolism and growth stimulation by IL-6 and HGF, two important biliary epithelial cell and cholangiocarcinoma mitogens. Incubation of SG231, a well-characterized human cholangiocarcinoma cell line, with HGF, IL-6, PGE 2 , or PGF 2 ␣ resulted in significantly increased cell growth. HGF and IL-6 also induced a rapid release of arachidonic acid (AA) from SG231 and increased the synthesis of PGE 2 and PGF 2 ␣. The cPLA 2 inhibitor arachidonyl fluorophosphonate (MAFP) and the COX-2 inhibitor NS-398 significantly inhibited HGF-and IL-6-induced release of AA, PG synthesis, and proliferation in SG231 cells as well as two other human cholangiocarcinoma cell lines, HuCCT1 and CC-LP-1 cells. Thus, PGs alone can induce cholangiocarcinoma growth, and the HGF-and IL-6-induced proliferation is mediated, at least in part, by PGs. HGF and IL-6 also induced a rapid phosphorylation of cPLA 2 (within 1 minute) but did not alter cPLA 2 and COX-2 protein expression. The HGF-and IL-6-induced cPLA 2 phosphorylation was blocked by the inhibitors of p38 and p42/44 MAP kinases, protein kinase C, calmodulin kinase, and tyrosine kinase, showing that HGF-and IL-6-induced AA release and PG production are mediated by phosphorylation of cPLA 2 . In conclusion, molecular pathways link classic biliary epithelial cell mitogens to PG metabolism constituents in cholangiocarcinoma growth, which may be exploited as potential therapeutic targets.

show abstract

Relationship between interleukin‐6 and proliferation and differentiation in cholangiocarcinoma

Abstract: IL-6 expression is inversely related to cell proliferation and positively related to differentiation in cholangiocarcinoma.

Cited by 90 publications

References 19 publications

Growth control of human biliary epithelial cells by interleukin 6, hepatocyte growth factor, transforming growth factor β1, and activin a: Comparison of a cholangiocarcinoma cell line with primary cultures of non-neoplastic biliary epithelial cells

Growth control of human biliary epithelial cells by interleukin 6, hepatocyte growth factor, transforming growth factor β1, and activin a: Comparison of a cholangiocarcinoma cell line with primary cultures of non-neoplastic biliary epithelial cells

Interleukin 6 upregulates myeloid cell leukemia‐1 expression through a STAT3 pathway in cholangiocarcinoma cells†

Involvement of 85-kd cytosolic phospholipase A2 and cyclooxygenase-2 in the proliferation of human cholangiocarcinoma cells

Contact Info

Product

Resources

About