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Higher proliferation of peritumoral endothelial cells to IL-6/sIL-6R than tumoral endothelial cells in hepatocellular carcinoma.

Zhuang PY, Wang JD, Tang ZH, Zhou XP, Quan ZW, Liu YB, Shen J - BMC Cancer (2015)

Bottom Line: Peritumoral IL-6, IL-6R, gp130, CD68, and HIF-1α expression, as well as MVD, gradually increased during tumor growth.The co-culture of IL-6/sIL-6R induced much higher PEC proliferation and gp130 expression, as well as the elevated phosphorylation of JAK2 and STAT3, however not the phosphorylation of PI3K and AKT.PEC and its associated peritumoral angiogenesis microenvironment may be a potential novel target for anti-angiogenic treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, 1665 Kong jiang Street, Shanghai, 200082, China. pyzhuang@gmail.com.

ABSTRACT

Background: This study aimed to explore the responses to the interleukin-6 (IL-6)/soluble interleukin-6 receptor (sIL-6R) complex in peritumoral endothelial cells (PECs) and tumor endothelial cells (TECs), as well as determine the signaling pathways in the angiogenesis of hepatocellular carcinoma (HCC).

Methods: The expression of IL-6, IL-6R, gp130, CD68, HIF-1α, and microvessel density (MVD) were assessed with an orthotopic xenograft model in nude mice. ECs were incubated under hypoxic conditions to detect IL-6 and gp130. The proliferation of PECs and TECs in the presence of IL-6 and sIL-6R, as well as the expression of gp130, JAK2/STAT3, PI3K/AKT in endothelial cells were measured.

Results: Peritumoral IL-6, IL-6R, gp130, CD68, and HIF-1α expression, as well as MVD, gradually increased during tumor growth. Hypoxia could directly induce IL-6 expression, but not gp130 in PECs. The co-culture of IL-6/sIL-6R induced much higher PEC proliferation and gp130 expression, as well as the elevated phosphorylation of JAK2 and STAT3, however not the phosphorylation of PI3K and AKT.

Conclusions: PECs exhibited higher proliferation in response to IL-6/sIL-6R co-treatment compared with TECs in HCC via the up-regulation of gp130 /JAK2/STAT3. PEC and its associated peritumoral angiogenesis microenvironment may be a potential novel target for anti-angiogenic treatment.

No MeSH data available.


Related in: MedlinePlus

a–d Hypoxia induced IL-6 expression in PECs. Hypoxia could significantly and directly up-regulate the expression of IL-6 after 48 h in PECs, as indicated by immunocytochemistry (a), IHC (b), and RT-PCR (c). However, hypoxia had no direct effects on gp130 expression in PECs, as indicated by immunocytochemistry (a) and RT-PCR (c). Bar, 50 μm
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Fig2: a–d Hypoxia induced IL-6 expression in PECs. Hypoxia could significantly and directly up-regulate the expression of IL-6 after 48 h in PECs, as indicated by immunocytochemistry (a), IHC (b), and RT-PCR (c). However, hypoxia had no direct effects on gp130 expression in PECs, as indicated by immunocytochemistry (a) and RT-PCR (c). Bar, 50 μm

Mentions: To further elucidate the peritumoral microenvironment during the up-regulation of IL-6, we stained peritumoral tissues with the hypoxia indicator HIF-1α. The peritumoral expression of IL-6 gradually increased during tumor growth (Fig. 1a, c). Peritumoral HIF-1α were in accordance with the peritumoral IL-6 expression (rr = 0.721, P = 0.004). To determine whether hypoxia can directly up-regulate the expression of IL-6 in PECs, we treated PECs to hypoxic or normoxic conditions for 24 and 48 h. The results demonstrated that IL-6 was significantly up-regulated in PECs under hypoxic conditions for 48 h, which was confirmed by immunocytochemistry (Fig. 2a), IHC (Fig. 2b), and RT-PCR (mean − △CT, −0.01 ± 0.003 vs. –0.17 ± 0.052 for hypoxic and normoxic conditions, P = 0.014, Fig. 2c). However, we found that hypoxia had no direct effect on PEC proliferation in vitro for 24 and 48 h (1.17 ± 0.01 vs. 1.16 ± 0.01, P = 0.714 and 2.23 ± 0.01 vs. 2.25 ± 0.02, P = 0.628 under hypoxic and normoxic conditions for 24 and 48 h, respectively; cell proliferation was evaluated by the CCK-8 assay).Fig. 2


Higher proliferation of peritumoral endothelial cells to IL-6/sIL-6R than tumoral endothelial cells in hepatocellular carcinoma.

Zhuang PY, Wang JD, Tang ZH, Zhou XP, Quan ZW, Liu YB, Shen J - BMC Cancer (2015)

a–d Hypoxia induced IL-6 expression in PECs. Hypoxia could significantly and directly up-regulate the expression of IL-6 after 48 h in PECs, as indicated by immunocytochemistry (a), IHC (b), and RT-PCR (c). However, hypoxia had no direct effects on gp130 expression in PECs, as indicated by immunocytochemistry (a) and RT-PCR (c). Bar, 50 μm
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4629315&req=5

Fig2: a–d Hypoxia induced IL-6 expression in PECs. Hypoxia could significantly and directly up-regulate the expression of IL-6 after 48 h in PECs, as indicated by immunocytochemistry (a), IHC (b), and RT-PCR (c). However, hypoxia had no direct effects on gp130 expression in PECs, as indicated by immunocytochemistry (a) and RT-PCR (c). Bar, 50 μm
Mentions: To further elucidate the peritumoral microenvironment during the up-regulation of IL-6, we stained peritumoral tissues with the hypoxia indicator HIF-1α. The peritumoral expression of IL-6 gradually increased during tumor growth (Fig. 1a, c). Peritumoral HIF-1α were in accordance with the peritumoral IL-6 expression (rr = 0.721, P = 0.004). To determine whether hypoxia can directly up-regulate the expression of IL-6 in PECs, we treated PECs to hypoxic or normoxic conditions for 24 and 48 h. The results demonstrated that IL-6 was significantly up-regulated in PECs under hypoxic conditions for 48 h, which was confirmed by immunocytochemistry (Fig. 2a), IHC (Fig. 2b), and RT-PCR (mean − △CT, −0.01 ± 0.003 vs. –0.17 ± 0.052 for hypoxic and normoxic conditions, P = 0.014, Fig. 2c). However, we found that hypoxia had no direct effect on PEC proliferation in vitro for 24 and 48 h (1.17 ± 0.01 vs. 1.16 ± 0.01, P = 0.714 and 2.23 ± 0.01 vs. 2.25 ± 0.02, P = 0.628 under hypoxic and normoxic conditions for 24 and 48 h, respectively; cell proliferation was evaluated by the CCK-8 assay).Fig. 2

Bottom Line: Peritumoral IL-6, IL-6R, gp130, CD68, and HIF-1α expression, as well as MVD, gradually increased during tumor growth.The co-culture of IL-6/sIL-6R induced much higher PEC proliferation and gp130 expression, as well as the elevated phosphorylation of JAK2 and STAT3, however not the phosphorylation of PI3K and AKT.PEC and its associated peritumoral angiogenesis microenvironment may be a potential novel target for anti-angiogenic treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, 1665 Kong jiang Street, Shanghai, 200082, China. pyzhuang@gmail.com.

ABSTRACT

Background: This study aimed to explore the responses to the interleukin-6 (IL-6)/soluble interleukin-6 receptor (sIL-6R) complex in peritumoral endothelial cells (PECs) and tumor endothelial cells (TECs), as well as determine the signaling pathways in the angiogenesis of hepatocellular carcinoma (HCC).

Methods: The expression of IL-6, IL-6R, gp130, CD68, HIF-1α, and microvessel density (MVD) were assessed with an orthotopic xenograft model in nude mice. ECs were incubated under hypoxic conditions to detect IL-6 and gp130. The proliferation of PECs and TECs in the presence of IL-6 and sIL-6R, as well as the expression of gp130, JAK2/STAT3, PI3K/AKT in endothelial cells were measured.

Results: Peritumoral IL-6, IL-6R, gp130, CD68, and HIF-1α expression, as well as MVD, gradually increased during tumor growth. Hypoxia could directly induce IL-6 expression, but not gp130 in PECs. The co-culture of IL-6/sIL-6R induced much higher PEC proliferation and gp130 expression, as well as the elevated phosphorylation of JAK2 and STAT3, however not the phosphorylation of PI3K and AKT.

Conclusions: PECs exhibited higher proliferation in response to IL-6/sIL-6R co-treatment compared with TECs in HCC via the up-regulation of gp130 /JAK2/STAT3. PEC and its associated peritumoral angiogenesis microenvironment may be a potential novel target for anti-angiogenic treatment.

No MeSH data available.


Related in: MedlinePlus