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Reoxygenation from chronic hypoxia promotes metastatic processes in pancreatic cancer through the Hedgehog signaling.

Morifuji Y, Onishi H, Iwasaki H, Imaizumi A, Nakano K, Tanaka M, Katano M - Cancer Sci. (2014)

Bottom Line: A Hedgehog (Hh) signaling component, Gli1, was significantly increased by reoxygenation.Gli1 knockdown inhibited reoxygenation-induced increases in proliferation and tumorigenicity and decreased invasiveness through suppression of matrix metalloproteinase (MMP) 2 and MMP9.These results suggest that metastatic processes in PDAC are induced through activation of the Hh signaling pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

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Reoxygenation enhances tumorigenicity by Gli1 in vivo. (a) Colony number in wild type cells and reoxygenated Ch-H-R cells was evaluated (n = 3). (b) Wild-type cells cultured under normoxia and reoxygenated Ch-H-R cells derived from AsPC-1 were implanted into flank regions of BALB/c nude mice. Tumor volume was evaluated at the indicated day (left panel) (n = 6). Representative images of tumor-bearing mice (right panels). (c) GLI1 expression in tumors from each mouse was determined by immunofluorescence staining (upper panels) (×630). The graph shows relative ratio of GLI1 positive cells in tumors (lower panel). (d) Colony number in Gli1 siRNA transfected-reoxygenated Ch-H-R cells was estimated (n = 3). (e) Control or Gli1 siRNA-transfected-reoxygenated Ch-H-R cells derived from AsPC-1 were implanted into flank regions of BALB/c nude mice. Tumor volume was evaluated on the indicated day (n = 6). The graph shows mean ± SD. *P < 0.05.
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fig05: Reoxygenation enhances tumorigenicity by Gli1 in vivo. (a) Colony number in wild type cells and reoxygenated Ch-H-R cells was evaluated (n = 3). (b) Wild-type cells cultured under normoxia and reoxygenated Ch-H-R cells derived from AsPC-1 were implanted into flank regions of BALB/c nude mice. Tumor volume was evaluated at the indicated day (left panel) (n = 6). Representative images of tumor-bearing mice (right panels). (c) GLI1 expression in tumors from each mouse was determined by immunofluorescence staining (upper panels) (×630). The graph shows relative ratio of GLI1 positive cells in tumors (lower panel). (d) Colony number in Gli1 siRNA transfected-reoxygenated Ch-H-R cells was estimated (n = 3). (e) Control or Gli1 siRNA-transfected-reoxygenated Ch-H-R cells derived from AsPC-1 were implanted into flank regions of BALB/c nude mice. Tumor volume was evaluated on the indicated day (n = 6). The graph shows mean ± SD. *P < 0.05.

Mentions: To confirm the observed increase in proliferation by reoxygenation in vitro, we investigated the tumorigenicity of reoxygenated Ch-H-R cells. Normal PDAC cells cultured under normoxia were used as a control in this experiment. Anchorage-independent proliferation in reoxygenated Ch-H-R cells was significantly higher than that in wild type PDAC cells (Fig.5a). Tumors from mice administered with reoxygenated Ch-H-R cells were significantly larger than those from mice injected with wild-type cells (Fig.5b). Gli1 positive cells in tumors from mice injected with reoxygenated Ch-H-R cells were significantly higher than those in the controls (Fig.5c). Next, the effect of Hh signaling in increased tumorigenicity by reoxygenation was examined. Anchorage-independent proliferation in Gli1 siRNA transfected-reoxygenated Ch-H-R cells was significantly lower than that in the control (Fig.5d) in vitro. In vivo, tumors from mice injected with Gli1 siRNA-transfected-reoxygenated Ch-H-R cells were significantly smaller than those from mice injected with control siRNA-transfected cells (Fig.5e). These results suggest that Gli1 plays a pivotal role in tumorigenicity in reoxygenation in vivo.


Reoxygenation from chronic hypoxia promotes metastatic processes in pancreatic cancer through the Hedgehog signaling.

Morifuji Y, Onishi H, Iwasaki H, Imaizumi A, Nakano K, Tanaka M, Katano M - Cancer Sci. (2014)

Reoxygenation enhances tumorigenicity by Gli1 in vivo. (a) Colony number in wild type cells and reoxygenated Ch-H-R cells was evaluated (n = 3). (b) Wild-type cells cultured under normoxia and reoxygenated Ch-H-R cells derived from AsPC-1 were implanted into flank regions of BALB/c nude mice. Tumor volume was evaluated at the indicated day (left panel) (n = 6). Representative images of tumor-bearing mice (right panels). (c) GLI1 expression in tumors from each mouse was determined by immunofluorescence staining (upper panels) (×630). The graph shows relative ratio of GLI1 positive cells in tumors (lower panel). (d) Colony number in Gli1 siRNA transfected-reoxygenated Ch-H-R cells was estimated (n = 3). (e) Control or Gli1 siRNA-transfected-reoxygenated Ch-H-R cells derived from AsPC-1 were implanted into flank regions of BALB/c nude mice. Tumor volume was evaluated on the indicated day (n = 6). The graph shows mean ± SD. *P < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig05: Reoxygenation enhances tumorigenicity by Gli1 in vivo. (a) Colony number in wild type cells and reoxygenated Ch-H-R cells was evaluated (n = 3). (b) Wild-type cells cultured under normoxia and reoxygenated Ch-H-R cells derived from AsPC-1 were implanted into flank regions of BALB/c nude mice. Tumor volume was evaluated at the indicated day (left panel) (n = 6). Representative images of tumor-bearing mice (right panels). (c) GLI1 expression in tumors from each mouse was determined by immunofluorescence staining (upper panels) (×630). The graph shows relative ratio of GLI1 positive cells in tumors (lower panel). (d) Colony number in Gli1 siRNA transfected-reoxygenated Ch-H-R cells was estimated (n = 3). (e) Control or Gli1 siRNA-transfected-reoxygenated Ch-H-R cells derived from AsPC-1 were implanted into flank regions of BALB/c nude mice. Tumor volume was evaluated on the indicated day (n = 6). The graph shows mean ± SD. *P < 0.05.
Mentions: To confirm the observed increase in proliferation by reoxygenation in vitro, we investigated the tumorigenicity of reoxygenated Ch-H-R cells. Normal PDAC cells cultured under normoxia were used as a control in this experiment. Anchorage-independent proliferation in reoxygenated Ch-H-R cells was significantly higher than that in wild type PDAC cells (Fig.5a). Tumors from mice administered with reoxygenated Ch-H-R cells were significantly larger than those from mice injected with wild-type cells (Fig.5b). Gli1 positive cells in tumors from mice injected with reoxygenated Ch-H-R cells were significantly higher than those in the controls (Fig.5c). Next, the effect of Hh signaling in increased tumorigenicity by reoxygenation was examined. Anchorage-independent proliferation in Gli1 siRNA transfected-reoxygenated Ch-H-R cells was significantly lower than that in the control (Fig.5d) in vitro. In vivo, tumors from mice injected with Gli1 siRNA-transfected-reoxygenated Ch-H-R cells were significantly smaller than those from mice injected with control siRNA-transfected cells (Fig.5e). These results suggest that Gli1 plays a pivotal role in tumorigenicity in reoxygenation in vivo.

Bottom Line: A Hedgehog (Hh) signaling component, Gli1, was significantly increased by reoxygenation.Gli1 knockdown inhibited reoxygenation-induced increases in proliferation and tumorigenicity and decreased invasiveness through suppression of matrix metalloproteinase (MMP) 2 and MMP9.These results suggest that metastatic processes in PDAC are induced through activation of the Hh signaling pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Show MeSH
Related in: MedlinePlus