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Metastasis-associated in colon cancer-1 promotes vasculogenic mimicry in gastric cancer by upregulating TWIST1/2.

Wang L, Lin L, Chen X, Sun L, Liao Y, Huang N, Liao W - Oncotarget (2015)

Bottom Line: Moreover, nuclear expression of MACC1, TWIST1, and TWIST2 was upregulated in GC tissues compared with matched adjacent non-tumorous tissues (p < 0.05).Hepatocyte growth factor (HGF) increased the nuclear translocation of MACC1, TWIST1, and TWIST2, while a c-Met inhibitor reduced these effects.These findings indicate that MACC1 promotes VM in GC by regulating the HGF/c-Met-TWIST1/2 signaling pathway, which means that MACC1 and this pathway are potential new therapeutic targets for GC.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.

ABSTRACT
Vasculogenic mimicry (VM) is a blood supply modality that is strongly associated with the epithelial-mesenchymal transition (EMT), TWIST1 activation and tumor progression. We previously reported that metastasis-associated in colon cancer-1 (MACC1) induced the EMT and was associated with a poor prognosis of patients with gastric cancer (GC), but it remains unknown whether MACC1 promotes VM and regulates the TWIST signaling pathway in GC. In this study, we investigated MACC1 expression and VM by immunohistochemistry in 88 patients with stage IV GC, and also investigated the role of TWIST1 and TWIST2 in MACC1-induced VM by using nude mice with GC xenografts and GC cell lines. We found that the VM density was significantly increased in the tumors of patients who died of GC and was positively correlated with MACC1 immunoreactivity (p < 0.05). The 3-year survival rate was only 8.6% in patients whose tumors showed double positive staining for MACC1 and VM, whereas it was 41.7% in patients whose tumors were negative for both MACC1 and VM. Moreover, nuclear expression of MACC1, TWIST1, and TWIST2 was upregulated in GC tissues compared with matched adjacent non-tumorous tissues (p < 0.05). Overexpression of MACC1 increased TWIST1/2 expression and induced typical VM in the GC xenografts of nude mice and in GC cell lines. MACC1 enhanced TWIST1/2 promoter activity and facilitated VM, while silencing of TWIST1 or TWIST2 inhibited VM. Hepatocyte growth factor (HGF) increased the nuclear translocation of MACC1, TWIST1, and TWIST2, while a c-Met inhibitor reduced these effects. These findings indicate that MACC1 promotes VM in GC by regulating the HGF/c-Met-TWIST1/2 signaling pathway, which means that MACC1 and this pathway are potential new therapeutic targets for GC.

No MeSH data available.


Related in: MedlinePlus

MACC1 promotes VM in vivo and in vitro(A) Representative CD31/PAS stained images of tumor sections from GC xenografts with overexpression or silencing of MACC1 (oxMACC1 and shMACC1) and their corresponding controls. Red arrows indicate a typical VM structure. Black arrows indicate a endothelial vessel. (B) Quantitation of VM density in GC xenografts shows that it is higher in the MACC1-overexpressing group than in other groups. *p < 0.05; **p < 0.01, n = 6 vs. the corresponding control group. (C) Size (left panel) and tumor volume curves (right panel) of GC xenografts harvested at 18 days after inoculation. *p < 0.05; **p < 0.01, n = 6. (D) Metastases (black arrows) in the lungs at 40 days after inoculation. Metastases were frequent in the MACC1-overexpressing group, but were seldom detected in the MACC1-silenced group. (E) The VM density of xenograft GC tissues was positively correlated with the number of lung metastases (r = 0.857, p < 0.001; n = 6). (F) Representative VM images and quantitation of tube formation by BGC-823 GC cells after 3D culture for 12 hours. Scale bar = 50 μm. *p < 0.05; **p < 0.01, n = 3.
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Figure 3: MACC1 promotes VM in vivo and in vitro(A) Representative CD31/PAS stained images of tumor sections from GC xenografts with overexpression or silencing of MACC1 (oxMACC1 and shMACC1) and their corresponding controls. Red arrows indicate a typical VM structure. Black arrows indicate a endothelial vessel. (B) Quantitation of VM density in GC xenografts shows that it is higher in the MACC1-overexpressing group than in other groups. *p < 0.05; **p < 0.01, n = 6 vs. the corresponding control group. (C) Size (left panel) and tumor volume curves (right panel) of GC xenografts harvested at 18 days after inoculation. *p < 0.05; **p < 0.01, n = 6. (D) Metastases (black arrows) in the lungs at 40 days after inoculation. Metastases were frequent in the MACC1-overexpressing group, but were seldom detected in the MACC1-silenced group. (E) The VM density of xenograft GC tissues was positively correlated with the number of lung metastases (r = 0.857, p < 0.001; n = 6). (F) Representative VM images and quantitation of tube formation by BGC-823 GC cells after 3D culture for 12 hours. Scale bar = 50 μm. *p < 0.05; **p < 0.01, n = 3.

Mentions: To investigate whether MACC1 contributes to VM, we generated subcutaneous GC implantation and lung metastasis models in NOD-SCID nude mice (n = 6/group), as described previously [14]. We also established BGC-823 cell lines with stable overexpression of the MACC1 gene (oxMACC1) and with silencing of MACC1 (shMACC1). As shown in Figure 3A and 3B, CD31/PAS staining revealed that VM was significantly increased in oxMACC1 GC xenografts compared with the vector-control group (p = 0.002). In contrast, VM was markedly reduced in shMACC1 xenografts compared with the scramble-control group (p = 0.012). Tumors were larger and there were more lung metastases in the oxMACC1 group than in the vector-control group, while shMACC1 tumors were significantly smaller and pulmonary metastases were fewer than in the scramble-control group (Figure 3C and 3D). Strikingly, the VM density in xenograft GC tissues was strongly correlated with the number of lung metastases (r = 0.857, p < 0.001, Figure 3E), suggesting that VM is associated with metastasis of GC.


Metastasis-associated in colon cancer-1 promotes vasculogenic mimicry in gastric cancer by upregulating TWIST1/2.

Wang L, Lin L, Chen X, Sun L, Liao Y, Huang N, Liao W - Oncotarget (2015)

MACC1 promotes VM in vivo and in vitro(A) Representative CD31/PAS stained images of tumor sections from GC xenografts with overexpression or silencing of MACC1 (oxMACC1 and shMACC1) and their corresponding controls. Red arrows indicate a typical VM structure. Black arrows indicate a endothelial vessel. (B) Quantitation of VM density in GC xenografts shows that it is higher in the MACC1-overexpressing group than in other groups. *p < 0.05; **p < 0.01, n = 6 vs. the corresponding control group. (C) Size (left panel) and tumor volume curves (right panel) of GC xenografts harvested at 18 days after inoculation. *p < 0.05; **p < 0.01, n = 6. (D) Metastases (black arrows) in the lungs at 40 days after inoculation. Metastases were frequent in the MACC1-overexpressing group, but were seldom detected in the MACC1-silenced group. (E) The VM density of xenograft GC tissues was positively correlated with the number of lung metastases (r = 0.857, p < 0.001; n = 6). (F) Representative VM images and quantitation of tube formation by BGC-823 GC cells after 3D culture for 12 hours. Scale bar = 50 μm. *p < 0.05; **p < 0.01, n = 3.
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Figure 3: MACC1 promotes VM in vivo and in vitro(A) Representative CD31/PAS stained images of tumor sections from GC xenografts with overexpression or silencing of MACC1 (oxMACC1 and shMACC1) and their corresponding controls. Red arrows indicate a typical VM structure. Black arrows indicate a endothelial vessel. (B) Quantitation of VM density in GC xenografts shows that it is higher in the MACC1-overexpressing group than in other groups. *p < 0.05; **p < 0.01, n = 6 vs. the corresponding control group. (C) Size (left panel) and tumor volume curves (right panel) of GC xenografts harvested at 18 days after inoculation. *p < 0.05; **p < 0.01, n = 6. (D) Metastases (black arrows) in the lungs at 40 days after inoculation. Metastases were frequent in the MACC1-overexpressing group, but were seldom detected in the MACC1-silenced group. (E) The VM density of xenograft GC tissues was positively correlated with the number of lung metastases (r = 0.857, p < 0.001; n = 6). (F) Representative VM images and quantitation of tube formation by BGC-823 GC cells after 3D culture for 12 hours. Scale bar = 50 μm. *p < 0.05; **p < 0.01, n = 3.
Mentions: To investigate whether MACC1 contributes to VM, we generated subcutaneous GC implantation and lung metastasis models in NOD-SCID nude mice (n = 6/group), as described previously [14]. We also established BGC-823 cell lines with stable overexpression of the MACC1 gene (oxMACC1) and with silencing of MACC1 (shMACC1). As shown in Figure 3A and 3B, CD31/PAS staining revealed that VM was significantly increased in oxMACC1 GC xenografts compared with the vector-control group (p = 0.002). In contrast, VM was markedly reduced in shMACC1 xenografts compared with the scramble-control group (p = 0.012). Tumors were larger and there were more lung metastases in the oxMACC1 group than in the vector-control group, while shMACC1 tumors were significantly smaller and pulmonary metastases were fewer than in the scramble-control group (Figure 3C and 3D). Strikingly, the VM density in xenograft GC tissues was strongly correlated with the number of lung metastases (r = 0.857, p < 0.001, Figure 3E), suggesting that VM is associated with metastasis of GC.

Bottom Line: Moreover, nuclear expression of MACC1, TWIST1, and TWIST2 was upregulated in GC tissues compared with matched adjacent non-tumorous tissues (p < 0.05).Hepatocyte growth factor (HGF) increased the nuclear translocation of MACC1, TWIST1, and TWIST2, while a c-Met inhibitor reduced these effects.These findings indicate that MACC1 promotes VM in GC by regulating the HGF/c-Met-TWIST1/2 signaling pathway, which means that MACC1 and this pathway are potential new therapeutic targets for GC.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.

ABSTRACT
Vasculogenic mimicry (VM) is a blood supply modality that is strongly associated with the epithelial-mesenchymal transition (EMT), TWIST1 activation and tumor progression. We previously reported that metastasis-associated in colon cancer-1 (MACC1) induced the EMT and was associated with a poor prognosis of patients with gastric cancer (GC), but it remains unknown whether MACC1 promotes VM and regulates the TWIST signaling pathway in GC. In this study, we investigated MACC1 expression and VM by immunohistochemistry in 88 patients with stage IV GC, and also investigated the role of TWIST1 and TWIST2 in MACC1-induced VM by using nude mice with GC xenografts and GC cell lines. We found that the VM density was significantly increased in the tumors of patients who died of GC and was positively correlated with MACC1 immunoreactivity (p < 0.05). The 3-year survival rate was only 8.6% in patients whose tumors showed double positive staining for MACC1 and VM, whereas it was 41.7% in patients whose tumors were negative for both MACC1 and VM. Moreover, nuclear expression of MACC1, TWIST1, and TWIST2 was upregulated in GC tissues compared with matched adjacent non-tumorous tissues (p < 0.05). Overexpression of MACC1 increased TWIST1/2 expression and induced typical VM in the GC xenografts of nude mice and in GC cell lines. MACC1 enhanced TWIST1/2 promoter activity and facilitated VM, while silencing of TWIST1 or TWIST2 inhibited VM. Hepatocyte growth factor (HGF) increased the nuclear translocation of MACC1, TWIST1, and TWIST2, while a c-Met inhibitor reduced these effects. These findings indicate that MACC1 promotes VM in GC by regulating the HGF/c-Met-TWIST1/2 signaling pathway, which means that MACC1 and this pathway are potential new therapeutic targets for GC.

No MeSH data available.


Related in: MedlinePlus