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Suppression of Human Liver Cancer Cell Migration and Invasion via the GABAA Receptor.

Chen ZA, Bao MY, Xu YF, Zha RP, Shi HB, Chen TY, He XH - Cancer Biol Med (2012)

Bottom Line: The effects of GABA on liver cancer cell cytoskeletal were determined by immunofluorescence staining.GABA inhibited human liver cancer cell migration and invasion via the ionotropic GABAA receptor as a result of the induction of liver cancer cell cytoskeletal reorganization.Pretreatment with GABA also significantly reduced intrahepatic liver metastasis and primary tumor formation in vivo.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China.

ABSTRACT

Objective: To investigate the roles of the γ-aminobutyric acid (GABA) in the metastasis of hepatocellular carcinoma (HCC) and to explore the potential of a novel therapeutic approach for the treatment of HCC.

Methods: The expression levels of GABA receptor subunit genes in various HCC cell lines and patients' tissues were detected by quantitative real-time polymerase chain reaction and Western blot analysis. Transwell cell migration and invasion assays were carried out for functional analysis. The effects of GABA on liver cancer cell cytoskeletal were determined by immunofluorescence staining. And the effects of GABA on HCC metastasis in nude mice were evaluated using an in vivo orthotopic model of liver cancer.

Results: The mRNA level of GABA receptor subunits varied between the primary hepatocellular carcinoma tissue and the adjacent non-tumor liver tissue. GABA inhibited human liver cancer cell migration and invasion via the ionotropic GABAA receptor as a result of the induction of liver cancer cell cytoskeletal reorganization. Pretreatment with GABA also significantly reduced intrahepatic liver metastasis and primary tumor formation in vivo.

Conclusions: These findings introduce a potential and novel therapeutic approach for the treatment of cancer patients based on the modulation of the GABAergic system.

No MeSH data available.


Related in: MedlinePlus

GABA-inhibited HCC cell invasion and metastasis in vivo. A, B: Hematoxylin-eosin-stained sections of intrahepatic metastatic nodules and distal metastatic nodules in the lung formed by SMMC-7721 cells with or without GABA pretreatment at the eighth week after intraperitoneal transplantation. Black arrows indicate the metastatic foci in the liver or the lung. Magnification: a, b, e, and f, × 100; c, d, g, and h, × 200. Tumor intrahepatic metastasis and distant lung metastasis were determined by histology. Metastasis frequency was then calculated. C: The numbers of metastatic nodules in each mouse liver were counted.
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f5: GABA-inhibited HCC cell invasion and metastasis in vivo. A, B: Hematoxylin-eosin-stained sections of intrahepatic metastatic nodules and distal metastatic nodules in the lung formed by SMMC-7721 cells with or without GABA pretreatment at the eighth week after intraperitoneal transplantation. Black arrows indicate the metastatic foci in the liver or the lung. Magnification: a, b, e, and f, × 100; c, d, g, and h, × 200. Tumor intrahepatic metastasis and distant lung metastasis were determined by histology. Metastasis frequency was then calculated. C: The numbers of metastatic nodules in each mouse liver were counted.

Mentions: From our in vitro experiments, the effects of GABA in an in vivo orthotopic model of liver cancer was subsequently tested. The HCC cell line SMMC-7721, which has relatively strong in vitro invasive properties, has been employed in in vivo metastasis assays in nude mice [29]. Thus, the effect of GABA on the formation of primary and metastatic tumors was evaluated by injecting 5 × 105 SMMC-7721 cells pretreated with 10 µM GABA or vehicle control into the liver of each mouse. Eight weeks later, a necropsy was performed to determine tumor growth and metastatic pattern. In the control group, 7 of 10 mice developed intrahepatic liver metastasis compared with only 2 of 10 mice in the GABA group (Figure 5A, P=0.021). Regarding the metastatic spread to the lungs, none of the mice in the GABA group developed distant lung metastases while 2 of 10 mice in the control group had lung metastases (Figure 5B, P=0.084). Interestingly, the number of metastatic nodules in the liver dramatically decreased in the GABA group when compared with the vector controls (Figure 5C, P=0.023).


Suppression of Human Liver Cancer Cell Migration and Invasion via the GABAA Receptor.

Chen ZA, Bao MY, Xu YF, Zha RP, Shi HB, Chen TY, He XH - Cancer Biol Med (2012)

GABA-inhibited HCC cell invasion and metastasis in vivo. A, B: Hematoxylin-eosin-stained sections of intrahepatic metastatic nodules and distal metastatic nodules in the lung formed by SMMC-7721 cells with or without GABA pretreatment at the eighth week after intraperitoneal transplantation. Black arrows indicate the metastatic foci in the liver or the lung. Magnification: a, b, e, and f, × 100; c, d, g, and h, × 200. Tumor intrahepatic metastasis and distant lung metastasis were determined by histology. Metastasis frequency was then calculated. C: The numbers of metastatic nodules in each mouse liver were counted.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3643652&req=5

f5: GABA-inhibited HCC cell invasion and metastasis in vivo. A, B: Hematoxylin-eosin-stained sections of intrahepatic metastatic nodules and distal metastatic nodules in the lung formed by SMMC-7721 cells with or without GABA pretreatment at the eighth week after intraperitoneal transplantation. Black arrows indicate the metastatic foci in the liver or the lung. Magnification: a, b, e, and f, × 100; c, d, g, and h, × 200. Tumor intrahepatic metastasis and distant lung metastasis were determined by histology. Metastasis frequency was then calculated. C: The numbers of metastatic nodules in each mouse liver were counted.
Mentions: From our in vitro experiments, the effects of GABA in an in vivo orthotopic model of liver cancer was subsequently tested. The HCC cell line SMMC-7721, which has relatively strong in vitro invasive properties, has been employed in in vivo metastasis assays in nude mice [29]. Thus, the effect of GABA on the formation of primary and metastatic tumors was evaluated by injecting 5 × 105 SMMC-7721 cells pretreated with 10 µM GABA or vehicle control into the liver of each mouse. Eight weeks later, a necropsy was performed to determine tumor growth and metastatic pattern. In the control group, 7 of 10 mice developed intrahepatic liver metastasis compared with only 2 of 10 mice in the GABA group (Figure 5A, P=0.021). Regarding the metastatic spread to the lungs, none of the mice in the GABA group developed distant lung metastases while 2 of 10 mice in the control group had lung metastases (Figure 5B, P=0.084). Interestingly, the number of metastatic nodules in the liver dramatically decreased in the GABA group when compared with the vector controls (Figure 5C, P=0.023).

Bottom Line: The effects of GABA on liver cancer cell cytoskeletal were determined by immunofluorescence staining.GABA inhibited human liver cancer cell migration and invasion via the ionotropic GABAA receptor as a result of the induction of liver cancer cell cytoskeletal reorganization.Pretreatment with GABA also significantly reduced intrahepatic liver metastasis and primary tumor formation in vivo.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China.

ABSTRACT

Objective: To investigate the roles of the γ-aminobutyric acid (GABA) in the metastasis of hepatocellular carcinoma (HCC) and to explore the potential of a novel therapeutic approach for the treatment of HCC.

Methods: The expression levels of GABA receptor subunit genes in various HCC cell lines and patients' tissues were detected by quantitative real-time polymerase chain reaction and Western blot analysis. Transwell cell migration and invasion assays were carried out for functional analysis. The effects of GABA on liver cancer cell cytoskeletal were determined by immunofluorescence staining. And the effects of GABA on HCC metastasis in nude mice were evaluated using an in vivo orthotopic model of liver cancer.

Results: The mRNA level of GABA receptor subunits varied between the primary hepatocellular carcinoma tissue and the adjacent non-tumor liver tissue. GABA inhibited human liver cancer cell migration and invasion via the ionotropic GABAA receptor as a result of the induction of liver cancer cell cytoskeletal reorganization. Pretreatment with GABA also significantly reduced intrahepatic liver metastasis and primary tumor formation in vivo.

Conclusions: These findings introduce a potential and novel therapeutic approach for the treatment of cancer patients based on the modulation of the GABAergic system.

No MeSH data available.


Related in: MedlinePlus