title: 3'3-Diindolylmethane inhibits migration, invasion and metastasis of hepatocellular carcinoma by suppressing FAK signaling.
abstract: Late stage hepatocellular carcinoma (HCC) usually has a low survival rate because it has high potential of metastases and there is no effective cure. 3'3-Diindolylmethane (DIM) is the major product of the acid-catalyzed oligomerization of indole-3-carbinol present in cruciferous vegetables. DIM has been proved to exhibit anticancer properties. In this study, we explored the effects and molecular mechanisms of anti-metastasis of DIM on HCC cells both in vitro and in vivo. We chose two HCC cell lines SMMC-7721 and MHCC-97H that have high potential of invasion. The results showed that DIM inhibited the proliferation, migration and invasion of these two cell lines in vitro. In addition, in vivo study demonstrated that DIM significantly decreased the volumes of SMMC-7721 orthotopic liver tumor and suppressed lung metastasis in nude mice. Focal Adhesion Kinase (FAK) is found over activated in HCC cells. We found that DIM decreased the level of phospho-FAK (Tyr397) both in vitro and in vivo. DIM inhibition of phospho-FAK (Tyr397) led to down-regulation of MMP2/9 and decreased potential of metastasis. DIM also repressed the migration and invasion induced by vitronectin through inactivation of FAK pathway and down-regulation of MMP2/9 in vitro. We also found that pTEN plays a role in down-regulation of FAK by DIM. These results demonstrated that DIM blocks HCC cell metastasis by suppressing tumor cell migration and invasion. The anti-metastasis effect of DIM could be explained to be its down-regulated expression and activation of MMP2/9 partly induced by up-regulation of pTEN and inhibition of phospho-FAK (Tyr397).
authors.affiliation: Dearpartmant of Toxicology, Guangzhou Center for Disease Control and Prevention, Guangzhou, China.
authors.forename: Wen-Xue
authors.initials: WX
authors.lastname: Li
authors.affiliation: Faculty of Toxicology, School of Public Health, Sun Yet-sen University, Guangzhou, China.
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Chen
authors.affiliation: Dearpartmant of Toxicology, Guangzhou Center for Disease Control and Prevention, Guangzhou, China.
authors.forename: Min-Ying
authors.initials: MY
authors.lastname: Sun
authors.affiliation: Dearpartmant of Toxicology, Guangzhou Center for Disease Control and Prevention, Guangzhou, China.
authors.forename: Jun-Tao
authors.initials: JT
authors.lastname: Li
authors.affiliation: Dearpartmant of Toxicology, Guangzhou Center for Disease Control and Prevention, Guangzhou, China.
authors.forename: Hua-Zhang
authors.initials: HZ
authors.lastname: Liu
authors.affiliation: Dearpartmant of Toxicology, Guangzhou Center for Disease Control and Prevention, Guangzhou, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects* / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary*; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009368:Neoplasm Transplantation; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D014183:Transplantation, Heterologous; D019096:Vitronectin / Q000494:pharmacology; D014945:Wound Healing / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D034741:RNA, Small Interfering; D019096:Vitronectin; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; C016392:3,3'-diindolylmethane
keywords: MMP2/9; diindolylmethane (DIM); focal adhesion kinase (FAK); hepatocellular carcinoma; pTEN