Inhibition of mTOR pathway attenuates migration and invasion of gallbladder cancer via EMT inhibition.

Abstract

Gallbladder cancer (GBC) is an aggressive disease in which epithelial-mesenchymal transition (EMT) plays a critical role. Whether inhibition of mTOR effects via EMT reversal in GBC remains unclear. Using genetic and pharmacologic inhibitions of mTOR, we investigated the changes of EMT levels in GBC cells. Expressions of EMT related genes were also studied. Migration and invasion assays were carried out and in vivo tumour metastasis mouse models were established. Circulating tumour DNA was quantified. We used EMT index (ratio of Vimentin/Ecadherin expression) to profile EMT levels. We found that inhibition of mTOR using shRNAs and rapamycin inhibited EMT in GBC-SD gallbladder cancer cells. Inhibition of mTOR inhibited EMT in GBC-SD cells in TGF-β-dependent manner, which was contributed majorly by mTORC2 inhibition. Rapamycin decreased invasiveness and migration of GBC-SD cells in vitro and in vivo. We have in the current study shown that rapamycin diminishes the ability of invasion and migration of GBC via inhibition of TGF-β-dependent EMT. Our findings contribute to the understanding of the carcinogenesis of GBC.

• Authors: Huajie Zong, Baobing Yin, Huading Zhou, Duan Cai, Baojin Ma, Yang Xiang
• Journal: Molecular biology reports (Mol Biol Rep) Vol. 41 Issue 7 Pg. 4507-12 (Jul 2014) ISSN: 1573-4978 [Electronic] Netherlands
• PMID: 24623408 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cadherins
• Immunosuppressive Agents
• Multiprotein Complexes
• RNA, Small Interfering
• Transforming Growth Factor beta
• Vimentin
• Mechanistic Target of Rapamycin Complex 2
• TOR Serine-Threonine Kinases
• Sirolimus

Topics

• Animals
• Cadherins (genetics, metabolism)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Epithelial-Mesenchymal Transition (drug effects, genetics)
• Gallbladder Neoplasms (drug therapy, genetics, metabolism, pathology)
• Gene Expression Regulation, Neoplastic
• Humans
• Immunosuppressive Agents (pharmacology)
• Male
• Mechanistic Target of Rapamycin Complex 2
• Mice
• Mice, Nude
• Multiprotein Complexes (antagonists & inhibitors, genetics, metabolism)
• Neoplasm Invasiveness
• RNA, Small Interfering (genetics, metabolism)
• Signal Transduction (drug effects)
• Sirolimus (pharmacology)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, genetics, metabolism)
• Transforming Growth Factor beta (genetics, metabolism)
• Vimentin (genetics, metabolism)