Heat shock protein 90 promotes epithelial to mesenchymal transition, invasion, and migration in colorectal cancer.

Epithelial to mesenchymal transition (EMT), invasion, and motility are essential steps in colorectal cancer (CRC) metastasis regulated by HIF-1α and NF-κB. Since HSP90 activates HIF-1α and NF-κB, we hypothesized that inhibition of HSP90 leads to inhibition of HIF-1α and NF-κB resulting in inhibition of EMT, invasion, and motility. Treatment of colorectal cancer cell lines HT-29 and HCT-116 with ganetespib at 50 nM for 24 h inhibited EMT (downregulated vimentin and upregulated E-cadherin), matrigel invasion, and spheroid migration. Ganetespib treatment or HSP90 knockdown downregulated molecular pathways associated with EMT, invasion, and motility. The overexpression of HIF-1α or NF-κB resulted in increased EMT, invasion, and motility in both cell lines and these effects were inhibited by ganetespib. Similar effects were observed in animal xenografts treated with ganetespib. Taken together, our data demonstrate for the first time that inhibition of HSP90 downregulates both HIF-1α and NF-κB leading to inhibition of EMT, motility, and invasiveness in colorectal cancer.

Nagaraju GP ，Long TE ，Park W ，Landry JC ，Taliaferro-Smith L ，Farris AB ，Diaz R ，El-Rayes BF ... -  《-》

Antiangiogenic effects of ganetespib in colorectal cancer mediated through inhibition of HIF-1α and STAT-3.

Nagaraju GP ，Park W ，Wen J ，Mahaseth H ，Landry J ，Farris AB ，Willingham F ，Sullivan PS ，Proia DA ，El-Hariry I ，Taliaferro-Smith L ，Diaz R ，El-Rayes BF ... -  《-》

HIF-1α Promotes Epithelial-Mesenchymal Transition and Metastasis through Direct Regulation of ZEB1 in Colorectal Cancer.

Zhang W ，Shi X ，Peng Y ，Wu M ，Zhang P ，Xie R ，Wu Y ，Yan Q ，Liu S ，Wang J ... -  《PLoS One》

Deferoxamine enhances cell migration and invasion through promotion of HIF-1α expression and epithelial-mesenchymal transition in colorectal cancer.

Zhang W ，Wu Y ，Yan Q ，Ma F ，Shi X ，Zhao Y ，Peng Y ，Wang J ，Jiang B ... -  《-》

Genetic and epigenetic down-regulation of microRNA-212 promotes colorectal tumor metastasis via dysregulation of MnSOD.

Altered functions of microRNAs (miRNAs) have been associated with colorectal cancer (CRC). miR-212 is transcribed from a stable intron of a non-protein coding gene, and is reportedly down-regulated in different tumor types. We investigated the role of miR-212 in colorectal carcinogenesis and progression. We analyzed the expression of miR-212 by real-time polymerase chain reaction (PCR) analysis of colorectal cell lines and 180 paired tumor samples and surrounding healthy tissue. We overexpressed and knocked down miR-212 in CRC cell lines and assessed the in vitro effects. We also studied the effects of miR-212 overexpression on metastasis of tumors grown from HCT116 cells in nude mice. Overexpression of miR-212 inhibited CRC cell migration and invasion in vitro and formation of intrahepatic and pulmonary metastasis in vivo. We identified manganese superoxide dismutase (MnSOD) messenger RNA as a direct target of miR-212, and observed an inverse correlation between the level of miR-212 and MnSOD protein in colorectal tumor samples. MnSOD was required for down-regulation of epithelial markers and up-regulation of mesenchymal markers in CRC cells, indicating that it promoted the epithelial-mesenchymal transition. Overexpression of miR-212 reduced the levels of MnSOD to block the epithelial-mesenchymal transition process. Loss of heterozygosity and promoter hypermethylation each contributed to the down-regulation of miR-212. Reduced levels of miR-212 were associated with a more aggressive tumor phenotype and short disease-free survival times of patients (P = .0045; overall survival, P = .0015). miR-212 is down-regulated in human CRC tissues via genetic and epigenetic mechanisms. miR-212 might prevent tumor progression by targeting MnSOD messenger RNA; reduction of miR-212 could be a prognostic marker for patients with CRC. miR-212 and MnSOD might also be therapeutic targets for cancer.

Meng X ，Wu J ，Pan C ，Wang H ，Ying X ，Zhou Y ，Yu H ，Zuo Y ，Pan Z ，Liu RY ，Huang W ... -  《-》