Arsenic trioxide attenuates the invasion potential of human liver cancer cells through the demethylation-activated microRNA-491.

Hepatocellular carcinoma (HCC) represents the third leading cause of cancer-related mortality worldwide. Current standard practices for treatment of HCC are less than satisfactory because of metastasis and recurrence. In addition to treating acute promyelocytic leukemia (APL), arsenic trioxide (As2O3) also suppresses other solid tumors, such as HCC. However, the effects of As2O3 on the migration/invasion potential of liver cancer cells and the molecular mechanisms underlying in remain unclear. Here we found that As2O3 attenuated the migration/invasion potential of HCC cell lines by blocking matrix metalloproteinases (MMPs) activities and inducing a mesenchymal to epithelial transition (MET). Indeed, As2O3 elevated the expression of microRNA-491 (miR-491) via demethylation. On one hand, as a target miRNA of MMP9, miR-491 decreased the MMP9 expression. On the other hand, miR-491 blocked the activation of nuclear factor κB (NF-κB), which transcriptionally inactivated MMP2 and induced a MET (as determined by the increased expression of E-cadherin and decreased expressions of snail, slug, and vimentin). Knockdown of miR-491 abolished the As2O3-induced MMPs inactivation, MET, and the migration/invasion potential of HCC cell lines. By understanding a novel mechanism how As2O3 inhibits the migration/invasion potential of liver cancer cells, our study may help to identify potential therapeutic targets for liver cancer.

Wang X ，Jiang F ，Mu J ，Ye X ，Si L ，Ning S ，Li Z ，Li Y ... -  《-》

Inhibition of TGF-β/SMAD3/NF-κB signaling by microRNA-491 is involved in arsenic trioxide-induced anti-angiogenesis in hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide. Current standard practices for treatment of HCC are less than satisfactory because of metastasis and recurrence, which are primarily attributed to the angiogenesis. So, the anti-angiogenesis treatment has become the new approach for HCC therapy. In addition to treating leukemia, arsenic trioxide (As2O3) also suppresses other solid tumors, including HCC. However, the roles of As2O3 in the angiogenesis potential of HCC cells remain unclear. In our present study, As2O3 attenuated the angiogenic ability by the microRNA-491 (miR-491)-mediated inhibition of TGF-β/SMAD3/NF-κB signal pathway in MHCC97H and MHCC97L cells. Briefly, in these cells, As2O3 improved the expression of miR-491 via DNA-demethylation; miR-491, which targeted the SMAD3-3'-UTR, decreased the expression/function of SMAD3, leading to the inactivation of NF-κB/IL-6/STAT-3 signaling; knockdown of miR-491 abolished the As2O3-induced inhibitions of the TGF-β/SMAD3/NF-κB pathway, the VEGF secretion, and the angiogenesis. By understanding a novel mechanism whereby As2O3 inhibits the angiogenic potential in HCC cells, our study would help in the design of future strategies of developing As2O3 as a potential chemopreventive agent when used alone or in combination with other current anticancer drugs.

Jiang F ，Wang X ，Liu Q ，Shen J ，Li Z ，Li Y ，Zhang J ... -  《-》

Induction of the mesenchymal to epithelial transition by demethylation- activated microRNA-200c is involved in the anti-migration/invasion effects of arsenic trioxide on human breast cancer cells.

Breast cancer is a major health problem worldwide. Current standard practices for treatment of breast cancer are less than satisfactory because of high rates of metastasis. Arsenic trioxide (As(2)O(3)), which induces demethylation of DNA and causes apoptosis, has been used as an anti-tumor agent. Little is known, however, regarding its anti-metastatic effects. The microRNA-200c (miR-200c), which is frequently lowly expressed in triple negative breast cancers (TNBCs), inhibits metastasis by inducing the mesenchymal to epithelial transition (MET). Here, we report that As(2)O(3) attenuates the migratory and invasive capacities of breast cancer cells, MDA-MB-231 and BT-549. Notably, As(2)O(3) induces an MET in vitro and in vivo, as determined by the increased expression of the epithelial marker, E-cadherin and decreased expressions of mesenchymal markers, N-cadherin and vimentin. Moreover, As(2)O(3) up-regulates the expression of miR-200c through demethylation. Over-expression of miR-200c enhances the expression of E-cadherin and decreases the expressions of N-cadherin and vimentin. Further, in MDA-MB-231 cells exposed to As(2)O(3), knockdown of miR-200c blocks the As(2)O(3) -induced MET. Finally, in MDA-MB-231 and BT-549 cells exposed to As(2)O(3), knockdown of miR-200c decreases the As(2)O(3) -induced inhibition of the migratory and invasive capacities. By identifying a mechanism whereby As(2)O(3) regulates miR-200c and MET, the results establish the anti-migration/invasion potential of arsenic trioxide.

Si L ，Jiang F ，Li Y ，Ye X ，Mu J ，Wang X ，Ning S ，Hu C ，Li Z ... -  《-》

Inhibition of the cancer stem cells-like properties by arsenic trioxide, involved in the attenuation of endogenous transforming growth factor beta signal.

The elevation of cancer stem cells (CSCs)-like properties is involved in the initiation and progression of various human cancers. Current standard practices for treatment of cancers are less than satisfactory because of CSCs-mediated recurrence. For this reason, targeting the CSCs or the cancer cells with CSCs-like properties has become the new approach for the cancer treatments. In addition to treating leukemia, arsenic trioxide (As₂O₃) also suppresses other solid tumors. However, the roles of As₂O₃ in the regulation of CSCs-like properties remain largely uninvestigated. Here by using sphere formation assay, luciferase reporter assay, and some other molecular biology approaches, we found that As₂O₃ attenuated the CSCs-like properties in human hepatocellular carcinoma (HCC). Briefly, in HCC cells and mice xenograft models, As₂O₃ improved the expression of miR-491 by DNA-demethylation. MiR-491, which targeted the SMAD3-3'-UTR, decreased the expressions of SMAD3, and inhibited the CSCs-like properties in HCC cells. Knockdown of either miR-491 or SMAD3 attenuated the As₂O₃-induced inhibition of endogenous transforming growth factor beta signal and the CSCs-like properties. Further, in HCC patients, miR-491 is inversely correlated with the expressions of SMAD3, CD133, and the metastasis/recurrence outcome. By understanding a novel mechanism whereby As₂O₃ inhibits the CSCs-like properties in HCC, our study would help in the design of future strategies of developing As₂O₃ as a potential HCC chemopreventive agent when used alone or in combination with other current drugs.

Li Y ，Jiang F ，Liu Q ，Shen J ，Wang X ，Li Z ，Zhang J ，Lu X ... -  《-》

MiR-491 attenuates cancer stem cells-like properties of hepatocellular carcinoma by inhibition of GIT-1/NF-κB-mediated EMT.

Yang X ，Ye J ，Yan H ，Tang Z ，Shen J ，Zhang J ，Yang L ... -  《-》