Salvianolic acid B targets mortalin and inhibits the migration and invasion of hepatocellular carcinoma via the RECK/STAT3 pathway.

BACKGROUND: Tumor migration and invasion is a complex and diverse process that involves the epithelial-mesenchymal transition (EMT) of tumor cells and degradation of the extracellular matrix by matrix metalloproteases (MMPs). Mortalin is an important oncogene. It has been reported to play an important role in tumor migration and invasion through various signaling pathways, but the underlying mechanism is not fully understood. METHODS: Here, we investigated the role of mortalin in the migration of the hepatocellular carcinoma (HCC) cell lines HepG2 and HCCLM3. RESULTS: The overexpression of mortalin in HepG2 cells decreased the protein level of reversion-inducing cysteine-rich protein with Kazal motifs (RECK) and activated the phosphorylation and acetylation of STAT3, thereby up-regulating matrix metalloproteinase 9 (MMP9) and promoting cell migration and invasion. In contrast, in HCCLM3 cells, mortalin knockdown increased the expression of RECK, inhibited the STAT3 pathway and the activity of MMP9, and inhibited cell migration and invasion. Furthermore, we found that salvianolic acid B, a caffeic acid phenethyl ester analog, specifically bound to mortalin and increased the degradation of mortalin proteasomes through ubiquitination, thereby up-regulating RECK, inhibiting STAT3, and finally inhibiting the migration and invasion of HCC cells. CONCLUSION: Our work suggested that mortalin is a potential therapeutic target for hepatocellular carcinoma.

The 14-3-3η/GSK-3ß/ß-catenin complex regulates EndMT induced by 27-hydroxycholesterol in HUVECs and promotes the migration of breast cancer cells.

Endothelial-mesenchymal transition (EndMT) is the transformation of endothelial cell morphology to mesenchymal cell morphology, accompanied by decline of endothelial function and enhancement of mesenchymal function, which promotes tumor progression and tumor cell invasion and metastasis. 27-Hydroxycholesterol (27-HC) is a cholesterol metabolite, which has a high content in human blood. 27-HC promotes breast cancer cell proliferation, invasion, and migration. We previously showed that 27-HC promotes EndMT; however, the underlying mechanism still needs to be further explored. We studied the role of the 14-3-3η/GSK-3ß/ß-catenin complex in EndMT. Our results show that 27-HC induces oxidative stress in HUVECs and activates the p38 signaling pathway, thereby inhibiting the binding of 14-3-3η/GSK-3ß/ß-catenin, promoting the increase of free ß-catenin and nuclear translocation, and finally inducing EndMT. Treatment with N-acetylcysteine (NAC) blocked 27-HC-induced ROS generation and p38 signaling pathway activation, prevented ß-catenin from release from binding, and inhibited EndMT. Blocking ROS production or p38 signaling or knocking down 14-3-3η inhibited 27-HC-induced EndMT and inhibited breast cancer cell metastasis. These findings indicate 14-3-3η is necessary for interactions between the p38 kinase and the GSK-3ß/ß-catenin complex and serves as an adaptor to transmit the upstream kinase signal to the downstream signal, thereby promoting EndMT and breast cancer cell migration.

Genistein induces endocrine resistance in human breast cancer by suppressing H3K27 trimethylation.

Genistein (GE), the most important phytoestrogen in diet, is known to behave as a partial agonist of estrogen receptor α and shows a proliferative effect on the growth of breast cancer cell lines. Recent research has reported that long-term consumption of low doses of GE results in hormone-independent growth phenotypes of MCF-7 tumors, with increased HER2. Overexpression of HER2 has been associated with endocrine resistance in human breast cancer, but whether long-term low-level GE-induced HER2 expression is the cause of endocrine resistance remains to be determined. Short-term and long-term treatments with GE may have different effects on HER2 expression. We found that low doses of GE had estrogen-like effects and inhibited HER2 expression after short-term exposure in estrogen receptor-positive breast cancers cells. However, in contrast to short-term exposure, long-term exposure induced an increase in HER2 expression, which led to endocrine resistance. During long-term low-level exposure, the continuous activation of ERK1/2-phosphorylated EZH2 at Ser21 resulted in a decrease of lysine 27 trimethylation. As H3K27me3 levels decreased, the expression of interleukin-6 (IL-6) and IL-8 increased, and HER2 levels gradually increased, forming a feedback loop of ERK1/2/EZH2/IL-6 and IL-8/HER2. We identified a novel pathway by which EZH2 phosphorylation contributed to long-term low-level GE-induced HER2 overexpression and provided new insight for long-term low-level GE-induced acquired endocrine resistance. For breast cancer patients, long-term low-level use of soy supplements has potential health risks, and monitoring dietary exposure to GE is advisable when patients are treated with tamoxifen.