Activated platelets facilitate hematogenous metastasis of breast cancer by modulating the PDGFR-ß/COX-2 axis.

Platelets have been widely recognized as a bona fide mediator of malignant diseases, and they play significant roles in influencing various aspects of tumor progression. Paracrine interactions between platelets and tumor cells have been implicated in promoting the dissemination of malignant cells to distant sites. However, the underlying mechanisms of the platelet-tumor cell interactions for promoting hematogenous metastasis are not yet fully understood. We found that activated platelets with high expression of CD36 were prone to release a plethora of growth factors and cytokines, including high levels of PDGF-B, compared to resting platelets. PDGF-B activated the PDGFR-ß/COX-2 signaling cascade, which elevated an array of pro-inflammatory factors levels, thereby aggravating tumor metastasis. The collective administration of CD36 inhibitor and COX-2 inhibitor resolved the interactions between platelets and tumor cells. Collectively, our findings demonstrated that targeting the crosstalk between platelets and tumor cells offers potential therapeutic strategies for inhibiting tumor metastasis.

MRG15 aggravates non-alcoholic steatohepatitis progression by regulating the mitochondrial proteolytic degradation of TUFM.

BACKGROUND & AIMS: How hepatic steatosis progresses to non-alcoholic steatohepatitis (NASH) is complicated and remains unclear. The mortality factor 4-like protein 1 (MORF4L1, also called MRG15) was previously identified as a master nuclear chromatin remodeler in the rhythmic regulation of lipid synthesis gene expression in the liver. Whether it also contributes to the progression from liver steatosis to NASH is unclear. METHODS: We adopted 2 different murine NASH models, liver biopsies from patients with NASH, and primary mouse and human hepatocyte cultures for functional examination of MRG15 in NASH progression. Immunoprecipitation-mass spectrometry was applied to identify protein partners of MRG15, and CRISPR targeting was used for gene depletion in liver cells in vivo. RESULTS: The MRG15 level is increased in the livers of humans and mice with NASH. The inflammatory cytokines in NASH livers stabilize MRG15 by increasing its acetylation. Considerable amounts of MRG15 associate with the outer mitochondrial membrane, where it interacts with and deacetylates the mitochondrial Tu translation elongation factor (TUFM). Deacetylated TUFM, especially at the K82 and K91 sites, is subjected to accelerated degradation by the mitochondrial ClpXP protease system. Reduced liver TUFM consequently results in impaired mitophagy, increased oxidative stress and activation of the NLRP3 inflammasome pathway. Blocking MRG15 expression protects the liver from NASH progression by increasing the stability of liver TUFM. Liver samples from patients with NASH also display a clear reduction in TUFM level, which correlates with increased MRG15 expression. CONCLUSION: Collectively, these findings uncover a mitochondrial MRG15-TUFM regulatory pathway that contributes significantly to progression from simple steatosis to NASH, and which could potentially be targeted to treat NASH. LAY SUMMARY: The incidence of non-alcoholic fatty liver disease and its progressive form non-alcoholic steatohepatitis (NASH) is increasing, posing a significant global health challenge. Herein, we have uncovered the importance of the MRG15-TUFM pathway in NASH development. This pathway is active in the mitochondria (energy powerhouse of the cell) and could be targeted for the treatment of NASH.

The LINC00152/miR-138 Axis Facilitates Gastric Cancer Progression by Mediating SIRT2.

Gastric cancer (GC) is the most common gastrointestinal cancer and the main cause of tumor-related death. Exploring markers for early diagnosis and new therapeutic targets is always on the way. In the last 10 years, long noncoding RNAs (lncRNAs) have been widely proved to be involved in the progress of many tumors and are regarded as potential targets for tumor therapy. We found that LINC00152, a newly identified lncRNA, was significantly upregulated in GC tissues and affected clinicopathological characteristics in GC patients. Furthermore, we observed that LINC00152 knockdown can significantly reduce cell proliferation and promote apoptosis in human gastric cancer cells. Further bioinformatic analysis indicated that LINC00152 competitively bound with miR-138 and regulated the expression of miR-138. Moreover, SIRT2 was further proved to be a downstream target of miR-138. Overall, this study elucidates the molecular mechanism of LINC00152 underlying the malignant phenotype of GC cells by mediating miR-138/SIRT2 axis, which provides a new understanding of the role and molecular mechanism of lncRNA in GC and also provides a new way for the treatment of gastric cancer.

Apigenin inhibits cell migration through MAPK pathways in human bladder smooth muscle cells.

Apigenin, a nonmutagenic flavonoid, has been shown to possess free radical scavenging activities, anticarcinogenic properties, antioxidant and anti-inflammatory effects. Recently, apigenin was reported to cause gastric relaxation in murine. To assess possible effects of apigenin on migration of bladder smooth muscle (SM) cell, we isolated SM cells from peri-cancer tissue of human bladder and established a cell model that was capable to overexpress transiently MEKK1 (MEK kinase 1). Results showed that overexpression of active human MEKK1 by adenoviruses infection induced migration of human bladder smooth muscle (hBSM) cells and phosphorylation of MAPKs, ERK, JNK and p38, which are the downstream molecules of MEKK1. Then, hBSM cell overexpressing MEKK1 were exposed to apigenin (50 microM). Our data indicated that apigenin inhibited significantly activation/phosphorylation of MAPKs and migration of hBSM cells induced by MEKK1 overexpression. Besides, apigenin inhibited actin polymerization, which underlines muscle contraction and cell migration. The results suggest that apigenin inhibits activation of MAPKs and thereby the cell migration. The mechanism might be that apigenin blocks signal transmission from MEKK1 to MAPKs.

MLCK-independent phosphorylation of MLC20 and its regulation by MAP kinase pathway in human bladder smooth muscle cells.

Myosins are a superfamily of actin-based molecular motor proteins, which hydrolyze ATP and generate various forms of eukaryotic motility and muscle contraction. Myosin light chain 20 (MLC20) is small ring around the neck region of heavy chain of myosins. Phosphorylation of MLC20 is thought to play a key role in regulation of smooth muscle contraction. Calcium- and calmodulin-dependent myosin light chain kinase (MLCK) is considered the primary regulator of MLC20 phosphorylation. However, several observations in smooth muscle contraction cannot be explained by the mode of phosphorylation. By performing a series of experiments in vitro and in vivo, we report here MLCK-independent MLC20 phosphorylation. Gene expression study reveals that expression of MLCK in smooth muscles is inconsistent with MLC20 phosphorylation at Ser19. None of inactivating calmodulin/MLCK, depriving of calcium and silencing MLCK expression by siRNA blocks effectively the phosphorylation of MLC20 at Ser19. In addition, by overexpressing active human MAP (mitogen-activated protein)-ERK kinase kinase-1 (MEKK1) and blocking its downstream messengers, we have demonstrated a new regulatory system of MLC phosphorylation via MEKK1, which downregulates Ser19 phosphorylation of MLC20 through its downstream molecules, p38, JNK, and ERK in human bladder smooth muscle cells.