BACKGROUND: Gene expression can be posttranscriptionally regulated by a complex network of proteins. N1-methyladenosine (m1A) is a newly validated RNA modification. However, little is known about both its influence and biogenesis in tumor development. METHODS: This study analyzed TCGA data of patients with five kinds of gastrointestinal (GI) cancers. Using data from cBioPortal, molecular features of the nine known m1A-related enzymes in GI cancers were investigated. Using a variety of bioinformatics approach, the impact of m1A regulators on its downstream signaling pathway was studied. To further confirm this regulation, the effect of m1A writer ALKBH3 knockdown was studied using RNA-seq data from published database. RESULTS: Dysregulation and multiple types of genetic alteration of putative m1A-related enzymes in tumor samples were observed. The ErbB and mTOR pathways with ErbB2, mTOR, and AKT1S1 hub genes were identified as being regulated by m1A-related enzymes. The expression of both ErbB2 and AKT1S1 was decreased after m1A writer ALKBH3 knockdown. Furthermore, Gene Ontology analysis revealed that m1A downstream genes were associated with cell proliferation, and the results showed that m1A genes are reliably linked to mTOR. CONCLUSION: This study demonstrated for the first time the dysregulation of m1A regulators in GI cancer and its signaling pathways and will contribute to the understanding of RNA modification in cancer.

Over the past two decades, obesity has been one of the major public health concerns in most countries. In the search for new molecules that could be used for the treatment of obesity, good perspectives have been opened up for polyphenols, a class of natural bioactive phytochemicals. Experimental and limited clinical trial evidence supports that some polyphenols such as quercetin, curcumin, and resveratrol have potential benefit functions on obesity treatment. This brief review focuses on the main functions of the above-named polyphenols on adipose tissue. These polyphenols may play beneficial effects on adipose tissue under obese condition by alleviating intracellular oxidative stress, reducing chronic low-grade inflammation, inhibiting adipogenesis and lipogenesis, and suppressing the differentiation of preadipocytes to mature adipocytes.

Mutations in HFE are the most common cause of hereditary hemochromatosis (HH). HFE mutations result in reduced expression of hepcidin, a hepatic hormone, which negatively regulates iron absorption from the duodenum and iron release from macrophages. However, the mechanism by which HFE regulates hepcidin expression in hepatocytes is not well understood. It is known that the bone morphogenetic protein (BMP) pathway plays a central role in controlling hepcidin expression in the liver. Here we show that HFE overexpression increased Smad1/5/8 phosphorylation and hepcidin expression, whereas inhibition of BMP signaling abolished HFE-induced hepcidin expression in Hep3B cells. HFE was found to associate with ALK3, inhibiting ALK3 ubiquitination and proteasomal degradation and increasing ALK3 protein expression and accumulation on the cell surface. The 2 HFE mutants associated with HH, HFE C282Y and HFE H63D, regulated ALK3 protein ubiquitination and trafficking differently, but both failed to increase ALK3 cell-surface expression. Deletion of Hfe in mice resulted in a decrease in hepatic ALK3 protein expression. Our results provide evidence that HFE induces hepcidin expression via the BMP pathway: HFE interacts with ALK3 to stabilize ALK3 protein and increase ALK3 expression at the cell surface. (Blood. 2014;124(8):1335-1343

Endoplasmic reticulum (ER) stress has been implicated in several neurodegenerative diseases. Although CCAAT/enhancer-binding protein homologous protein (CHOP) has been shown to play a critical role in ER stress, the precise apoptosis cascade downstream of CHOP is unknown. In this report, we investigated the mechanism of ER stress-mediated apoptosis as well as the action of IGF-I in PC-12 neuronal cells. Our results demonstrated that tribbles-related protein 3 (TRB3), which is a target gene of CHOP, was responsible for tunicamycin (an ER stress inducer)-induced apoptosis. TRB3 could promote dephosphorylation of Akt in PC-12 cells. IGF-I inhibited ER stress-induced apoptosis by restoring the phosphorylation level of Akt. Both wortmannin (a phosphatidylinositide 3-kinase inhibitor) and SB 212090 (a p38 MAPK inhibitor) suppressed the protective effect of IGF-I on ER stress-induced apoptosis. Interestingly, IGF-I attenuated ER stress-mediated expression of TRB3 but not CHOP. This action of IGF-I was abolished by SB 212090 but not by wortmannin. Immunoprecipitation analysis revealed that IGF-I promoted the phosphorylation of CHOP by activating p38 MAPK, probably leading to a decrease in the transcriptional activity of CHOP. The dephosphorylation of Akt resulted in increased expression of a proapoptotic protein, p53 up-regulated modulator of apoptosis (PUMA), in a forkhead box O3a-dependent manner. Knockdown of PUMA by short hairpin RNA attenuated ER stress-mediated apoptosis. Thus, our current study indicates that both TRB3 and PUMA are critical molecules in ER stress-induced apoptosis. IGF-I effectively protects PC-12 neuronal cells against ER stress-induced apoptosis through the phosphatidylinositide 3-kinase/Akt and p38 MAPK pathways.

Fibrosis is recognized as the major pathological change in adipose tissue during the development of obesity. However, the detailed mechanisms governing the interactions between the fibrotic components and their modifiers remain largely unclear. Here, we reported that matrix metalloproteinase 14 (MMP14), a key pericellular collagenase, is dramatically upregulated in obese adipose tissue. We generated a doxycycline-inducible adipose tissue-specific MMP14 overexpression model to study its regulatory function. We found that overexpression of MMP14 in the established obese adipose tissue leads to enlarged adipocytes and increased body weights in transgenic mice. Furthermore, the mice exhibited decreased energy expenditure, impaired lipid metabolism, and insulin resistance. Mechanistically, we found that MMP14 digests collagen 6α3 to produce endotrophin, a potent costimulator of fibrosis and inflammation. Unexpectedly, when overexpressing MMP14 in the early-stage obese adipose tissue, the transgenic mice showed a healthier metabolic profile, including ameliorated fibrosis and inflammation, as well as improved lipid and glucose metabolism. This unique metabolic phenotype is likely due to digestion/modification of the dense adipose tissue extracellular matrix by MMP14, thereby releasing the mechanical stress to allow for its healthy expansion. Understanding these dichotomous impacts of MMP14 provides novel insights into strategies to treat obesity-related metabolic disorders.