Volume 403, Issue 7

Chemerin is a small chemotactic protein and a key player in initiating the early immune response. As an adipokine, chemerin is also involved in energy homeostasis and the regulation of reproductive functions. Secreted as inactive prochemerin, it relies on proteolytic activation by serine proteases to exert biological activity. Chemerin binds to three distinct G protein-coupled receptors (GPCR), namely chemokine-like receptor 1 (CMKLR1, recently named chemerin 1 ), G protein-coupled receptor 1 (GPR1, recently named chemerin 2 ), and CC-motif chemokine receptor-like 2 (CCRL2). Only CMKLR1 displays conventional G protein signaling, while GPR1 only recruits arrestin in response to ligand stimulation, and no CCRL2-mediated signaling events have been described to date. However, GPR1 undergoes constitutive endocytosis, making this receptor perfectly adapted as decoy receptor. Here, we discuss expression pattern, activation, and receptor binding of chemerin. Moreover, we review the current literature regarding the involvement of chemerin in cancer and several obesity-related diseases, as well as recent developments in therapeutic targeting of the chemerin system.

We compared the binding properties and dynamics of three experimentally reviewed isoforms of human dihydrofolate reductase (DHFR). The cytoplasmic variants including isoforms1 and 2 (iso1 and iso2) are produced by alternative splicing; while the mitochondrial form is located in the mitochondria. The iso1 as the canonical sequence contains 187 residues, and iso2 differs from the iso1, where it has 1–52 residues missing at the N-terminus of canonical sequence. Here, the structural models of the iso2 and mitochondrial forms were constructed by the MODELLER program using the crystal structure of the iso1 as the template. Bioinformatics analysis on ligand-bearing structures demonstrates that mitochondrial variant forms more stable complex with ligands compared with iso1 and 2, indicating their different binding properties. The root mean square fluctuation (RMSF) data suggest that C-terminus of iso1 contains two representative highly flexible fragments, while iso2 contains a highly flexible fragment at N-terminus end. Interestingly, both ends of mitochondrial variant have a degree of rigidity. Finally, the observation of differences in structural dynamics and binding properties predicts that the simultaneous existence of enzyme isoforms is a way to increase the speed of the enzyme maneuver in response to various environmental conditions. This prediction needs to be tested experimentally.

To explore the expression and the functions of SRPK1 in osteosarcoma, we retrieved transcription profiling dataset by array of human bone specimens from patients with osteosarcoma from ArrayExpress (accession E-MEXP-3628) and from Gene Expression Omnibus (accession GSE16102) and analyzed expression level of SRPK1 and prognostic value in human osteosarcoma. Then we examined the effect of differential SRPK1 expression levels on the progression of osteosarcoma, including cell proliferation, cell cycle, apoptosis, and investigated its underlying molecular mechanism using in vitro osteosarcoma cell lines and in vivo nude mouse xenograft models. High expression level of SRPK1 was found in human osteosarcoma tissues and cell lines as compared to the normal bone tissues and osteoblast cells, and predicted poor prognosis of human osteosarcoma. Overexpression of SRPK1 in osteosarcoma U2OS cells led to cell proliferation but inhibition of apoptosis. In contrast, knockdown of SRPK1 in HOS cells impeded cell viability and induction of apoptosis. Moreover, silencing SRPK1 inhibited osteosarcoma tumor growth in nude mice. Mechanistic studies revealed that SRPK1 promoted cell cycle transition in osteosarcoma cells and activation of NF-κB is required for SRPK1 expression and its pro-survival signaling. SRPK1 promoted human osteosarcoma cell proliferation and tumor growth by regulating NF-κB signaling pathway.

Hepatocellular carcinoma (HCC) is one of the most common human cancers. Long non-coding RNA (lncRNA) has been demonstrated to play an important role in regulating tumor development. The current study aims to explore the specific role of LINC00520 during HCC progression. The present study identified that LINC00520 was upregulated in HCC tissues and indicated poor patient survival. Overexpression of LINC00520 promoted HCC cell proliferation, migration and invasion, while LINC00520 downregulation led to the opposite effects. Besides, LINC00520 knockdown was found to inhibit tumor growth in vivo . Furthermore, LINC00520 acted as a sponge of miR-4516 to regulate SRY-related high mobility group box 5 (SOX5). In addition, the inhibition of miR-4516 partly reversed the inhibitory effect of LINC00520 silencing on HCC cell proliferation, migration and invasion. In conclusion, the inhibition of LINC00520 suppressed HCC cell proliferation, migration and invasion through mediating miR-4516/SOX5 axis. Therefore, our study provides a basis for the development of treatment strategies for HCC.

Glioma is one of the most common primary intracranial carcinomas and typically associated with a dismal prognosis and poor quality of life. The identification of novel oncogenes is clinically valuable for early screening and prevention. Recently, the studies have revealed that long non-coding RNAs (lncRNAs) play important roles in the development and progression of cancers including glioma. The expression of lncRNA FAM66C is reduced in glioma cell lines and clinical samples compared to non-tumor samples. Knockdown of FAM66C in U87 and U251 cells significantly promoted cell proliferation and migration, respectively. Furthermore, the correlation between FAM66C and Hippo pathway regulators YAP1 and LATS1, along with the alteration of their protein expression level indicated that FAM66C regulated cell growth through this pathway. Moreover, luciferase assay demonstrated that another two noncoding RNAs, miR15a/miR15b, directly bonded to the 3′UTR of LATS1 to facilitated its transcriptional expression and inhibited cell growth. In addition, the luciferase activity of FAM66C was block by miR15a/miR15b, and the promotion of cell growth effects caused by FAM66C deficiency was attenuated by miR15a/miR15b mimics, further proved that FAM66C functioned as a competing endogenous RNA to regulate glioma growth via the miRNA/LATS1 signaling pathway.

Recent studies showed that Ceramide Kinase-Like Protein (CERKL)was expressed in the nerve cells and could regulate autophagy. Sirtuin-1 (SIRT1) is the regulator of the mitophagy, which can be stabilized by CERKL. Furthermore, the study also revealed that the SIRT1 induced mitophagy by activating PINK1/Parkin signaling. Therefore, we speculated that CERKL has potential to activate the SIRT1/PINK1/Parkin pathway to induce mitophagy. In this study, cerebral ischemia reperfusion mouse model was established. CERKL was overexpressed in those mice and human neuroblastoma cells. Tunel staining and flow cytometry were applied for the detection of cell apoptosis. The ratios of LC3Ⅱ to LC3Ⅰ and the expression of LC3Ⅱ in mitochondria were determined by gel electrophoresis. Overexpression of CERKL alleviated the cerebral ischemia reperfusion injury and damage to OGD/R human neuroblastoma cells. Overexpression of CERKL enhanced the expression of LC3 Ⅱ in mitochondria and induced occurrence of mitophagy. Overexpression of CERKL promoted the stability of SIRT1 and facilitated the expression of PINK1 and Parkin in those cells. Knockdown of PINK1 impeded the mitophagy and suppressed the expression of LC3 Ⅱ in mitochondria. It can be concluded that CERKL alleviated the ischemia reperfusion induced nervous system injury through inducing mitophagy in a SIRT1/PINK1/Parkin dependent pathway.