Methyltransferase-like proteins in cancer biology and potential therapeutic targeting.

RNA modification has recently become a significant process of gene regulation, and the methyltransferase-like (METTL) family of proteins plays a critical role in RNA modification, methylating various types of RNAs, including mRNA, tRNA, microRNA, rRNA, and mitochondrial RNAs. METTL proteins consist of a unique seven-beta-strand domain, which binds to the methyl donor SAM to catalyze methyl transfer. The most typical family member METTL3/METTL14 forms a methyltransferase complex involved in N6-methyladenosine (m6A) modification of RNA, regulating tumor proliferation, metastasis and invasion, immunotherapy resistance, and metabolic reprogramming of tumor cells. METTL1, METTL4, METTL5, and METTL16 have also been recently identified to have some regulatory ability in tumorigenesis, and the rest of the METTL family members rely on their methyltransferase activity for methylation of different nucleotides, proteins, and small molecules, which regulate translation and affect processes such as cell differentiation and development. Herein, we summarize the literature on METTLs in the last three years to elucidate their roles in human cancers and provide a theoretical basis for their future use as potential therapeutic targets.

Comprehensive transcriptomic profiling and mutational landscape of primary gastric linitis plastica.

BACKGROUND: Primary gastric linitis plastica (GLP) is a distinct phenotype of gastric cancer with poor survival. Comprehensive molecular profiles and putative therapeutic targets of GLP remain undetermined. METHODS: We subjected 10 tumor-normal tissue pairs to whole exome sequencing (WES) and whole transcriptome sequencing (WTS). 10 tumor samples were all GLP which involves 100% of the gastric wall macroscopically. TCGA data were compared to generate the top mutated genes and the overexpressed genes in GLP. RESULTS: Our results reveal that GLP has distinctive genomic and transcriptomic features, dysfunction in the Hippo pathway is likely to be a key step during GLP development. 6 genes were identified as significantly highly mutated genes in GLP, including AOX1, ANKRD36C, CPXM1, PTPN14, RPAP1, and DCDC1). MUC6, as a previously identified gastric cancer driver gene, has a high mutation rate (20%) in GLP. 20% of patients in our GLP cohort had CDH1 mutations, while none had RHOA mutations. GLP exhibits high immunodeficiency and low AMPK pathway activity. Our WTS results showed that 3 PI3K-AKT pathway-related genes (PIK3R2, AKT3, and IGF1) were significantly up-regulated in GLP. Two genes were identified using immunohistochemistry (IHC), IGF2BP3 and MUC16, which specifically expressed in diffuse-type-related gastric cancer cell lines, and its knockdown inhibits PI3K-AKT pathway activity. CONCLUSIONS: We provide the first integrative genomic and transcriptomic profiles of GLP, which may facilitate its diagnosis, prognosis, and treatment.

Effects of hyperbaric oxygen on NLRP3 inflammasome activation in the brain after carbon monoxide poisoning.

Neuroinflammation plays an important role in brain damage after acute carbon monoxide poisoning (ACOP). The nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing (NLRP) 3 inflammasome triggers the activation of inflammatory caspases and maturation of interleukin (IL)-1ß and -18, and has been linked to various human autoinflammatory and autoimmune diseases. In this study we investigated the effects of hyperbaric oxygen (HBO2) on NLRP3 inflammasome activation after ACOP. Mice were randomly divided into four groups: sham group (exposure to normobaric air - i.e., 21% O2 at 1 atmosphere absolute); HBO2-only group; CO + normobaric air group; and CO + HBO2 group. Cognitive function was evaluated with the Morris water maze; myelin injury was assessed by FluoroMyelin GreenTM fluorescent myelin staining and myelin basic protein (MBP) immunostaining; and mRNA and protein levels of NLRP3 inflammasome complex proteins were measured by quantitative real-time PCR and Western blot, respectively. Additionally, serum and brain levels of IL-1ßß and -18 and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase were determined by enzyme-linked immunosorbent assay. It was found that HBO2 improved learning and memory, and alleviated myelin injury in mice subjected to acute CO exposure. Furthermore, HBO2 decreased NLRP3, absent in melanoma 2 (AIM2), caspase-1, and apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain mRNA and protein levels, and reduced brain and serum concentrations of IL-1ß and -18 and NADPH oxidase. These results indicate that HBO2 suppresses the inflammatory response after ACOP by blocking NLRP3 inflammasome activation, thereby alleviating cognitive deficits.

[Correlation of insulin resistance with male reproductive hormone levels and semen parameters].

OBJECTIVE: To investigate the influence of insulin resistance on male reproductive hormones and semen quality. METHODS: Using the electrochemiluminescence method, we measured the levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), estradiol (E2) and testosterone (T) in the serum of 83 infertile males. We detected the levels of fasting plasma glucose (FPG) and fasting insulin (FINS) and calculated the insulin resistance index presented as homeostasis model assessment of insulin resistance (HOMA-IR). Based on HOMA-IR, we divided the patients into three tertile groups, T1 (HOMA-IR 0.36－0.55, n = 27), T2 (HOMA-IR 0.56－0.80, n = 28) and T3 (HOMA-IR 0.81－1.97, n = 28), obtained their semen parameters by computer-assisted semen analysis (CASA) and analyzed the correlation of HOMA-IR with male reproductive hormone levels and semen parameters. RESULTS: With the elevation of HOMA-IR, the patients of the T1, T2 and T3 groups showed significant decreases in the serum T level (ï¼»14,26 ± 4.27ï¼½ vs ï¼»14.75 ± 5.00ï¼½ vs ï¼»11.62 ± 3.68ï¼½ nmol/L, P <0.05) and the percentage of progressively motile sperm (PMS) (ï¼»51.04 ± 15.10ï¼½% vs ï¼»48.04 ± 16.24ï¼½% vs ï¼»37.84 ± 18.23ï¼½%, P <0.05). HOMA-IR was correlated negatively with the serum T level (r = －0.333, P = 0.002), semen volume (r = －0.23, P = 0.029) and PMS (r = －0.27, P = 0.015), and so was FINS with the serum T level (r = －0.327, P = 0.003) and PMS (r = －0.315, P = 0.004), while the semen volume was correlated positively with the levels of serum T (r = 0.221, P = 0.048) and FSH (r = 0.222, P = 0.047). Multivariate linear regression analysis showed that HOMA-IR was an independent influencing factor for PMS and the body mass index (BMI) was that for the semen volume and total sperm count. CONCLUSIONS: Insulin resistance may reduce semen quality by changing the levels of male reproductive hormones.