LncRNA SNHG26 promotes gastric cancer progression and metastasis by inducing c-Myc protein translation and an energy metabolism positive feedback loop.

Metastasis is a bottleneck in cancer treatment. Studies have shown the pivotal roles of long noncoding RNAs (lncRNAs) in regulating cancer metastasis; however, our understanding of lncRNAs in gastric cancer (GC) remains limited. RNA-seq was performed on metastasis-inclined GC tissues to uncover metastasis-associated lncRNAs, revealing upregulated small nucleolar RNA host gene 26 (SNHG26) expression, which predicted poor GC patient prognosis. Functional experiments revealed that SNHG26 promoted cellular epithelial-mesenchymal transition and proliferation in vitro and in vivo. Mechanistically, SNHG26 was found to interact with nucleolin (NCL), thereby modulating c-Myc expression by increasing its translation, and in turn promoting energy metabolism via hexokinase 2 (HK2), which facilitates GC malignancy. The increase in energy metabolism supplies sufficient energy to promote c-Myc translation and expression, forming a positive feedback loop. In addition, metabolic and translation inhibitors can block this loop, thus inhibiting cell proliferation and mobility, indicating potential therapeutic prospects in GC.

Aldolase A Accelerates Cancer Progression by Modulating mRNA Translation and Protein Biosynthesis via Noncanonical Mechanisms.

Aldolase A (ALDOA), a crucial glycolytic enzyme, is often aberrantly expressed in various types of cancer. Although ALDOA has been reported to play additional roles beyond its conventional enzymatic role, its nonmetabolic function and underlying mechanism in cancer progression remain elusive. Here, it is shown that ALDOA promotes liver cancer growth and metastasis by accelerating mRNA translation independent of its catalytic activity. Mechanistically, ALDOA interacted with insulin- like growth factor 2 mRNA-binding protein 1 (IGF2BP1) to facilitate its binding to m6 A-modified eIF4G mRNA, thereby increasing eIF4G protein levels and subsequently enhancing overall protein biosynthesis in cells. Importantly, administration of GalNAc-conjugated siRNA targeting ALDOA effectively slows the tumor growth of orthotopic xenografts. Collectively, these findings uncover a previously unappreciated nonmetabolic function of ALDOA in modulating mRNA translation and highlight the potential of specifically targeting ALDOA as a prospective therapeutic strategy in liver cancer.

CRISPR/Cas9 Screens Reveal that Hexokinase 2 Enhances Cancer Stemness and Tumorigenicity by Activating the ACSL4-Fatty Acid ß-Oxidation Pathway.

Metabolic reprogramming is often observed in carcinogenesis, but little is known about the aberrant metabolic genes involved in the tumorigenicity and maintenance of stemness in cancer cells. Sixty-seven oncogenic metabolism-related genes in liver cancer by in vivo CRISPR/Cas9 screening are identified. Among them, acetyl-CoA carboxylase 1 (ACC1), aldolase fructose-bisphosphate A (ALDOA), fatty acid binding protein 5 (FABP5), and hexokinase 2 (HK2) are strongly associated with stem cell properties. HK2 further facilitates the maintenance and self-renewal of liver cancer stem cells. Moreover, HK2 enhances the accumulation of acetyl-CoA and epigenetically activates the transcription of acyl-CoA synthetase long-chain family member 4 (ACSL4), leading to an increase in fatty acid ß-oxidation activity. Blocking HK2 or ACSL4 effectively inhibits liver cancer growth, and GalNac-siHK2 administration specifically targets the growth of orthotopic tumor xenografts. These results suggest a promising therapeutic strategy for the treatment of liver cancer.

The effect of perceived social support during early pregnancy on depressive symptoms at 6 weeks postpartum: a prospective study.

BACKGROUND: Postpartum depression was associated with maternal suffering and diminished functioning, increased risk of marital conflict as well as adverse child outcomes. Perceived social support during pregnancy was associated with postpartum depression among women. However, its causal relationship remains unclear. Therefore, we prospectively evaluate the association between perceived social support during early pregnancy and postpartum depressive symptoms. METHODS: We prospectively examined whether perceived social support during early pregnancy affected depressive symptoms at 6 weeks postpartum in a cohort of 3310 women. Perceived social support and postpartum depression were assessed by ENRICHD Social Support Instrument (ESSI) and the postpartum Edinburgh Postpartum Depression Scale (EPDS), respectively. Prevalence of postpartum depressive symptoms was 11.4% (EPDS cutoff≥10). As a test of heterogeneity of association in subpopulations, logistic regression models were performed to analyze the association between social support and postpartum depressive symptoms in strata which were defined by the potential confounder candidates. After multiple imputation, multivariable logistic regression was performed to assess the effect of social support on postpartum symptoms in individual items and total score. Two models were built. Model I adjusted for the variables associated with social support or postpartum depression and changed the association estimates by ≥10%. Model II adjusted for all variables that may be related to social support or postpartum depression. RESULTS: Significant associations between low perceived social support and postpartum depressive symptoms was found(Model I odds ratio: 1.63, 95% confidence interval: 1.15, 2.30; Model II odds ratio: 1.77, 95% confidence interval: 1.24-2.52). Stratified analyses showed that there was little evidence of heterogeneity of association in subpopulations by basic characteristics of participants. CONCLUSIONS: These findings suggest that early intervention may be able to help protect against depression symptoms at 6 weeks postpartum.

Variant Alleles of the ESR1, PPARG, HMGA2, and MTHFR Genes Are Associated With Polycystic Ovary Syndrome Risk in a Chinese Population: A Case-Control Study.

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age, with a prevalence of 6-8%. Although the etiology of PCOS has been investigated extensively, the association between genetic predisposition and PCOS risk is largely unknown. In this study, we genotyped 63 SNPs in 10 genes among 361 PCOS patients and 331 healthy controls in a Chinese Han population. The following variant alleles were significantly associated with decreased PCOS risk: ESR1 rs9340799 (P = 0.000), PPARG rs709154 (P = 0.013), and rs1151996 (P = 0.013), HMGA2 rs2272046 (P = 0.000), MTHFR rs1801133 (P = 0.000). Accordingly, the following genotypes at various loci were associated with reduced PCOS risk: GA genotype at rs9340799 (P < 0.0001) in ESR1, TA genotype at rs709154(P < 0.0001) in PPARG and CA genotype at rs2272046 (P < 0.0001) in HMGA2. Moreover, GA genotype at rs1999805 (P = 0.013) in ESR1 and TT genotype at rs1801133 in MTHFR (P < 0.0001) correlated with elevated PCOS risk. Furthermore, haplotype analysis revealed significant differences in haplotype distributions of CYP11A1, ESR2 and PPARG gene between cases and controls. In addition to confirming that ESR1 rs9340799, HMGA2 rs2272046 and MTHFR rs1801133 are related to the risk of PCOS, these findings also provide the first evidence that PPARG rs709154 and ESR1 rs1999805 are significantly associated with PCOS risk in a Chinese population. Further functional studies are warranted to elucidate the underlying biological mechanisms.

A genetic variant in the placenta-derived MHC class I chain-related gene A increases the risk of preterm birth in a Chinese population.

Preterm birth (PTB) is a predominant contributor to neonatal mortality and morbidity worldwide. However, the pathophysiology of PTB is not well-understood. We tested the hypothesis that single-nucleotide polymorphisms (SNPs) in the placenta-derived MHC class I chain-related gene A (MICA) could disrupt placental development and hence result in PTB. Nineteen selected SNPs in MICA were genotyped in a case-control study of 127 premature infants and 634 term controls in a Chinese Han population. We found that significantly increased PTB risk was associated with homozygosity for the A variant of rs2256318 (adjusted odds ratio = 6.97 and 95% confidence interval = 2.34-20.74 for A/A, compared with G/G genotype, P = 0.001). In addition, the A/A genotype of rs2256318 was associated with decreased placental weight of neonates (ß = -25.331; P = 0.033). Furthermore, stratified analysis demonstrated that the A/A genotype of rs2256318 was associated with increased PTB risk in female group. In addition, we observed statistical interaction between the polymorphism rs2516448 and sex (P = 0.04). No significant differences in the distribution of haplotypes between cases and controls were detected. Our results indicate that the polymorphism of rs2256318 in MICA may contribute to the etiology of PTB through interfering with placental development. These findings need to be further validated in larger and multi-ethnic populations.

Mechanisms of pyruvate kinase M2 isoform inhibits cell motility in hepatocellular carcinoma cells.

AIM: To investigate biological mechanisms underlying pyruvate kinase M2 isoform (PKM2) regulation of cell migration and invasion in hepatocellular carcinoma cells. METHODS: HepG2 and Huh-7 hepatocellular carcinoma cell lines were stably transfected and cultured in DMEM (HyClone, Logan, UT, United States). To investigate the effects of PKM2 on cellular proliferation, hepatocellular carcinoma cells were subjected to the Cell Counting Kit-8 (Dojindo, Kamimashiki-gun, Kumamoto, Japan). And investigate the effects of PKM2 on cell signal pathway related with migration and invasion, Western immunoblotting were used to find out the differential proteins. All the antibody used was purchaseed from Cell Signal Technology. In order to explore cell motility used Transwell invasion and wound healing assays. The transwell plate with 0.5 mg/mL collagen type I (BD Bioscience, San Jose, CA)-coated filters. The wound-healing assay was performed in 6-well plates. Total RNA was extracted using TRIzol reagent (Invitrogen, CA, United States) and then reverse transcription was conducted. Quantitative reverse transcription-polymerase chain reaction (PCR) analysis was performed with the ABI 7500 real-time PCR system (Applied Biosystems). We further use digital gene expression tag profiling and identification of differentially expressed genes. RESULTS: The cells seeded in four 96-well plates were measured OD450 by conducted Cell Counting Kit-8. From this conduction we observed that both HepG2 and Huh-7 hepatocellular carcinoma cells with silenced PKM2 turn on a proliferate inhibition; however, cell migration and invasion were enhanced compared with the control upon stimulation with epidermal growth factor (EGF). Our results indicate that the knockdown of PKM2 decreased the expression of E-cadherin and enhanced the activity of the EGF/EGFR signaling pathway, furthermore up-regulate the subsequent signal molecular the PLCγ1 and extracellular signal-regulated kinase 1/2 expression in the hepatocellular carcinoma cell lines HepG2 and Huh-7, which regulates cell motility. These variations we observed were due to the activation of the transforming growth factor beta (TGFß) signaling pathway after PKM2 knockdown. We also found that the expression of TGFBRI was increased and the phosphorylation of Smad2 was enhanced. Taken together, our findings demonstrate that PKM2 can regulate cell motility through the EGF/EGFR and TGFß/TGFR signaling pathways in hepatocellular carcinoma cells. CONCLUSION: PKM2 play different roles in modulating the proliferation and metastasis of hepatocellular carcinoma cells, and this finding could help to guide the future targeted therapies.