HOXD8 suppresses renal cell carcinoma growth by upregulating SHMT1 expression.

Amplification of amino acids synthesis is reported to promote tumorigenesis. The serine/glycine biosynthesis pathway is a reversible conversion of serine and glycine catalyzed by cytoplasmic serine hydroxymethyltransferase (SHMT)1 and mitochondrial SHMT2; however, the role of SHTM1 in renal cell carcinoma (RCC) is still unclear. We found that low SHMT1 expression is correlated with poor survival of RCC patients. The in vitro study showed that overexpression of SHMT1 suppressed RCC proliferation and migration. In the mouse tumor model, SHMT1 significantly retarded RCC tumor growth. Furthermore, by gene network analysis, we found several SHMT1-related genes, among which homeobox D8 (HOXD8) was identified as the SHMT1 regulator. Knockdown of HOXD8 decreased SHMT1 expression, resulting in faster RCC growth, and rescued the SHMT1 overexpression-induced cell migration defects. Additionally, ChIP assay found the binding site of HOXD8 to SHMT1 promoter was at the -456~-254 bp region. Taken together, SHMT1 functions as a tumor suppressor in RCC. The transcription factor HOXD8 can promote SHMT1 expression and suppress RCC cell proliferation and migration, which provides new mechanisms of SHMT1 in RCC tumor growth and might be used as a potential therapeutic target candidate for clinical treatment.

Identification of the regulatory mechanism of ACE2 in COVID-19-induced kidney damage with systems genetics approach.

Studies showed that SARS-CoV-2 can directly target the kidney and induce renal damage. As the cell surface receptor for SARS-CoV-2 infection, the angiotensin-converting enzyme 2 (ACE2) plays a pivotal role for renal physiology and function. Thus, it is important to understand ACE2 through which pathway influences the pathogenesis of renal damage induced by COVID-19. In this study, we first performed an eQTL mapping for Ace2 in kidney tissues in 53 BXD mice strains. Results demonstrated that Ace2 is highly expressed and strongly controlled by a genetic locus on chromosome 16 in the kidney, with six genes (Dnase1, Vasn, Usp7, Abat, Mgrn1, and Rbfox1) dominated as the upstream modulator, as they are highly correlated with Ace2 expression. Gene co-expression analysis showed that Ace2 co-variates are significantly involved in the renin-angiotensin system (RAS) pathway which acts as a reno-protector. Importantly, we also found that Ace2 is positively correlated with Pdgf family members, particularly Pdgfc, which showed the most association among the 76 investigated growth factors. Mammalian Phenotype Ontology enrichment indicated that the cognate transcripts for both Ace2 and Pdgfc were mainly involved in regulating renal physiology and morphology. Among which, Cd44, Egfr, Met, Smad3, and Stat3 were identified as hub genes through protein-protein interaction analysis. Finally, in aligning with our systems genetics findings, we found ACE2, pdgf family members, and RAS genes decreased significantly in the CAKI-1 kidney cancer cells treated with S protein and receptor binding domain structural protein. Collectively, our data suggested that ACE2 work with RAS, PDGFC, as well as their cognate hub genes to regulate renal function, which could guide for future clinical prevention and targeted treatment for COVID-19-induced renal damage outcomes. KEY MESSAGES: • Ace2 is highly expressed and strongly controlled by a genetic locus on chromosome 16 in the kidney. • Ace2 co-variates are enriched in the RAS pathway. • Ace2 is strongly correlated with the growth factor Pdgfc. • Ace2 and Pdgfc co-expressed genes involved in the regulation of renal physiology and morphology. • SARS-CoV-2 spike glycoprotein induces down-regulation of Ace2, RAS, and Pdgfc.

Analysis of the expression, function and signaling of glycogen phosphorylase isoforms in hepatocellular carcinoma.

Glycogen phosphorylase (GP) is an essential enzyme for glycolysis via the glycogen degradation pathway. It consists of three isoforms: PYGB (brain form), PYGL (liver form) and PYGM (muscle form). Although the abnormal expression of GP is associated with a variety of tumors, its relationship with hepatocellular carcinoma (HCC) and whether it can be used as a prognostic marker of HCC remains unclear. In the present study, the expression levels of PYGB, PYGL and PYGM were analyzed. It was found that the expression levels of PYGB in tumor tissues were higher than those in normal tissues, particularly in HCC. The high expression of PYGB (hazard ratios=1.801; 95% confidence interval: 1.266-2.562) could predict the poor prognosis of HCC patients but not PYGL and PYGM. Inhibition of PYGB with GP inhibitor CP91149 significantly suppressed the HCC cell proliferation in the HCC cell model. In addition, combination treatment with sorafenib, a standard treatment for HCC, showed a great inhibition on tumor growth and angiogenesis. These findings suggested that PYGB may be used as a therapeutic and prognostic indicator for HCC.

Quantitative proteomics approach reveals novel biomarkers and pathological mechanism of keloid.

BACKGROUND: Keloid is a pathological skin scar formation with complex and unclear molecular pathology mechanism. Novel biomarkers and associated mechanisms are needed to improve current therapies. OBJECTIVES: To identify novel biomarkers and underlying pathological mechanisms of keloids. METHODS: Six pairs of keloid scar tissues and corresponding normal skin tissues were quantitatively analyzed by a high-resolution label-free mass spectrometry-based proteomics approach. Differential protein expression data was further analyzed by a comprehensive bioinformatics approach to identify novel biomarkers and mechanistic pathways for keloid formation. Candidate biomarkers were validated experimentally. RESULTS: In total, 1359 proteins were identified by proteomic analysis. Of these, 206 proteins exhibited a significant difference in expression between keloid scar and normal skin tissues. RCN3 and CALU were significantly upregulated in keloids. RCN1 and PDGFRL were uniquely expressed in keloids. Pathway analysis suggested that the XBP1-mediated unfolded protein response (UPR) pathway was involved in keloid formation. Moreover, a PDGFRL centric gene coexpression network was constructed to illustrate its function in skin. CONCLUSIONS AND CLINICAL RELEVANCE: Our study proposed four novel biomarkers and highlighted the role of XBP1-mediated UPR pathway in the pathology of keloids. It provided novel biological insights that contribute to develop novel therapeutic strategies for keloids.

Transcriptome-wide association study reveals cholesterol metabolism gene Lpl is a key regulator of cognitive dysfunction.

Cholesterol metabolism in the brain plays a crucial role in normal physiological function, and its aberrations are associated with cognitive dysfunction. The present study aimed to determine which cholesterol-related genes play a vital role in cognitive dysfunction and to dissect its underlying molecular mechanisms using a systems genetics approach in the BXD mice family. We first systematically analyzed the association of expression of 280 hippocampal genes related to cholesterol metabolism with cognition-related traits and identified lipoprotein lipase (Lpl) as a critical regulator. This was further confirmed by phenome-wide association studies that indicate Lpl associated with hippocampus volume residuals and anxiety-related traits. By performing expression quantitative trait locus mapping, we demonstrate that Lpl is strongly cis-regulated in the BXD hippocampus. We also identified ∼3,300 genes significantly (p < 0.05) correlated with the Lpl expression. Those genes are mainly involved in the regulation of neuron-related traits through the MAPK signaling pathway, axon guidance, synaptic vesicle cycle, and NF-kappa B signaling pathway. Furthermore, a protein-protein interaction network analysis identified several direct interactors of Lpl, including Rab3a, Akt1, Igf1, Crp, and Lrp1, which indicates that Lpl involves in the regulation of cognitive dysfunction through Rab3a-mediated synaptic vesicle cycle and Akt1/Igf1/Crp/Lrp1-mediated MAPK signaling pathway. Our findings demonstrate the importance of the Lpl, among the cholesterol-related genes, in regulating cognitive dysfunction and highlighting the potential signaling pathways, which may serve as novel therapeutic targets for the treatment of cognitive dysfunction.

Hippocampal Transcriptome-Wide Association Study Reveals Correlations Between Impaired Glutamatergic Synapse Pathway and Age-Related Hearing Loss in BXD-Recombinant Inbred Mice.

Age-related hearing loss (ARHL) is associated with cognitive dysfunction; however, the detailed underlying mechanisms remain unclear. The aim of this study is to investigate the potential underlying mechanism with a system genetics approach. A transcriptome-wide association study was performed on aged (12-32 months old) BXD mice strains. The hippocampus gene expression was obtained from 56 BXD strains, and the hearing acuity was assessed from 54 BXD strains. Further correlation analysis identified a total of 1,435 hearing-related genes in the hippocampus (p < 0.05). Pathway analysis of these genes indicated that the impaired glutamatergic synapse pathway is involved in ARHL (p = 0.0038). Further gene co-expression analysis showed that the expression level of glutamine synthetase (Gls), which is significantly correlated with ARHL (n = 26, r = -0.46, p = 0.0193), is a crucial regulator in glutamatergic synapse pathway and associated with learning and memory behavior. In this study, we present the first systematic evaluation of hippocampus gene expression pattern associated with ARHL, learning, and memory behavior. Our results provide novel potential molecular mechanisms involved in ARHL and cognitive dysfunction association.

Differences in clinical features of hypertrophic cardiomyopathy with or without left ventricular enlargement.

BACKGROUND: Few studies have focused on the clinical features of hypertrophic cardiomyopathy (HCM) with enlarged left ventricle (ELV). METHODS: In this study, participants were patients with HCM (n=170), who were divided into two groups [ELV and normal left ventricle (NLV)] according to left ventricle size. Age at diagnosis, sex, complications, electrocardiogram (ECG), symptoms, drug treatment, and echocardiographic parameters were compared between the NLV (n=153) and ELV (n=17) groups. RESULTS: The incidence of end-stage HCM (ES-HCM) among all HCM patients was 5.29%, while that of ELV was 10.0%. For all patients with HCM and those with asymmetric septal HCM (ASHCM), there were more males with ELV than NLV. Of the patients with HCM and ASHCM, left ventricular ejection fraction (LVEF) was significantly lower in the ELV group than the NLV group; accordingly, the rates of diuretics use in the ELV group were higher than those in the NLV group. Among apical HCM (ApHCM) patients, the left atrial diameter (LAd), incidence of atrial fibrillation (Af) or ST-T change, and rate of angiotensin converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) use were all higher in the ELV group compared to the NLV group. CONCLUSIONS: These findings suggest that the prevalence of ES-HCM in HCM patients with ELV was higher than those with NLV. Additionally, ELV is more common in men than women and there are differences in the clinical features of different types of HCM with ELV.

The effect of hypertension on cardiac structure and function in different types of hypertrophic cardiomyopathy: A single-center retrospective study.

OBJECTIVES: To determine whether hypertension (HTN) affects cardiac structure and function in different types of hypertrophic cardiomyopathy (HCM). DESIGN: Patients with obstructive HCM (n = 40), septal HCM (n = 88), and apical HCM (n = 42) were separated into hypertensive and non-hypertensive subgroups, and echocardiographic parameters at baseline and at follow-up were compared between the subgroups. RESULTS: At follow-up, hypertensive obstructive HCM patients showed a decrease in end-diastolic volume (from 93.87 ± 26.08 mL to 79.06 ± 20.07 mL; p= 0.045) and in left ventricular end-diastolic diameter (from 45.00 ± 5.32 mm to 41.83 ± 4.58 mm; p =0.042). Non-hypertensive obstructive HCM patients showed a decrease in maximum aortic velocity (from 2.01 ± 0.53 m/s to 1.28 ± 0.25 m/s; p= 0.011) and in aortic maximum pressure gradient (from 17.22 ± 9.57 mm Hg to 6.79 ± 2.44 mm Hg; p= 0.03). Hypertensive apical HCM patients showed an increase in end-diastolic volume (from 95.28 ± 16.54 mL to 119.74 ± 25.19 mL; p= 0.016) and in left ventricular end-diastolic diameter (from 45.28 ± 3.36 mm to 50.20 ± 4.56 mm; p= 0.007). CONCLUSIONS: HTN can affect left ventricular capacity in obstructive HCM and apical HCM, causing a decrease in ventricular capacity in the former and increase in the latter; it has no significant effect on the size of the left ventricular cavity in septal HCM. HTN can lead to a poor therapeutic effect on aortic flow rate and pressure gradient in obstructive HCM patients.