A Novel Role for Tm7sf2 Gene in Regulating TNFα Expression

Cholesterol affects cancer progression, and acetyl‐CoA is the primary cholesterogenesis substrate. The previous work has defined cholesterol bioflux via lipoprotein/receptor route is the gastric cancer (GCa) prognosis biosignature. The prognosis importance of acetyl‐CoA to cholesterogenesis (mevalonate pathway) in GCa is yet to be defined. Using Kaplan–Meier Plotter web‐based gene survival analyzer and The Cancer Genome Atlas (TCGA)‐database analyzed with DBdriver.v2 platform, we revealed acetyl‐CoA production and the mevalonate pathway are associated with GCa prognosis. We found mitochondrial‐derived acetyl‐CoA contributing enzymes (acyl‐coA synthetase super‐family 3; ACSS3) is the GCa progression confounder. Interestingly, it is not HMGCR (the committee enzyme of mevalonate pathway), but lower mevalonate pathway enzymes (e.g., MVK, LSS, DHCR14A1, SC4MOL, HSD17B7, SC5D) promote GCa patients 5‐years overall survival in a differential level. Advanced analyses found ACSS3 is prognosis biosignatures for multiple GCa disease conditions. This report uncovered a higher expression of ACSS3 in tumor comparing to normal parental lesions, which implicates a targeting value for GCa therapy. While knockdown ACSS3 could suppress growth and invasion of GCa cells, of which even more impactful under starvation condition. This is the first report, surprisingly, revealed ACSS3 as important cancer prognosis biomarker. Targeting ACSS3 could be a novel therapeutic strategy for cancer, in this case, GCa.

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“…In addition, Bellezza et al. (2013) found that DHCR14 serves as innate immune modulator by regulating TNF α expression .…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Acetyl‐CoA Synthetase 3 is Biosignature of Gastric Cancer Progression

Chang

Cheng

et al. 2018

Cancer Medicine

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“…Can other factors affect the impairment in proliferation observed in absence of Tm7sf2 gene? Recently, it has been determined that Tm7sf2 KO mice present an altered ER stress response following different stress inducing treatments 27 and liver regeneration represents a strong stress condition in ER. Moreover, it has been demonstrated that lipids accumulated in hepatocytes after PH can trigger ER stress, which in turn may result in a delay in DNA replication and impairment of liver regeneration.…”

Section: Discussionmentioning

confidence: 99%

“…27 For this reason, we evaluated whether the adaptive program of the Unfolded Protein Response (UPR) triggered by ER stress was modified in ÃÃ P < 0.01, ÃÃÃ P < 0.001.…”

Section: Increased Er Stress Response During Liver Regeneration In Tmmentioning

confidence: 99%

“…23 However, abnormal activation of the ER stress response was documented in quiescent livers of these mice. 27 Moreover, affymetrix microarray analysis of gene expression conducted in the liver of Tm7sf2 KO mice showed that many genes involved in cell-cycle progression are downregulated whereas genes involved in xenobiotic metabolism are upregulated. 23 Because of the importance of cholesterol in cell structure and functionality, we asked whether the absence of Tm7sf2 would affect the process of liver regeneration.…”

Section: Introductionmentioning

confidence: 99%

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Impaired cell proliferation in regenerating liver of 3 β-hydroxysterol Δ14-reductase (TM7SF2) knock-out mice

et al. 2016

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The liver is the most important organ in cholesterol metabolism, which is instrumental in regulating cell proliferation and differentiation. The gene Tm7sf2 codifies for 3 b-hydroxysterol-D 14 -reductase (C14-SR), an endoplasmic reticulum resident protein catalyzing the reduction of C14-unsaturated sterols during cholesterol biosynthesis from lanosterol. In this study we analyzed the role of C14-SR in vivo during cell proliferation by evaluating liver regeneration in Tm7sf2 knockout (KO) and wild-type (WT) mice. Tm7sf2 KO mice showed no alteration in cholesterol content. However, accumulation and delayed catabolism of hepatic triglycerides was observed, resulting in persistent steatosis at all times post hepatectomy. Moreover, delayed cell cycle progression to the G1/S phase was observed in Tm7sf2 KO mice, resulting in reduced cell division at the time points examined. This was associated to abnormal ER stress response, leading to alteration in p53 content and, consequently, induction of p21 expression in Tm7sf2 KO mice. In conclusion, our results indicate that Tm7sf2 deficiency during liver regeneration alters lipid metabolism and generates a stress condition, which, in turn, transiently unbalances hepatocytes cell cycle progression.

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“…Transmembrane 7 superfamily member 2 (Tm7sf2) functions just downstream of Sqle in the cholesterol biosynthesis pathway, and its function is linked to liver X receptor (LXR) and NFκβ signaling, suggesting roles in both lipid homeostasis and inflammation (Bellezza et al 2013).…”

Section: Candidate Genes Fall Into Similar Functional Pathwaysmentioning

confidence: 99%

Suppressor mutations in Mecp2-null mice reveal that the DNA damage response is key to Rett syndrome pathology

Enikanolaiye

Ruston

Zeng

et al. 2019

Preprint

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Mutations in X-linked methyl-CpG-binding protein 2 (MECP2) cause Rett syndrome (RTT).We carried out a genetic screen for secondary mutations that improved phenotypes in Mecp2/Y mice after mutagenesis with N-ethyl-N-nitrosourea (ENU), aiming to identify potential therapeutic entry points. Here we report the isolation of 106 founder animals that show suppression of Mecp2-null traits from screening 3,177 Mecp2/Y genomes. Using exome sequencing, genetic crosses and association analysis, we identify 33 candidate genes in 30 of the suppressor lines. A network analysis shows that 61% of the candidate genes cluster into the functional categories of transcriptional repression, chromatin modification or DNA repair, delineating a pathway relationship with MECP2. Many mutations lie in genes that are predicted to modulate synaptic signaling or lipid homeostasis. Surprisingly, mutations in genes that function in the DNA damage response (DDR) also improve symptoms in Mecp2/Y mice. The combinatorial effects of multiple loci can be resolved by employing association analysis. One line, which was previously reported to carry a suppressor mutation in a gene required for cholesterol synthesis, Sqle, carries a second mutation in retinoblastoma binding protein 8 (Rbbp8 or CtIP), which regulates a DDR choice in double stranded break (DSB) repair. Cells from Mecp2/Y mice have increased DSBs, so this finding suggests that the balance between homology directed repair and non-homologous end joining is important for neuronal cells. In this and other lines, the presence of two suppressor mutations confers better symptom improvement than one locus alone, suggesting that combination therapies could be effective in RTT.

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A Novel Role for Tm7sf2 Gene in Regulating TNFα Expression

Cited by 25 publications

References 52 publications

Mitochondrial Acetyl‐CoA Synthetase 3 is Biosignature of Gastric Cancer Progression

Mitochondrial Acetyl‐CoA Synthetase 3 is Biosignature of Gastric Cancer Progression

Impaired cell proliferation in regenerating liver of 3 β-hydroxysterol Δ14-reductase (TM7SF2) knock-out mice

Suppressor mutations in Mecp2-null mice reveal that the DNA damage response is key to Rett syndrome pathology

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