Biology subjects

Li, C.-Q.

Publications and source records attributed to Li, C.-Q..

7 recordsLinked to original sources

bioRxiv2019

TP63, SOX2 and KLF5 Establish Core Regulatory Circuitry and Construct Cancer Specific Epigenome in Esophageal Squamous Cell Carcinoma

Transcriptional network is controlled by master transcription factors (TFs) and cis-regulatory elements through interacting with target sequences and recruiting epigenetic regulators. By integration of enhancer profiling and chromatin accessibility, we establish super-enhancer (SE) mediated core regulatory circuitry (CRC) for esophageal squamous cell carcinoma (ESCC) and identify tumor cells-dependent CRC TFs-TP63, SOX2 and KLF5. They preferentially co-occupy SE loci and form a positive interconnected auto-regulatory loop through SEs to orchestrate chromatin and transcriptional programming. SE-associated oncogene-ALDH3A1 is identified as a novel CRC target contributing to ESCC viability. Using circular chromosome conformation capture sequencing (4C-seq) and CRISPR/Cas9 genome editing, the direct interaction between TP63 promoter and functional enhancers which is mediated by CRC TFs is identified. Deletion of each enhancer decreases expression of CRC TFs and impairs cell viability, phenocopying the knockdown of each CRC TF. Targeting epigenetic regulation by inhibition of either the BET bromodomain or HDAC disrupts the CRC program and its dependent global epigenetic modification, consequently suppressing ESCC tumor growth. Importantly, combination of both compounds result in synergistic anti-tumor effect.\n\nGraphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=162 SRC=\"FIGDIR/small/825372v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (58K):\norg.highwire.dtl.DTLVardef@1a9f923org.highwire.dtl.DTLVardef@238c90org.highwire.dtl.DTLVardef@1e14f58org.highwire.dtl.DTLVardef@120249a_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LISuper-enhancers mediated transcriptional regulatory circuitry is established for ESCC\nC_LIO_LITP63, SOX2 and KLF5 as CRC TFs co-localize super-enhancer loci to orchestrate chromatin accessibility and transcriptional dysregulation\nC_LIO_LIComplex interaction between functional enhancers and TP63 promoter is mediated by CRC TFs\nC_LIO_LIALDH3A1 is a key downstream target of ESCC CRC and is essential for ESCC cell survival\nC_LIO_LIBET degrader-ARV-771 and HDAC inhibitor-Romidepsin synergistically inhibit ESCC tumor growth\nC_LI

cancer biology↗

bioRxiv2018

Reversal of microRNA-blocked tumor suppressors by biphenyl- dicarboxylate impedes endotoxin-induced hepatic hyperplasia

Hepatocellular carcinoma (HCC) is one of the most common malignant tumor and the leading cause of cancer-related death worldwide. Biphenyldicarboxylate (BPDC), an intermediate of schisandrin C from Schisandra chinensis, has been used as a hepatoprotective agent that compromises hepatic injuries in China for decades. Whether BPDC is also implicated in the prevention of HCC remains understood. Here, we report that the bacterial endotoxin lipopolysaccharide (LPS) promotes hepatic inflammation and hyperplasia, during which the common tumor markers, alpha fetoprotein (AFP) and carcinoembryonic antigen (CEA), were unregulated, whereas the tumor suppressors, PTEN, FOXO1 and MEN1, were downregulated through increasing the microRNAs, miR-21, miR-122 and miR-24. In contrast, BPDC dampened hepatic inflammation and hyperplasia accompanied by the upregulation of PTEN, FOXO1 and MEN1 through decreasing miR-21, miR-122 and miR-24. However, BPDC failed to downregulate the tumor marker AEG-1 via increasing miR-195. Taken together, BPDC exerts anti-tumor effects by upregulating tumor suppressors upon decreases of miRNAs rather than downregulating tumor markers by increases of miRNAs.

cancer biology↗

bioRxiv2018

Short-hairpin RNA-guided single gene knockdown reverses triple-negative breast cancer

BackgroundThe origin of breast cancer remains poorly understood. Here, we testify a putative mechanism of \"breast cancer origin from inducible nitric oxide synthase (iNOS) activation and oestrogen receptor alpha (ER) inactivation\", which are classified as the essential outcomes of chronic inflammatory responses.\n\nMethodsTo reverse breast cancer status, iNOS was downregulated by short-hairpin RNA (shRNA)-guided NOS2 knockdown from human triple-negative breast cancer (TNBC) cells. To re-enact breast cancer origin, ER was downregulated by shRNA-directed ESR1 knockdown in human mammary epithelial cells.\n\nResultsUpon NOS2 knockdown from HCC1937 cells, the specific TNBC transcription factor genes, RUNX1 and BCL11A, were downregulated, hypoxia was compromised, Warburg effects were attenuated, and tumourigenic proliferation was halted, accompanied by an increase in the tumour marker cyclin D1 (CD1) and a decrease in the tumour suppressor cyclin-dependent kinase inhibitor (CKI). In contrast, ESR1 knockdown from MCF-10A cells led to upregulated BCL11A and RUNX1 expression, augmented hypoxic responses, pronounced Warburg effects, and enhanced PI3K/Akt/mTOR signalling, together with low levels of CD1 and high levels of CKI induction.\n\nConclusionsBreast cancer should originate from inflammatory signalling, during which iNOS activation and ER inactivation elicit hypoxia, oxidation, mitochondrial dysfunction, and breast cancer-like hyperplasia, demonstrating that iNOS inhibitors and ER activators represent promising candidate prodrugs enabling breast cancer prevention in the early stage.

cancer biology↗

bioRxiv2017

Insulin Does Not Augment In Vitro Tumor Growth Under A Hyperglycemia-Mimicking Milieu And In A Calorie Restriction-Resembling Manner

BackgroundWhether insulin enhances or represses tumor cell proliferation remains debating and inconclusive although epidemiological data indicated insulin use raises a risk of cancer incidence in patients with diabetes mellitus (DM).\n\nMethodology/Principle FindingsWe cultured rat pituitary adenoma cells in a high-glucose medium to simulate hyperglycemia occurring in DM patients. Upon incubation with or without insulin, repressed tumor cell proliferation and downregulated tumor marker expression occur accompanying with mitigated oxidative stress and compromised apoptosis. Mechanistically, insulin resistance-abrogated glucose uptake was suggested to create an intracellular low-glucose milieu, leading to cellular starvation resembling calorie restriction (CR). While downregulation of insulin-like growth factor 1 (IGF-1) occurring in CR was validated, oncogene downregulation and tumor suppressor gene upregulation seen in CR was also replicated by NOS2 knockdown.\n\nConclusions/SignificanceCellular starvation can exert CR-like anti-tumor effects regardless of insulin presence or absence.

cancer biology↗

bioRxiv2017

Artemisinin mimics nitric oxide to reduce adipose weight by targeting mitochondrial complexes

It remains obscure how to medically manage visceral obesity that predisposes metabolic disorders. Here, we show for the first time that a trace amount of artemisinin (0.25 mg/kg) reduces adipose weight in an inflammatory obese mouse model induced by a high-fat diet with lipopolysaccharide (HFD+LPS). HFD+LPS trigger pro-inflammatory responses, upregulate NOS2 expression, elicit potent nitric oxide (NO) burst, and reinforce adipose mitochondrial dysfunctions that facilitate adipogenesis for visceral weight gain. By targeting mitochondrial complexes, artemisinin resembles the NO donor nitroglycerin to exert anti-inflammatory effects, downregulate NOS2 expression, maintain stable NO release, and augment adipose mitochondrial functions that necessitate adipolysis for visceral weight loss. Taken together, artemisinin plays adipose weight-reducing roles by rectifying inflammation-driven mitochondrial dysfunctions.

pharmacology and toxicology↗

bioRxiv2017

Chondroitin Sulfate Flourishes Gut Sulfatase-Secreting Bacteria To Damage Mucus Layers, Leak Bacterial Debris, And Trigger Inflammatory Lesions In Mice

BackgroundAn interaction of the food types with the gut microbiota changes is deeply implicated in human health and disease. To verify whether animal-based diets would lead to gut dysbiosis, systemic inflammation and inflammatory pathogenesis, we fed mice with chondroitin sulfate (CS), a sulfate-containing O-glycan naturally occurring in livestock and poultry products, and monitored the dynamic changes of microbial flores, inflammatory signatures, and pathogenic hallmarks.\n\nResultsA metagenomic gut microbiota analysis revealed the overgrowth of sulfatase-secreting bacteria and sulfate-reducing bacteria in the gastrointestinal tracts of mice upon daily CS feeding. Sulfatase-secreting bacteria compromise gut integrity through prompting mucin degradation and mucus lesions, which were evident from the upregulation of secretary leukocyte protease inhibitor (SLPI) and mucin 1/4 (MUC-1/4). A synchronous elevation of lipopolysaccharide (LPS) and tumor necrosis factor (TNF-) levels in the serum as well as cerebral, hepatic, cardiac and muscular tissues suggests bacterial endotoxinemia, chronic low-grade inflammation and mitochondrial dysfunction, eventually leading to the onset of global inflammatory pathogenesis towards arthritis, dementia, tumor, and fatty liver.\n\nConclusionsCS triggers the early-phase and multi-systemic pathogenesis like arthritis, dementia, tumor, and fatty liver by enhancing gut opportunistic infection and evoking low-grade inflammation in mice. A plausible reason for the inconsistency of CS in treatment of osteoarthritis (OA) was also discussed.

pathology↗

bioRxiv2017

Chondroitin sulfate elicits systemic pathogenesis in mice by interfering with gut microbiota homeostasis

Whether chondroitin sulfate (CS), a common ingredient naturally occurring in livestock and poultry products, improves osteoarthritis remains debating. Here, we show for the first time that CS induces steatogenesis, atherogenesis, and dementia-like pathogenesis in mice. Gut microbiome analysis revealed the sulfatase-secreting bacteria Rikenella and the sulfate-reducing bacteria Desulfovibrio are enriched. Surprisingly, berberine use boosts CS-induced multi-loci inflammatory manifestations by further increasing the abundance of Rikenella and Desulfovibrio, whereas cephalosporin reinforces the colon mucus barrier via flourishing Akkermansia muciniphila and upregulating mucin expression. Mechanistically, berberine aggravates mucus lining injury by prompting mucin degradation, endotoxin leakage, neutralizing antibody induction, pro-inflammatory cytokine burst, lactic acid accumulation and energy currency depletion in multiple organs and tissues. Taken together, CS evokes the early-phase pathogenesis toward steatohepatitis, atherosclerosis, and dementia upon augmenting gut opportunistic infection, and a sustained antibiotic monotherapy does not deprive the risk of CS-driven systemic inflammatory disorders.

pharmacology and toxicology↗