STAT3 activation of SCAP-SREBP-1 signaling upregulates fatty acid synthesis to promote tumor growth.

SCAP plays a central role in controlling lipid homeostasis by activating SREBP-1, a master transcription factor in controlling fatty acid (FA) synthesis. However, how SCAP expression is regulated in human cancer cells remains unknown. Here, we revealed that STAT3 binds to the promoter of SCAP to activate its expression across multiple cancer cell types. Moreover, we identified that STAT3 also concurrently interacts with the promoter of SREBF1 gene (encoding SREBP-1), amplifying its expression. This dual action by STAT3 collaboratively heightens FA synthesis. Pharmacological inhibition of STAT3 significantly reduces the levels of unsaturated FAs and phospholipids bearing unsaturated FA chains by reducing the SCAP-SREBP-1 signaling axis and its downstream effector SCD1. Examination of clinical samples from patients with glioblastoma, the most lethal brain tumor, demonstrates a substantial co-expression of STAT3, SCAP, SREBP-1, and SCD1. These findings unveil STAT3 directly regulates the expression of SCAP and SREBP-1 to promote FA synthesis, ultimately fueling tumor progression.

Association of Inpatient Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Mortality Among Patients With Hypertension Hospitalized With COVID-19.

RATIONALE: Use of ACEIs (angiotensin-converting enzyme inhibitors) and ARBs (angiotensin II receptor blockers) is a major concern for clinicians treating coronavirus disease 2019 (COVID-19) in patients with hypertension. OBJECTIVE: To determine the association between in-hospital use of ACEI/ARB and all-cause mortality in patients with hypertension and hospitalized due to COVID-19. METHODS AND RESULTS: This retrospective, multi-center study included 1128 adult patients with hypertension diagnosed with COVID-19, including 188 taking ACEI/ARB (ACEI/ARB group; median age 64 [interquartile range, 55-68] years; 53.2% men) and 940 without using ACEI/ARB (non-ACEI/ARB group; median age 64 [interquartile range 57-69]; 53.5% men), who were admitted to 9 hospitals in Hubei Province, China from December 31, 2019 to February 20, 2020. In mixed-effect Cox model treating site as a random effect, after adjusting for age, gender, comorbidities, and in-hospital medications, the detected risk for all-cause mortality was lower in the ACEI/ARB group versus the non-ACEI/ARB group (adjusted hazard ratio, 0.42 [95% CI, 0.19-0.92]; P=0.03). In a propensity score-matched analysis followed by adjusting imbalanced variables in mixed-effect Cox model, the results consistently demonstrated lower risk of COVID-19 mortality in patients who received ACEI/ARB versus those who did not receive ACEI/ARB (adjusted hazard ratio, 0.37 [95% CI, 0.15-0.89]; P=0.03). Further subgroup propensity score-matched analysis indicated that, compared with use of other antihypertensive drugs, ACEI/ARB was also associated with decreased mortality (adjusted hazard ratio, 0.30 [95% CI, 0.12-0.70]; P=0.01) in patients with COVID-19 and coexisting hypertension. CONCLUSIONS: Among hospitalized patients with COVID-19 and coexisting hypertension, inpatient use of ACEI/ARB was associated with lower risk of all-cause mortality compared with ACEI/ARB nonusers. While study interpretation needs to consider the potential for residual confounders, it is unlikely that in-hospital use of ACEI/ARB was associated with an increased mortality risk.

Single-cell proteomic chip for profiling intracellular signaling pathways in single tumor cells.

We describe a microchip designed to quantify the levels of a dozen cytoplasmic and membrane proteins from single cells. We use the platform to assess protein-protein interactions associated with the EGF-receptor-mediated PI3K signaling pathway. Single-cell sensitivity is achieved by isolating a defined number of cells (n = 0-5) in 2 nL volume chambers, each of which is patterned with two copies of a miniature antibody array. The cells are lysed on-chip, and the levels of released proteins are assayed using the antibody arrays. We investigate three isogenic cell lines representing the cancer glioblastoma multiforme, at the basal level, under EGF stimulation, and under erlotinib inhibition plus EGF stimulation. The measured protein abundances are consistent with previous work, and single-cell analysis uniquely reveals single-cell heterogeneity, and different types and strengths of protein-protein interactions. This platform helps provide a comprehensive picture of altered signal transduction networks in tumor cells and provides insight into the effect of targeted therapies on protein signaling networks.

Natural tea polyphenol functionalized graphene anode for simultaneous power production and degradation of methyl orange dye in microbial fuel cells.

The microbial fuel cell (MFCs) has dual functions, capable of achieving dye decolorization and synchronous power generation. Despite these advantages, the MFCs have faced challenges related to low electron transfer efficiencies and limited dye treatment capacity in wastewater applications. This work introduces an innovative approach by employing reduced graphene oxide-modified carbon cloth (TP-RGO@CC) anodes, utilizing tea polyphenols as the reducing agent. This modification significantly enhances the hydrophilicity and biocompatibility of the anodes. The MFC equipped with the TP-RGO@CC anode demonstrated a remarkable increase in the maximum power density, reaching 773.9 mW m-2, representing a 22% improvement over the plain carbon cloth electrode. The decolorization rate of methyl orange (50 mg L-1, pH 7) reached 99% within 48 h. Biodiversity analysis revealed that the TP-RGO@CC anode selectively enriched electrogens producing and organic matter-degrading bacteria, promoting a dual mechanism of dye decolorization, degradation, and simultaneous electro-production at the anode. This work highlights advanced anode materials that excel in effective pollutant removal, energy conversion, and biomass reuse.

Integrated tea polyphenols and polydopamine functionalized graphene anode for improved bioelectricity generation and Cr(VI) reduction in microbial fuel cells.

Microbial fuel cells (MFCs) have the dual advantage of mitigating Cr(Ⅵ) wastewater ecological threats while generating electricity. However, the low electron transfer efficiency and the limited enrichment of active electrogens are barriers to MFCs advancement. This study describes the synthesis of the TP-PDA-RGO@CC negative electrode using tea polyphenol as a reducing agent and polydopamine-doped graphene, significantly enhances the roughness and hydrophilicity of the anode. The charge transfer resistance was reduced by 94%, and the peak MFC power was 1375.80 mW·m-2. Under acidic conditions, the Cr(Ⅵ) reduction rate reached 92% within 24 h, with a 52% increase in coulombic efficiency. Biodiversity analysis shows that the TP-PDA-RGO@CC anode could enrich electrogens, thereby boosting the electron generation mechanism at the anode and enhancing the reduction efficiency of Cr(Ⅵ) in the cathode chamber. This work emphasizes high-performance anode materials for efficient pollutant removal, energy conversion, and biomass reuse.

The thioredoxin system determines CHK1 inhibitor sensitivity via redox-mediated regulation of ribonucleotide reductase activity.

Checkpoint kinase 1 (CHK1) is critical for cell survival under replication stress (RS). CHK1 inhibitors (CHK1i's) in combination with chemotherapy have shown promising results in preclinical studies but have displayed minimal efficacy with substantial toxicity in clinical trials. To explore combinatorial strategies that can overcome these limitations, we perform an unbiased high-throughput screen in a non-small cell lung cancer (NSCLC) cell line and identify thioredoxin1 (Trx1), a major component of the mammalian antioxidant-system, as a determinant of CHK1i sensitivity. We establish a role for redox recycling of RRM1, the larger subunit of ribonucleotide reductase (RNR), and a depletion of the deoxynucleotide pool in this Trx1-mediated CHK1i sensitivity. Further, the TrxR inhibitor auranofin, an approved anti-rheumatoid arthritis drug, shows a synergistic interaction with CHK1i via interruption of the deoxynucleotide pool. Together, we show a pharmacological combination to treat NSCLC that relies on a redox regulatory link between the Trx system and mammalian RNR activity.

Activation of Src induces mitochondrial localisation of de2-7EGFR (EGFRvIII) in glioma cells: implications for glucose metabolism.

A common mutation of the epidermal growth factor receptor in glioma is the de2-7EGFR (or EGFRvIII). Glioma cells expressing de2-7EGFR contain an intracellular pool of receptor with high levels of mannose glycosylation, which is consistent with delayed processing. We now show that this delay occurs in the Golgi complex. Low levels of de2-7EGFR were also seen within the mitochondria. Src activation dramatically increased the amount of mitochondrial de2-7EGFR, whereas its pharmacological inhibition caused a significant reduction. Because de2-7EGFR is phosphorylated by Src at Y845, we generated glioma cells expressing a Y845F-modified de2-7EGFR. The de2-7EGFR(845F) mutant failed to show mitochondrial localisation, even when co-expressed with constitutive active Src. Low levels of glucose enhanced mitochondrial localisation of de2-7EGFR, and glioma cells expressing the receptor showed increased survival and proliferation under these conditions. Consistent with this, de2-7EGFR reduced glucose dependency by stimulating mitochondrial oxidative metabolism. Thus, the mitochondrial localisation of de2-7EGFR contributes to its tumorigenicity and might help to explain its resistance to some EGFR-targeted therapeutics.

SREBF1/SREBP-1 concurrently regulates lipid synthesis and lipophagy to maintain lipid homeostasis and tumor growth.

Cholesterol is an essential structural component of the cell membrane, whereas excess cholesterol can be toxic and thus is stored in intracellular lipid droplets (LDs). Malignant tumor cells grow rapidly and require abundant cholesterol to build new membranes. How they maintain cholesterol homeostasis is largely unknown. We recently revealed that SREBF1/SREBP-1 (sterol regulatory element binding transcription factor 1), a key lipogenic transcription factor, plays a critical role in maintaining cholesterol homeostasis in tumor cells. We found that in addition to activation of de novo lipid synthesis and cholesterol uptake, SREBF1 also upregulates macroautophagy/autophagy to hydrolyze LDs, and increases the expression of NPC2, a lysosome cholesterol transporter, actively mobilizing LD-stored cholesterol and fatty acids to promote tumor growth. Our study demonstrates that SREBF1 controls the balance of lipid synthesis, uptake, storage and liberation to maintain lipid homeostasis for rapid tumor growth, while suggesting it as a very promising molecular target for cancer treatment.

SREBP-1 upregulates lipophagy to maintain cholesterol homeostasis in brain tumor cells.

Cholesterol is a structural component of cell membranes. How rapidly growing tumor cells maintain membrane cholesterol homeostasis is poorly understood. Here, we found that glioblastoma (GBM), the most lethal brain tumor, maintains normal levels of membrane cholesterol but with an abundant presence of cholesteryl esters (CEs) in its lipid droplets (LDs). Mechanistically, SREBP-1 (sterol regulatory element-binding protein 1), a master transcription factor that is activated upon cholesterol depletion, upregulates critical autophagic genes, including ATG9B, ATG4A, and LC3B, as well as lysosome cholesterol transporter NPC2. This upregulation promotes LD lipophagy, resulting in the hydrolysis of CEs and the liberation of cholesterol from the lysosomes, thus maintaining plasma membrane cholesterol homeostasis. When this pathway is blocked, GBM cells become quite sensitive to cholesterol deficiency with poor growth in vitro. Our study unravels an SREBP-1-autophagy-LD-CE hydrolysis pathway that plays an important role in maintaining membrane cholesterol homeostasis while providing a potential therapeutic avenue for GBM.

FCN3 inhibits the progression of hepatocellular carcinoma by suppressing SBDS-mediated blockade of the p53 pathway.

Hepatocellular carcinoma (HCC) is the third-leading cause of cancer deaths globally. Although considerable progress has been made in the treatment, clinical outcomes of HCC patients are still poor. Therefore, it is necessary to find novel prognostic factors upon which prevention and treatment strategies can be formulated. Ficolin-3 (FCN3) protein is a member of the human ficolin family. It activates complement through pathways associated with mannose-binding lectin-associated serine proteases. Herein, we identified that FCN3 was downregulated in HCC tissues and decreased FCN3 expression was closely related to poor prognosis. Overexpression of FCN3 induced apoptosis and inhibited cell proliferation via the p53 signaling pathway. Mechanistically, FCN3 modulated the nuclear translocation of eukaryotic initiation factor 6 (EIF6) by binding ribosome maturation factor (SBDS), which induced ribosomal stress and activation of the p53 pathway. In addition, Y-Box Binding Protein 1 (YBX1) involved in the transcription and translation level regulation of FCN3 to SBDS. Besides, a negative feedback loop in the downstream of FCN3 involving p53, YBX1 and SBDS was identified.

LncRNA TGFB2-OT1 Promotes Progression and Angiogenesis in Hepatocellular Carcinoma by Dephosphorylating ß-Catenin.

Introduction: Hepatocellular carcinoma (HCC) was the sixth most prevalent cancer worldwide. Long non-coding RNA TGFB2-OT1 has been proven to mediate inflammation and autophagy in vascular endothelial cells. However, its function in HCC is still unknown. Methods: We analyzed the relationship between TGFB2-OT1 expression and the clinicopathological features of 202 HCC patients. RT-qPCR was used to analyze the TGFB2-OT1 expression in HCC cell lines and tissues. In vitro and in vivo assays were conducted to verify the effect of TGFB2-OT1 on the phenotype of HCC. RNA pull-down assays were applied to reveal the proteins binding to the TGFB2-OT1. Western-blot assays were conducted to analyze the protein expression in HCC cell lines. Results: TGFB2-OT1 was found to be highly expressed in HCC samples and hepatoma cells. TGFB2-OT1 expression was significantly associated with age (P = 0.001), cirrhosis (P = 0.003), tumor size (P < 0.001), tumor encapsulation (P = 0.029), tumor protruding from the liver surface (P = 0.040), and alpha fetoprotein (AFP, P < 0.001) levels. TGFB2-OT1 promoted proliferation, migration, invasion, and angiogenesis in HCC cells, both in vitro and in vivo. TGFB2-OT1 binds to ß-catenin and competitively impaired the binding of ß-catenin to GSK3ß, thus suppressing the phosphorylation of ß-catenin at Ser33, Ser37, and Thr41. Conclusion: TGFB2-OT1 is overexpressed in HCC and predicts the poor prognosis of HCC patients. TGFB2-OT1 impedes the phosphorylation of ß-catenin and acts as an alternative activator of the Wnt/ß-catenin pathway to promote the progression and angiogenesis of HCC.

NOP2-mediated m5C Modification of c-Myc in an EIF3A-Dependent Manner to Reprogram Glucose Metabolism and Promote Hepatocellular Carcinoma Progression.

Mitochondrial dysfunction and glycolysis activation are improtant hallmarks of hepatocellular carcinoma (HCC). NOP2 is an S-adenosyl-L-methionine-dependent methyltransferase that regulates the cell cycle and proliferation activities. In this study, found that NOP2 contributes to HCC progression by promoting aerobic glycolysis. Our results revealed that NOP2 was highly expressed in HCC and that it was associated with unfavorable prognosis. NOP2 knockout in combination with sorafenib enhanced sorafenib sensitivity, which, in turn, led to marked tumor growth inhibition. Mechanistically, we identified that NOP2 regulates the c-Myc expression in an m5C-modification manner to promote glycolysis. Moreover, our results revealed that m5C methylation induced c-Myc mRNA degradation in an eukaryotic translation initiation factor 3 subunit A (EIF3A)-dependent manner. In addition, NOP2 was found to increase the expression of the glycolytic genes LDHA, TPI1, PKM2, and ENO1. Furthermore, MYC associated zinc finger protein (MAZ) was identified as the major transcription factor that directly controlled the expression of NOP2 in HCC. Notably, in a patient-derived tumor xenograft (PDX) model, adenovirus-mediated knockout of NOP2 maximized the antitumor effect and prolonged the survival of PDX-bearing mice. Our cumulative findings revealed the novel signaling pathway MAZ/NOP2/c-Myc in HCC and uncovered the important roles of NOP2 and m5C modifications in metabolic reprogramming. Therefore, targeting the MAZ/NOP2/c-Myc signaling pathway is suggested to be a potential therapeutic strategy for the treatment of HCC.

Unlocking Translational Potential: Conditionally Reprogrammed Cells in Advancing Breast Cancer Research.

Preclinical in vitro models play an important role in studying cancer cell biology and facilitating translational research, especially in the identification of drug targets and drug discovery studies. This is particularly relevant in breast cancer, where the global burden of disease is quite high based on prevalence and a relatively high rate of lethality. Predictive tools to select patients who will be responsive to invasive or morbid therapies (radiotherapy, chemotherapy, immunotherapy, and/or surgery) are relatively lacking. To be clinically relevant, a model must accurately replicate the biology and cellular heterogeneity of the primary tumor. Addressing these requirements and overcoming the limitations of most existing cancer cell lines, which are typically derived from a single clone, we have recently developed conditional reprogramming (CR) technology. The CR technology refers to a co-culture system of primary human normal or tumor cells with irradiated murine fibroblasts in the presence of a Rho-associated kinase inhibitor to allow the primary cells to acquire stem cell properties and the ability to proliferate indefinitely in vitro without any exogenous gene or viral transfection. This innovative approach fulfills many of these needs and offers an alternative that surpasses the deficiencies associated with traditional cancer cell lines. These CR cells (CRCs) can be reprogrammed to maintain a highly proliferative state and reproduce the genomic and histological characteristics of the parental tissue. Therefore, CR technology may be a clinically relevant model to test and predict drug sensitivity, conduct gene profile analysis and xenograft research, and undertake personalized medicine. This review discusses studies that have applied CR technology to conduct breast cancer research.

The AMPK agonist AICAR inhibits the growth of EGFRvIII-expressing glioblastomas by inhibiting lipogenesis.

The EGFR/PI3K/Akt/mTOR signaling pathway is activated in many cancers including glioblastoma, yet mTOR inhibitors have largely failed to show efficacy in the clinic. Rapamycin promotes feedback activation of Akt in some patients, potentially underlying clinical resistance and raising the need for alternative approaches to block mTOR signaling. AMPK is a metabolic checkpoint that integrates growth factor signaling with cellular metabolism, in part by negatively regulating mTOR. We used pharmacological and genetic approaches to determine whether AMPK activation could block glioblastoma growth and cellular metabolism, and we examined the contribution of EGFR signaling in determining response in vitro and in vivo. The AMPK-agonist AICAR, and activated AMPK adenovirus, inhibited mTOR signaling and blocked the growth of glioblastoma cells expressing the activated EGFR mutant, EGFRvIII. Across a spectrum of EGFR-activated cancer cell lines, AICAR was more effective than rapamycin at blocking tumor cell proliferation, despite less efficient inhibition of mTORC1 signaling. Unexpectedly, addition of the metabolic products of cholesterol and fatty acid synthesis rescued the growth inhibitory effect of AICAR, whereas inhibition of these lipogenic enzymes mimicked AMPK activation, thus demonstrating that AMPK blocked tumor cell proliferation primarily through inhibition of cholesterol and fatty acid synthesis. Most importantly, AICAR treatment in mice significantly inhibited the growth and glycolysis (as measured by (18)fluoro-2-deoxyglucose microPET) of glioblastoma xenografts engineered to express EGFRvIII, but not their parental counterparts. These results suggest a mechanism by which AICAR inhibits the proliferation of EGFRvIII expressing glioblastomas and point toward a potential therapeutic strategy for targeting EGFR-activated cancers.

Lipid Metabolism in Glioblastoma: From De Novo Synthesis to Storage.

Glioblastoma (GBM) is the most lethal primary brain tumor. With limited therapeutic options, novel therapies are desperately needed. Recent studies have shown that GBM acquires large amounts of lipids for rapid growth through activation of sterol regulatory element-binding protein 1 (SREBP-1), a master transcription factor that regulates fatty acid and cholesterol synthesis, and cholesterol uptake. Interestingly, GBM cells divert substantial quantities of lipids into lipid droplets (LDs), a specific storage organelle for neutral lipids, to prevent lipotoxicity by increasing the expression of diacylglycerol acyltransferase 1 (DGAT1) and sterol-O-acyltransferase 1 (SOAT1), which convert excess fatty acids and cholesterol to triacylglycerol and cholesteryl esters, respectively. In this review, we will summarize recent progress on our understanding of lipid metabolism regulation in GBM to promote tumor growth and discuss novel strategies to specifically induce lipotoxicity to tumor cells through disrupting lipid storage, a promising new avenue for treating GBM.

Predictors of Spontaneous Rupture of Hepatocellular Carcinoma and Clinical Outcomes Following Hepatectomy.

OBJECTIVE: To explore the independent predictive factors of spontaneous tumor rupture (STR) in patients undergoing curative resection of hepatocellular carcinoma (HCC), and to evaluate the impact of STRHCC on long-term survival after hepatectomy. METHODS: The clinicopathological parameters of 106 patients with STRHCC and 201 patients with non-ruptured HCC who underwent hepatectomy from January 2007 to November 2011 at the Eastern Hepatobiliary Surgery Hospital and Zhongnan Hospital of Wuhan University were analyzed using propensity score matching (PSM) and a logistic regression model. RESULTS: Factors including hypertension, cirrhosis, total bilirubin (TB), tumor size, and ascites were independent predictors of STR. For all 307 HCC patients, the 1-, 3- and 5-year overall survival (OS) rates were 54.0%, 37.3% and 33.8%, respectively. After PSM, the 1-, 3-, and 5-year OS rates in the ruptured group remained significantly lower at 41.5%, 23.5%, and 17.5% when compared with the non-ruptured group at 70.8%, 47.1%, and 37.6%, respectively, while the 1-, 3-, and 5-year disease-free survival (DFS) rates between the groups did not differ significantly (50.4%, 35.1%, 27.1% vs 55.4%, 38.2%, 27.4%). STRHCC was significantly associated with increased risk of OS, but not of shorter DFS. No significant difference in postoperative morbidity or hospital death was observed between the groups. CONCLUSION: Factors including hypertension, liver cirrhosis, higher TB levels, tumor size > 5cm, and ascites are significant predictors of STR. The recurrence rate of patients in the ruptured group was significantly higher than that of patients in the non-ruptured group. STR results in poorer OS but not DFS in patients undergoing curative resection for HCC. STRHCC has no impact on postoperative morbidity and mortality after hepatectomy.

Dose-response relationship between risk factors and incidence of COVID-19 in 325 hospitalized patients: A multicenter retrospective cohort study.

BACKGROUND: The epidemiological and clinical characteristics of coronavirus disease 2019 (COVID-19) patients have been widely reported, but the assessment of dose-response relationships and risk factors for mortality and severe cases and clinical outcomes remain unclear. AIM: To determine the dose-response relationship between risk factors and incidence of COVID-19. METHODS: In this retrospective, multicenter cohort study, we included patients with confirmed COVID-19 infection who had been discharged or had died by February 6, 2020. We used multivariable logistic regression and Cox proportional hazard models to determine the dose-response relationship between risk factors and incidence of COVID-19. RESULTS: It clarified that increasing risk of in-hospital death were associated with older age (HR: 1.04, 95%CI: 1.01-1.09), higher lactate dehydrogenase [HR: 1.04, 95% confidence interval (CI): 1.01-1.10], C-reactive protein (HR: 1.10, 95%CI: 1.01-1.23), and procalcitonin (natural log-transformed HR: 1.88, 95%CI: 1.22-2.88), and D-dimer greater than 1 µg/mL at admission (natural log transformed HR: 1.63, 95%CI: 1.03-2.58) by multivariable regression. D-dimer and procalcitonin were logarithmically correlated with COVID-19 mortality risk, while there was a linear dose-response correlation between age, lactate dehydrogenase, D-dimer and procalcitonin, independent of established risk factors. CONCLUSION: Higher lactate dehydrogenase, D-dimer, and procalcitonin levels were independently associated with a dose-response increased risk of COVID-19 mortality.

Long noncoding RNA Linc01612 represses hepatocellular carcinoma progression by regulating miR-494/ATF3/p53 axis and promoting ubiquitination of YBX1.

Long noncoding RNAs (lncRNAs) play an important role in the progression of hepatocellular carcinoma (HCC). Linc01612 is a novel lncRNA that function remains unknown in the progression of cancers, including HCC. In this study, we discovered that Linc01612 is significantly down-regulated in HCC tissues than in non-tumor tissues and correlated with poor prognosis. Linc01612 mainly localizes in the cytoplasm and functions as a tumor suppressor by repressing the growth and metastasis of hepatoma cells in vitro and in vivo. Mechanistically, in p53-expressing hepatoma cells, Linc01612 acts as a competitive endogenous RNA and promotes the expression of activation transcription factor 3 (ATF3) by sponging microRNA-494 (miR-494), which in turn inhibits MDM2-mediated ubiquitination of p53 and activates the p53 pathway. Furthermore, in p53-null hepatoma cells, Linc01612 exerts its biological functions by physically interacting with Y-box binding protein 1 protein (YBX1) and promoting the ubiquitin-mediated degradation of YBX1. Interestingly, the Linc01612-YBX1 signaling pathway is also present in p53-expressing hepatoma cells. In conclusion, our study indicated that Linc01612 is a functional lncRNA in HCC and Linc01612 may serve as a potential diagnostic biomarker and therapeutic target for HCC.

YY1-Targeted RBM15B Promotes Hepatocellular Carcinoma Cell Proliferation and Sorafenib Resistance by Promoting TRAM2 Expression in an m6A-Dependent Manner.

As one of the most common internal modifications in eukaryotic mRNA, N6-methyladenosine (m6A) modification is involved in the pathogenesis of many diseases, including hepatocellular carcinoma (HCC). In this study, we explored the prognostic significance of the expression of RNA binding motif protein 15B (RBM15B) in HCC, by studying specimens collected from clinical subjects. RBM15B is highly expressed in HCC patients and indicates a poor prognosis. Functionally, overexpression of RBM15B promotes HCC cell proliferation and invasion and induces sorafenib resistance in HCC cells. Mechanistically, we confirmed that RBM15B is transcriptionally activated by YY1 and regulates the stability of TRAM2 mRNA in an m6A-dependent manner. Overall, our results reveal a YY1-RBM15B-TRAM2 regulatory axis and highlight the critical role of RBM15B and m6A modifications in HCC. These findings may provide a novel mechanism and therapeutic targets for the treatment of HCC.

Ammonia stimulates SCAP/Insig dissociation and SREBP-1 activation to promote lipogenesis and tumour growth.

Tumorigenesis is associated with elevated glucose and glutamine consumption, but how cancer cells can sense their levels to activate lipid synthesis is unknown. Here, we reveal that ammonia, released from glutamine, promotes lipogenesis via activation of sterol regulatory element-binding proteins (SREBPs), endoplasmic reticulum-bound transcription factors that play a central role in lipid metabolism. Ammonia activates the dissociation of glucose-regulated, N-glycosylated SREBP-cleavage-activating protein (SCAP) from insulin-inducible gene protein (Insig), an endoplasmic reticulum-retention protein, leading to SREBP translocation and lipogenic gene expression. Notably, 25-hydroxycholesterol blocks ammonia to access its binding site on SCAP. Mutating aspartate D428 to alanine prevents ammonia binding to SCAP, abolishes SREBP-1 activation and suppresses tumour growth. Our study characterizes the unknown role, opposite to sterols, of ammonia as a key activator that stimulates SCAP-Insig dissociation and SREBP-1 activation to promote tumour growth and demonstrates that SCAP is a critical sensor of glutamine, glucose and sterol levels to precisely control lipid synthesis.