Hypoxia exosome derived CEACAM5 promotes tumor-associated macrophages M2 polarization to accelerate pancreatic neuroendocrine tumors metastasis via MMP9.

Exosomes play significant roles in the communications between tumor cells and tumor microenvironment. However, the specific mechanisms by which exosomes modulate tumor development under hypoxia in pancreatic neuroendocrine tumors (pNETs) are not well understood. This study aims to investigate these mechanisms and made several important discoveries. We found that hypoxic exosomes derived from pNETs cells can activate tumor-associated macrophages (TAM) to the M2 phenotype, in turn, the M2-polarized TAM, facilitate the migration and invasion of pNETs cells. Further investigation revealed that CEACAM5, a protein highly expressed in hypoxic pNETs cells, is enriched in hypoxic pNETs cell-derived exosomes. Hypoxic exosomal CEACAM5 was observed to induce M2 polarization of TAM through activation of the MAPK signaling pathway. Coculturing pNETs cells with TAM or treated with hypoxic exosomes enhanced the metastatic capacity of pNETs cells. In conclusion, these findings suggest that pNETs cells generate CEACAM5-rich exosomes in a hypoxic microenvironment, which in turn polarize TAM promote malignant invasion of pNETs cells. Targeting exosomal CEACAM5 could potentially serve as a diagnostic and therapeutic strategy for pNETs.

Hypoxic tumor-derived exosomal miR-4488 induces macrophage M2 polarization to promote liver metastasis of pancreatic neuroendocrine neoplasm through RTN3/FABP5 mediated fatty acid oxidation.

Tumor-associated macrophages (TAMs) represent a predominant cellular component within the tumor microenvironment (TME) of pancreatic neuroendocrine neoplasms (pNENs). There is a growing body of evidence highlighting the critical role of exosomes in facilitating communication between tumor cells and TAMs, thereby contributing to the establishment of the premetastatic niche. Nonetheless, the specific mechanisms through which exosomes derived from tumor cells influence macrophage polarization under hypoxic conditions in pNENs, and the manner in which these interactions support cancer metastasis, remain largely unexplored. Recognizing the capacity of exosomes to transfer miRNAs that can modify cellular behaviors, our research identified a significant overexpression of miR-4488 in exosomes derived from hypoxic pNEN cells. Furthermore, we observed that macrophages that absorbed circulating exosomal miR-4488 underwent M2-like polarization. Our investigations revealed that miR-4488 promotes M2-like polarization by directly targeting and suppressing RTN3 in macrophages. This suppression of RTN3 enhances fatty acid oxidation and activates the PI3K/AKT/mTOR signaling pathway through the interaction and downregulation of FABP5. Additionally, M2 polarized macrophages contribute to the formation of the premetastatic niche and advance pNENs metastasis by releasing MMP2, thereby establishing a positive feedback loop involving miR-4488, RTN3, FABP5, and MMP2 in pNEN cells. Together, these findings shed light on the role of exosomal miRNAs from hypoxic pNEN cells in mediating interactions between pNEN cells and intrahepatic macrophages, suggesting that miR-4488 holds potential as a valuable biomarker and therapeutic target for pNENs.

Potential molecular and cellular mechanisms of the effects of cuproptosis-related genes in the cardiomyocytes of patients with diabetic heart failure: a bioinformatics analysis.

Background: Diabetes mellitus is an independent risk factor for heart failure, and diabetes-induced heart failure severely affects patients' health and quality of life. Cuproptosis is a newly defined type of programmed cell death that is thought to be involved in the pathogenesis and progression of cardiovascular disease, but the molecular mechanisms involved are not well understood. Therefore, we aimed to identify biomarkers associated with cuproptosis in diabetes mellitus-associated heart failure and the potential pathological mechanisms in cardiomyocytes. Materials: Cuproptosis-associated genes were identified from the previous publication. The GSE26887 dataset was downloaded from the GEO database. Methods: The consistency clustering was performed according to the cuproptosis gene expression. Differentially expressed genes were identified using the limma package, key genes were identified using the weighted gene co-expression network analysis(WGCNA) method, and these were subjected to immune infiltration analysis, enrichment analysis, and prediction of the key associated transcription factors. Consistency clustering identified three cuproptosis clusters. The differentially expressed genes for each were identified using limma and the most critical MEantiquewhite4 module was obtained using WGCNA. We then evaluated the intersection of the MEantiquewhite4 output with the three clusters, and obtained the key genes. Results: There were four key genes: HSDL2, BCO2, CORIN, and SNORA80E. HSDL2, BCO2, and CORIN were negatively associated with multiple immune factors, while SNORA80E was positively associated, and T-cells accounted for a major proportion of this relationship with the immune system. Four enriched pathways were found to be associated: arachidonic acid metabolism, peroxisomes, fatty acid metabolism, and dorsoventral axis formation, which may be regulated by the transcription factor MECOM, through a change in protein structure. Conclusion: HSDL2, BCO2, CORIN, and SNORA80E may regulate cardiomyocyte cuproptosis in patients with diabetes mellitus-associated heart failure through effects on the immune system. The product of the cuproptosis-associated gene LOXL2 is probably involved in myocardial fibrosis in patients with diabetes, which leads to the development of cardiac insufficiency.

Synthesis of borocarbonitride nanosheets from biomass for enhanced charge separation and hydrogen production.

Borocarbonitride (BCN) materials have shown significant potential as photocatalysts for hydrogen production. However, traditional bulk BCN exhibits only moderate photocatalytic activity. In this study, we introduce an environmentally conscious and sustainable strategy utilizing biomass-derived carbon sources to synthesize BCN nanosheets. The hydrogen evolution efficiency of BCN-A nanosheets (110 µmol h-1 g-1) exceeds that of bulk BCN photocatalysts (12 µmol h-1 g-1) by 9.1 times, mainly due to the increased surface area (205 m2g-1) and the presence of numerous active sites with enhanced charge separation capabilities. Notably, the biomass-derived BCN nanosheets offer key advantages such as sustainability, cost-effectiveness, and reduced carbon footprint during hydrogen production. These findings highlight the potential of biomass-based BCN nanomaterials to facilitate a greener and more efficient route to hydrogen energy, contributing to the global transition towards renewable energy solutions.

Endoplasmic reticulum stress-related gene expression causes the progression of dilated cardiomyopathy by inducing apoptosis.

Background: Previous studies have shown that endoplasmic reticulum stress (ERS) -induced apoptosis is involved in the pathogenesis of dilated cardiomyopathy (DCM). However, the molecular mechanism involved has not been fully characterized. Results: In total, eight genes were obtained at the intersection of 1,068 differentially expressed genes (DEGs) from differential expression analysis between DCM and healthy control (HC) samples, 320 module genes from weighted gene co-expression network analysis (WGCNA), and 2,009 endoplasmic reticulum stress (ERGs). These eight genes were found to be associated with immunity and angiogenesis. Four of these genes were related to apoptosis. The upregulation of MX1 may represent an autocompensatory response to DCM caused by a virus that inhibits viral RNA and DNA synthesis, while acting as an autoimmune antigen and inducing apoptosis. The upregulation of TESPA1 would lead to the dysfunction of calcium release from the endoplasmic reticulum. The upregulation of THBS4 would affect macrophage differentiation and apoptosis, consistent with inflammation and fibrosis of cardiomyocytes in DCM. The downregulation of MYH6 would lead to dysfunction of the sarcomere, further explaining cardiac remodeling in DCM. Moreover, the expression of genes affecting the immune micro-environment was significantly altered, including TGF-ß family member. Analysis of the co-expression and competitive endogenous RNA (ceRNA) network identified XIST, which competitively binds seven target microRNAs (miRNAs) and regulates MX1 and THBS4 expression. Finally, bisphenol A and valproic acid were found to target MX1, MYH6, and THBS4. Conclusion: We have identified four ERS-related genes (MX1, MYH6, TESPA1, and THBS4) that are dysregulated in DCM and related to apoptosis. This finding should help deepen understanding of the role of endoplasmic reticulum stress-induced apoptosis in the development of DCM.

A Review: The Significance of Toll-Like Receptors 2 and 4, and NF-κB Signaling in Endothelial Cells during Atherosclerosis.

Atherosclerosis (AS) is a chronic inflammatory vascular disease that begins with endothelial activation followed by a series of inflammatory responses, plaque formation, and finally rupture. An early event in endothelial dysfunction is activation of the nuclear factor-κB (NF-κB) signaling axis. Toll-like receptors (TLRs) in endothelial cells (ECs) play an essential role in recognizing pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), and lifestyle-associated molecular patterns (LAMPs). Activation of the canonical NF-κB pathway stimulates the expression of cytokines, chemokines, and an array of additional genes which activate and amplify AS-associated inflammatory responses. In this review, we discuss the involvement of TLR2/4 and NF-κB signaling in ECs during AS initiation, as well as regulation of the inflammatory response during AS by noncoding RNAs, especially microRNA (miRNA) and circular RNA (circRNA).

Antibacterial Mechanisms and Antivirulence Activities of Oridonin against Pathogenic Aeromonas hydrophila AS 1.1801.

Aeromonas hydrophila, a Gram-negative bacterium widely found in freshwater environments, acts as a common conditional pathogen affecting humans, livestock, and aquatic animals. In this study, the impact of oridonin, an ent-kaurane diterpenoid compound derived from Rabdosia rubescens, on the virulence factors of A. hydrophila AS 1.1801 and its antibacterial mechanism was elucidated. The minimum inhibitory concentration (MIC) of oridonin against A. hydrophila AS 1.1801 was 100 µg/mL. Oridonin at inhibitory concentrations could significantly increase the electrical conductivity in the supernatant and escalate nucleic acid leakage (p < 0.01). This effect was concomitant with observed distortions in bacterial cells, the formation of cytoplasmic cavities, cellular damage, and pronounced inhibition of protein and nucleic acid synthesis. Additionally, oridonin at inhibitory levels exhibited a noteworthy suppressive impact on A. hydrophila AS 1.1801 across biofilm formation, motility, hemolytic activity, lipase activity, and protease activity (p < 0.05), demonstrating a dose-dependent enhancement. qRT-PCR analysis showed that the gene expression of luxR, qseB and omp were significantly downregulated after oridonin treatment in A. hydrophila AS 1.1801 (p < 0.05). Our results indicated that oridonin possessed significant antibacterial and anti-virulence effects on A. hydrophila AS 1.1801.

The multi-protective effect of IL-37-Smad3 against ox-LDL induced dysfunction of endothelial cells.

Atherosclerosis is a lipid-driven inflammatory arterial disease, with one crucial factor is oxidized low-density lipoprotein (ox-LDL), which can induce endothelial dysfunction through endoplasmic reticulum stress (ERS). Interleukin-37 (IL-37) exerts vascular protective functions. This study aims to investigates whether IL-37 can alleviate ERS and autophagy induced by ox-LDL, therely potentialy treating atherosclerosis. We found that ox-LDL enhances the wound healing rate in Rat Coronary Artery Endothelial Cells (RCAECs) and IL-37 reduce the ox-LDL-induced pro-osteogenic response, ERS, and autophagy by binding to Smad3. In RCAECs treated with ox-LDL and recombinant human IL-37, the wound healing rate was mitigated. The expression of osteogenic transcription factors and proteins involved in the ERS pathway was reduced in the group pretreated with IL-37 and ox-LDL. However, these responses were not alleviated when Smads silenced. Electron microscopy revealed that the IL-37/Smad3 complex could suppress endoplasmic reticulum autophagy under ox-LDL stimulation. Thus, IL-37 might treat atherosclerosis through its multi-protective effect by binding Smad3.

FOXA2-initiated transcriptional activation of INHBA induced by methylmalonic acid promotes pancreatic neuroendocrine neoplasm progression.

Pancreatic neuroendocrine neoplasms (PanNENs) are a group of highly heterogeneous neoplasms originating from the endocrine islet cells of the pancreas with characteristic neuroendocrine differentiation, more than 60% of which represent metastases when diagnosis, causing major tumor-related death. Metabolic alterations have been recognized as one of the hallmarks of tumor metastasis, providing attractive therapeutic targets. However, little is known about the molecular mechanism of metabolic changes regulating PanNEN progression. In this study, we first identified methylmalonic acid (MMA) as an oncometabolite for PanNEN progression, based on serum metabolomics of metastatic PanNEN compared with non-metastatic PanNEN patients. One of the key findings was the potentially novel mechanism of epithelial-mesenchymal transition (EMT) triggered by MMA. Inhibin ßA (INHBA) was characterized as a key regulator of MMA-induced PanNEN progression according to transcriptomic analysis, which has been validated in vitro and in vivo. Mechanistically, INHBA was activated by FOXA2, a neuroendocrine (NE) specific transcription factor, which was initiated during MMA-induced progression. In addition, MMA-induced INHBA upregulation activated downstream MITF to regulate EMT-related genes in PanNEN cells. Collectively, these data suggest that activation of INHBA via FOXA2 promotes MITF-mediated EMT during MMA inducing PanNEN progression, which puts forward a novel therapeutic target for PanNENs.

Frequency-Dependent Multistep Ferroelectric Polarization Switching Mechanism in P(VDF-TrFE)-Based Capacitors Induced by Polystyrene Electret-like Modulation.

In this work, we investigate multistep ferroelectric polarization switching dynamics of a series of poly(vinylidene fluoride-trifluoroethylene)/polystyrene, P(VDF-TrFE)/PS, as active layers in ferroelectric capacitors with variable P(VDF-TrFE)/PS thickness ratios and a wide range of driving voltage frequencies (1-1000 Hz). The PS electret-like modulation effects on the depolarized field fluctuation are proven to be responsible for this multistep ferroelectric polarization switching process. To be specific, the switching current density peak splits into two peaks in both positive and negative voltage ranges according to the stimulus-response (S-R) data from the metal-ferroelectric-electret-metal capacitor driven by a periodic triangular voltage wave. The double-peak current trough appears when the transitorily suppressed ferroelectric polarization switching occurs while the discharge and recharge of the PS electret by external voltage brings a specific dynamic change in the electric field across ferroelectric (EFE). We also propose a theoretical model to simulate the ferroelectric polarization switching process at a current trough zone. This phenomenon provides new concepts on the electret-modulated multistep ferroelectric switching dynamics, and such switching mechanisms are critical for realizing reliable nonvolatile memory applications in flexible electronics.

Hypoxia upregulating ACSS2 enhances lipid metabolism reprogramming through HMGCS1 mediated PI3K/AKT/mTOR pathway to promote the progression of pancreatic neuroendocrine neoplasms.

BACKGROUND: Pancreatic neuroendocrine neoplasms (pNENs) are relatively rare. Hypoxia and lipid metabolism-related gene acetyl-CoA synthetase 2 (ACSS2) is involved in tumor progression, but its role in pNENs is not revealed. This study showed that hypoxia can upregulate ACSS2, which plays an important role in the occurrence and development of pNENs through lipid metabolism reprogramming. However, the precise role and mechanisms of ACSS2 in pNENs remain unknown. METHODS: mRNA and protein levels of ACSS2 and 3-hydroxy-3-methylglutaryl-CoA synthase1 (HMGCS1) were detected using quantitative real-time PCR (qRT-PCR) and Western blotting (WB). The effects of ACSS2 and HMGCS1 on cell proliferation were examined using CCK-8, colony formation assay and EdU assay, and their effects on cell migration and invasion were examined using transwell assay. The interaction between ACSS2 and HMGCS1 was verified by Co-immunoprecipitation (Co-IP) experiments, and the functions of ACSS2 and HMGCS1 in vivo were determined by nude mouse xenografts. RESULTS: We demonstrated that hypoxia can upregulate ACSS2 while hypoxia also promoted the progression of pNENs. ACSS2 was significantly upregulated in pNENs, and overexpression of ACSS2 promoted the progression of pNENs and knockdown of ACSS2 and ACSS2 inhibitor (ACSS2i) treatment inhibited the progression of pNENs. ACSS2 regulated lipid reprogramming and the PI3K/AKT/mTOR pathway in pNENs, and ACSS2 regulated lipid metabolism reprogramming through the PI3K/AKT/mTOR pathway. Co-IP experiments indicated that HMGCS1 interacted with ACSS2 in pNENs. Overexpression of HMGCS1 can reverse the enhanced lipid metabolism reprogramming and tumor-promoting effects of knockdown of ACSS2. Moreover, overexpression of HMGCS1 reversed the inhibitory effect of knockdown of ACSS2 on the PI3K/AKT/mTOR pathway. CONCLUSION: Our study revealed that hypoxia can upregulate the lipid metabolism-related gene ACSS2, which plays a tumorigenic effect by regulating lipid metabolism through activating the PI3K/AKT/mTOR pathway. In addition, HMGCS1 can reverse the oncogenic effects of ACSS2, providing a new option for therapeutic strategy.

ALKBH5 enhances lipid metabolism reprogramming by increasing stability of FABP5 to promote pancreatic neuroendocrine neoplasms progression in an m6A-IGF2BP2-dependent manner.

The process of post-transcriptional regulation has been recognized to be significantly impacted by the presence of N6-methyladenosine (m6A) modification. As an m6A demethylase, ALKBH5 has been shown to contribute to the progression of different cancers by increasing expression of several oncogenes. Hence, a better understanding of the key targets of ALKBH5 in cancer cells could potentially lead to the development of new therapeutic targets. However, the specific role of ALKBH5 in pancreatic neuroendocrine neoplasms (pNENs) remains largely unknown. Here, we demonstrated that ALKBH5 was up-regulated in pNENs and played a critical role in tumor growth and lipid metabolism. Mechanistically, ALKBH5 over-expression was found to increase the expression of FABP5 in an m6A-IGF2BP2 dependent manner, leading to disorders in lipid metabolism. Additionally, ALKBH5 was found to activate PI3K/Akt/mTOR signaling pathway, resulting in enhanced lipid metabolism and proliferation abilities. In conclusion, our study uncovers the ALKBH5/IGF2BP2/FABP5/mTOR axis as a mechanism for aberrant m6A modification in lipid metabolism and highlights a new molecular basis for the development of therapeutic strategies for pNENs treatment.

Down-regulated FTO and ALKBH5 co-operatively activates FOXO signaling through m6A methylation modification in HK2 mRNA mediated by IGF2BP2 to enhance glycolysis in colorectal cancer.

BACKGROUND: N6-methyladenosine (m6A) modification is the most abundant reversible methylation modification in eukaryotes, and it is reportedly closely associated with a variety of cancers progression, including colorectal cancer (CRC). This study showed that activated lipid metabolism and glycolysis play vital roles in the occurrence and development of CRC. However, only a few studies have reported the biological mechanisms underlying this connection. METHODS: Protein and mRNA levels of FTO and ALKBH5 were measured using western blot and qRT-PCR. The effects of FTO and ALKBH5 on cell proliferation were examined using CCK-8, colony formation, and EdU assays, and the effects on cell migration and invasion were tested using a transwell assay. m6A RNA immunoprecipitation (MeRIP) and RNA-seq was used to explore downstream target gene. RIP was performed to verify the interaction between m6A and HK2. The function of FTO and ALKBH5 in vivo was determined by xenograft in nude mice. RESULTS: In this study, FTO and ALKBH5 were significantly down-regulated in CRC patients and cells both in vivo and in vitro in a high-fat environment. Moreover, FTO and ALKBH5 over-expression hampered cell proliferation both in vitro and in vivo. Conversely, FTO and ALKBH5 knockdown accelerated the malignant biological behaviors of CRC cells. The mechanism of action of FTO and ALKBH5 involves joint regulation of HK2, a key enzyme in glycolysis, which was identified by RNA sequencing and MeRIP-seq. Furthermore, reduced expression of FTO and ALKBH5 jointly activated the FOXO signaling pathway, which led to enhanced proliferation ability in CRC cells. IGF2BP2, as a m6A reader, positively regulated HK2 mRNA in m6A dependent manner. Additionally, down-regulation of FTO/ALKBH5 increased METTL3 and decreased METTL14 levels, further promoting CRC progression. CONCLUSION: In conclusion, our study revealed the FTO-ALKBH5/IGF2BP2/HK2/FOXO1 axis as a mechanism of aberrant m6A modification and glycolysis regulation in CRC.

FAM201A encodes small protein NBASP to inhibit neuroblastoma progression via inactivating MAPK pathway mediated by FABP5.

Increasing evidence indicates that long non-coding RNA (lncRNA) is one of the most important RNA regulators in the pathogenesis of neuroblastoma (NB). Here, we found that FAM201A was low expressed in NB and a variety of gain and loss of function studies elucidated the anti-tumor effects of FAM201A on the regulation of proliferation, migration and invasion of NB cells. Intriguingly, we identified the ability of FAM201A to encode the tumor-suppressing protein, NBASP, which interacted with FABP5 and negatively regulated its expression. In vivo assays also revealed NBASP repressed NB growth via inactivating MAPK pathway mediated by FABP5. In conclusion, our findings demonstrated that NBASP encoded by FAM201A played a tumor-suppressor role in NB carcinogenesis via down-regulating FABP5 to inactivate the MAPK pathway. These results extended our understanding of the relationship of lncRNA-encoded functional peptides and plasticity of tumor progression.

WTAP activates MAPK signaling through m6A methylation in VEGFA mRNA-mediated by YTHDC1 to promote colorectal cancer development.

N6-methyladenosine modification, especially Wilms tumor 1-associated protein (WTAP), is reportedly associated with a variety of cancers, including colorectal cancer (CRC). Angiogenesis also plays an important role in the occurrence and development of CRC. However, only a few studies have reported the biological mechanisms underlying this connection. Therefore, tissue microarray and public database were used to explore WTAP levels in CRC. Then, WTAP was down-regulated and over-expressed, respectively. CCK8, EdU, colony formation, and transwell experiments were performed to study the role of WTAP in CRC. Combined RNA sequencing and m6A RNA immunoprecipitation (MeRIP) sequencing, we found downstream molecules VEGFA. Moreover, a tube formation assay was executed for tumor angiogenesis. Finally, a subcutaneous tumorigenesis assay in nude mice was used to examine the tumor-promoting effect of WTAP in vivo. In the present study, WTAP was significantly upregulated in CRC cells and patients with CRC. Moreover, higher WTAP expression was observed in the TCGA and CPATC databases in CRC tissues. WTAP over-expression exacerbates cell proliferation, migration, invasion, and angiogenesis. Conversely, WTAP knockdown inhibited the malignant biological behavior of CRC cells. Mechanistically, WTAP positively regulated VEGFA, as identified using RNA sequencing and MeRIP sequencing. Moreover, we identified YTHDC1 as a downstream effector of the YTHDC1-VEGFA axis in CRC. Furthermore, increased WTAP expression activated the MAPK signaling pathway, which led to enhanced angiogenesis. In conclusion, our study revealed that the WTAP/YTHDC1/VEGFA axis promotes CRC development, especially angiogenesis, suggesting that it may act as a potential biomarker of CRC.

Methylmalonic acid promotes colorectal cancer progression via activation of Wnt/ß-catenin pathway mediated epithelial-mesenchymal transition.

BACKGROUND: It has been manifested in several studies that age-related metabolic reprogramming is associated with tumor progression, in particular, colorectal cancer (CRC). Here we investigated the role of upregulated metabolites of the aged serum, including methylmalonic acid (MMA), phosphoenolpyruvate (PEP), and quinolinate (QA), in CRC. METHODS: Functional assays including CCK-8, EdU, colony formation and transwell experiments were used to ascertain which upregulated metabolite of elderly serum was related to tumor progression. RNA-seq analysis was conducted to explore the potential mechanisms of MMA-induced CRC progression. Subcutaneous tumorigenesis and metastatic tumor models were constructed to verify the function of MMA in vivo. RESULTS: Among three consistently increased metabolites of the aged sera, MMA was responsible for tumorigenesis and metastasis in CRC, according to functional assays. The promotion of Epithelial-mesenchymal transition (EMT) was observed in CRC cells treated with MMA, on the basis of protein expression of EMT markers. Moreover, combined with transcriptome sequencing, Wnt/ß-catenin signaling pathway was activated in CRC cells treated with MMA, which was verified by western blot and qPCR experiments. Furthermore, animal assays demonstrated the pro-proliferation and promotion of metastasis role of MMA in vivo. CONCLUSION: We have identified that age-dependent upregulation of MMA in serum promoted the progression of CRC via Wnt/ß-catenin signaling pathway mediated EMT. These collective findings provide valuable insights into the vital role of age-related metabolic reprogramming in CRC progression and propose a potential therapeutic target for elderly CRC.

FABP5 suppresses colorectal cancer progression via mTOR-mediated autophagy by decreasing FASN expression.

Lipid metabolism plays an important role in the occurrence and development of cancer, in particular, digestive system tumors such as colon cancer. Here, we investigated the role of the fatty acid-binding protein 5 (FABP5) in colorectal cancer (CRC). We observed marked down-regulation of FABP5 in CRC. Data from functional assays revealed inhibitory effects of FABP5 on cell proliferation, colony formation, migration, invasion as well as tumor growth in vivo. In terms of mechanistic insights, FABP5 interacted with fatty acid synthase (FASN) and activated the ubiquitin proteasome pathway, leading to a decrease in FASN expression and lipid accumulation, moreover, suppressing mTOR signaling and facilitating cell autophagy. Orlistat, a FASN inhibitor, exerted anti-cancer effects both in vivo and in vitro. Furthermore, the upstream RNA demethylase ALKBH5 positively regulated FABP5 expression via an m6A-independent mechanism. Overall, our collective findings offer valuable insights into the critical role of the ALKBH5/FABP5/FASN/mTOR axis in tumor progression and uncover a potential mechanism linking lipid metabolism to development of CRC, providing novel therapeutic targets for future interventions.

Orlistat Induces Ferroptosis in Pancreatic Neuroendocrine Tumors by Inactivating the MAPK Pathway.

Background: Orlistat is an antiobesity drug approved by the US Food and Drug Administration (FDA) with potential antitumor activity against a few malignant tumors, however, whether orlistat affects the progression of pancreatic neuroendocrine tumors (pNETs) remains unknown. Methods: Protein and mRNA levels of FASN were measured using western blotting (WB) and qRT-PCR. The effects of FASN and orlistat on cell proliferation were examined using CCK-8, colony formation, and EdU assays. The effects of FASN and orlistat on cell migration and invasion were tested using a transwell assay. A lipid peroxidation assay was used to explore the effects of orlistat on ferroptosis. The function of orlistat in vivo was determined by xenograft in nude mice. Results: Based on the results of WB and qRT-PCR, FASN was significantly up-regulated in pNET cell lines and public database indicated increased expression of FASN correlated with poor prognosis for patients with pNET. CCK-8, colony formation, and EdU assays showed that knockdown of FASN or treatment with orlistat suppressed the proliferation of pNET cells. The transwell assay indicated that the knockdown of FASN or treatment with orlistat inhibited the migration and invasion of pNET cells. WB and the peroxidation assay showed that orlistat induced ferroptosis in pNET cells. Moreover, orlistat was also found to inhibit the MAPK pathway in pNETs. Furthermore, orlistat showed excellent anti-tumor effects in xenografts in nude mice. Conclusion: Altogether, our study demonstrates that orlistat inhibits the progression of pNETs by inducing ferroptosis mediated by inactivation of the MAPK signaling pathway. Therefore, orlistat is a promising candidate for the treatment of pNETs.

FABP5 regulates lipid metabolism to facilitate pancreatic neuroendocrine neoplasms progression via FASN mediated Wnt/ß-catenin pathway.

Pancreatic neuroendocrine neoplasms (pNENs) are among the most frequently occurring neuroendocrine neoplasms (NENs) and require targeted therapy. High levels of fatty acid binding protein 5 (FABP5) are involved in tumor progression, but its role in pNENs remains unclear. We investigated the mRNA and protein levels of FABP5 in pNEN tissues and cell lines and found them to be upregulated. We evaluated changes in cell proliferation using CCK-8, colony formation, and 5-ethynyl-2'-deoxyuridine assays and examined the effects on cell migration and invasion using transwell assays. We found that knockdown of FABP5 suppressed the proliferation, migration, and invasion of pNEN cell lines, while overexpression of FABP5 had the opposite effect. Co-immunoprecipitation experiments were performed to clarify the interaction between FABP5 and fatty acid synthase (FASN). We further showed that FABP5 regulates the expression of FASN via the ubiquitin proteasome pathway and both proteins facilitate the progression of pNENs. Our study demonstrated that FABP5 acts as an oncogene by promoting lipid droplet deposition and activating the WNT/ß-catenin signaling pathway. Moreover, the carcinogenic effects of FABP5 can be reversed by orlistat, providing a novel therapeutic intervention option.

Novel insights into the interplay between m6A modification and programmed cell death in cancer.

N6-methyladenosine (m6A) methylation, the most prevalent and abundant RNA modification in eukaryotes, has recently become a hot research topic. Several studies have indicated that m6A modification is dysregulated during the progression of multiple diseases, especially in cancer development. Programmed cell death (PCD) is an active and orderly method of cell death in the development of organisms, including apoptosis, autophagy, pyroptosis, ferroptosis, and necroptosis. As the study of PCD has become increasingly profound, accumulating evidence has revealed the mutual regulation of m6A modification and PCD, and their interaction can further influence the sensitivity of cancer treatment. In this review, we summarize the recent advances in m6A modification and PCD in terms of their interplay and potential mechanisms, as well as cancer therapeutic resistance. Our study provides promising insights and future directions for the examination and treatment of cancers.