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D-A type axially chiral biphenyl luminescent molecules are directly constructed through ingenious functionalization of the octahydro-binaphthol skeleton without optical resolution. The circularly polarized organic light-emitting diodes based on them display remarkable circularly polarized electroluminescence emission, a high luminance of >10â¯000 cd m-2, a maximum external quantum efficiency of 6.6%, and an extremely low-efficiency roll-off. This work provides a universal strategy for developing efficient and diverse axially chiral biphenyl emitters.
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Organic light-emitting diodes (OLEDs) suffer from carrier imbalance under high temperatures. We improved their thermal stability by using space interlayers adjacent to the charge transport layers. The current efficiency of the optimized OLEDs increased under high temperature, with an increase of over one order of magnitude of the electron mobility.
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In this work, we investigated the influence of MoS2 functioning as an electron transport layer (ETL) on the inverted flexible organic photovoltaics (FOPVs). Three ETLs, including MoS2, lithium quinolate (Liq), and a MoS2/Liq bilayer, were evaporated onto ITO-integrated polyethylene terephthalate substrates (PET-ITO), and the properties of transmittance, water contact angle, and reflectivity of the films were analyzed. The results revealed that MoS2 was helpful to improve the lipophilicity of the surface of the ETL, which was conducive to the deposition of the active layer. In addition, the reflectivity of MoS2 to the light ranging from 400 to 600 nm was the largest among the pristine PET-ITO substrate and the PET-ITO coated with three ETLs, which promoted the efficient use of the light. The efficiency of the FOPV with MoS2/Liq ETL was 73% higher than that of the pristine device. This was attributed to the nearly two-fold amplification of the MoS2 array to the light field, which promoted the FOPV to absorb more light. Moreover, the efficiency of the FOPV with MoS2 was maintained under different illumination angles and bending angles. The results demonstrate the promising applications of MoS2 in the fabrication of FOPVs.
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Iluminação , Molibdênio , Transporte de Elétrons , Transporte de Íons , LítioRESUMO
Developing new organic reactions with excellent atom economy and high selectivity is significant and urgent. Herein, by ingeniously regulating the reaction conditions, highly selective transformations of propargylamines have been successfully implemented. The palladium-catalyzed cyclization of propargylamines generates a series of functionalized quinoline heterocycles, while the base-promoted isomerization of propargylamines affords diverse 1-azadienes. Both reactions have good functional group tolerance, mild conditions, excellent atom economy and high yields of up to 93%. More importantly, these quinoline heterocycles and 1-azadienes could be flexibly transformed into valuable compounds, illustrating the validity and practicability of the propargylamine-based highly selective reactions.
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DNA high methylation is one of driving force for colorectal carcinoma (CRC) pathogenesis. Transcription factors (TFs) can determine cell fate and play fundamental roles in multistep process of tumorigenesis. Dysregulation of DNA methylation of TFs should be vital for the progression of CRC. Here, we demonstrated that TBX20, a T-box TF family protein, was downregulated with hypermethylation of promoter in early-stage CRC tissues and correlated with a poor prognosis for CRC patients. Moreover, we identified PDZRN3 as the E3 ubiquitin ligase of TBX20 protein, which mediated the ubiquitination and degradation of TBX20. Furthermore, we revealed that TBX20 suppressed cell proliferation and tumor growth through impairing non-homologous DNA end joining (NHEJ)-mediated double-stranded break repair by binding the middle domain of both Ku70 and Ku80 and therefore inhibiting their recruitment on chromatin in CRC cells. Altogether, our results reveal the tumor-suppressive role of TBX20 by inhibiting NHEJ-mediated DNA repair in CRC cells, and provide a potential biomarker for predicting the prognosis of patients with early-stage CRC and a therapeutic target for combination therapy.
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Neoplasias Colorretais , Quebras de DNA de Cadeia Dupla , Proteínas com Domínio T , Proteínas Mutadas de Ataxia Telangiectasia , Carcinogênese , Neoplasias Colorretais/genética , DNA , Reparo do DNA por Junção de Extremidades/genética , Reparo do DNA/genética , Humanos , Proteínas com Domínio T/genéticaRESUMO
BACKGROUND: Metastasis causes the vast majority of colorectal carcinoma (CRC)-related deaths. However, little is known about the specific traits and underlying mechanisms of metastasis-initiating cells in primary CRC. And whether or not circular RNAs (circRNAs) take part in this particular event remain not adequately stated yet. METHODS: A screening method based on Transwell assay was first applied to build CRC subgroups with different metastatic potential. High throughput RNA sequencing was used to find out novel metastatic drivers in CRC metastasis-initiating step. A series of in vitro and in vivo assays were further applied to elucidate the functions and underlying molecular mechanisms of circRNAs in CRC metastasis. RESULTS: A circRNA consisting of exon 8-11 of LONP2, termed as circLONP2, was upregulated in metastasis-initiating CRC subgroups. Aberrant higher expression of circLONP2 was observed in primary CRC tissues with established metastasis, and along the invasive margin in metastatic site. High expression of circLONP2 predicted unfavorable overall survival. Functional studies revealed that circLONP2 could enhance the invasiveness of CRC cells in vitro, and targeting circLONP2 through anti-sense oligonucleotide (ASO) dramatically reduced the penetrance of metastasis to foreign organs in vivo. Mechanically, circLONP2 directly interacted with and promoted the processing of primary microRNA-17 (pri-miR-17), through recruiting DiGeorge syndrome critical region gene 8 (DGCR8) and Drosha complex in DDX1-dependent manner. Meanwhile, upregulated mature miR-17-5p could be assembled into exosomes and internalized by neighboring cells to enhance their aggressiveness. CONCLUSIONS: Our data indicate that circLONP2 acts as key metastasis-initiating molecule during CRC progression through modulating the intracellular maturation and intercellular transfer of miR-17, resulting in dissemination of metastasis-initiating ability in primary site and acceleration of metastasis formation in foreign organs. circLONP2 could serve as an effective prognostic predictor and/or novel anti-metastasis therapeutic target in CRC treatment.
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Neoplasias Colorretais/patologia , RNA Helicases DEAD-box/metabolismo , Exossomos/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/secundário , MicroRNAs/genética , RNA Circular/genética , Proteases Dependentes de ATP/genética , Animais , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , RNA Helicases DEAD-box/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Camundongos Nus , Invasividade Neoplásica , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
We report here an efficient one-pot method for the synthesis of α,ß-differentiated diamino esters directly from cinnamate esters using N,N-dichloro-p-toluenesulfonamide and benzylamine as nitrogen sources. The key transformations include a Cu-catalyzed aminohalogenation and aziridination, followed by an intermolecular SN2 nucleophilic ring opening by benzylamine. The reactions feature a wide scope of substrates and proceed with excellent stereo- and regioselectivity (anti:syn >99:1) .
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Through facilitating DNA homologous recombination repair, PPIP5K2 has been proven to be essential for improving colorectal cancer survival in our previous research. However, its function in the tumorigenesis of NSCLC, the most common cancer and the primary cause of cancer-related death globally, is still unknown. Here, we initially discovered that PPIP5K2 had significant effects on proliferation of NSCLC cells through loss- and gain-of-function assays in vitro and in vivo. Moreover, PPIP5K2 is capable of regulating NSCLC cells metastasis in an EMT-dependent manner. In terms of mechanism exploration, we found that PPIP5K2 knockdown can significantly inhibit the phosphorylation of AKT/mTOR signaling pathway, whereas the overexpression of PPIP5K2 resulted in converse effects. By employing AKT signaling related agonists or antagonists, we further demonstrated that PPIP5K2 regulates NSCLC tumorigenesis partly via the AKT/mTOR pathway. In conclusion, PPIP5K2 plays a key oncogenic role in NSCLC by the activation of the AKT/mTOR signaling axis. It is anticipated that targeting PPIP5K2 might emerge as a viable therapeutic approach for NSCLC patients.
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Urolithin families are gut-microbial metabolites of ellagic acid (EA). Although urolithin A (UA) and urolithin B (UB) were reported to have antiproliferative activities in cancer cells, the role and related mechanisms of urolithin C (UC) in colorectal cancer (CRC) have not yet been clarified. In this study, we assess the antitumor activities of UC in vitro and in vivo and further explore the underlying mechanisms in CRC cell lines. We found that UC inhibited the proliferation and migration of CRC cells, induced apoptosis, and arrested the cell cycle at the G2/M phase in vitro, and UC inhibited tumor growth in a subcutaneous transplantation tumor model in vivo. Mechanically, UC blocked the activation of the AKT/mTOR signaling pathway by decreasing the expression of Y-box binding protein 1(YBX1). The AKT agonist SC79 could reverse the suppression of cell proliferation in UC-treated CRC cells. In conclusion, our research revealed that UC could prevent the progression of CRC by blocking AKT/mTOR signaling, suggesting that it may have potential therapeutic values.
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Deficiency of DNA repair pathways drives the development of colorectal cancer. However, the role of the base excision repair (BER) pathway in colorectal cancer initiation remains unclear. This study shows that Nei-like DNA glycosylase 1 (NEIL1) is highly expressed in colorectal cancer (CRC) tissues and associated with poorer clinical outcomes. Knocking out neil1 in mice markedly suppresses tumorigenesis and enhances infiltration of CD8+ T cells in intestinal tumors. Furthermore, NEIL1 directly forms a complex with SATB2/c-Myc to enhance the transcription of COL17A1 and subsequently promotes the production of immunosuppressive cytokines in CRC cells. A NEIL1 peptide suppresses intestinal tumorigenesis in ApcMin/+ mice, and targeting NEIL1 demonstrates a synergistic suppressive effect on tumor growth when combined with a nuclear factor κB (NF-κB) inhibitor. These results suggest that combined targeting of NEIL1 and NF-κB may represent a promising strategy for CRC therapy.
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Neoplasias Colorretais , DNA Glicosilases , Animais , Camundongos , Carcinogênese , Linfócitos T CD8-Positivos/metabolismo , Neoplasias Colorretais/genética , DNA Glicosilases/metabolismo , Reparo do DNA , NF-kappa B/metabolismoRESUMO
Hepatocellular carcinoma (HCC) acquires an immunosuppressive microenvironment, leading to unbeneficial therapeutic outcomes. Hyaluronan-mediated motility receptor (HMMR) plays a crucial role in tumor progression. Here, we found that aberrant expression of HMMR could be a predictive biomarker for the immune suppressive microenvironment of HCC, but the mechanism remains unclear. We established an HMMR-/- liver cancer mouse model to elucidate the HMMR-mediated mechanism of the dysregulated "don't eat me" signal. HMMR knockout inhibited liver cancer growth and induced phagocytosis. HMMRhigh liver cancer cells escaped from phagocytosis via sustaining CD47 signaling. Patients with HMMRhighCD47high expression showed a worse prognosis than those with HMMRlowCD47low expression. HMMR formed a complex with FAK/SRC in the cytoplasm to activate NF-κB signaling, which could be independent of membrane interaction with CD44. Notably, targeting HMMR could enhance anti-PD-1 treatment efficiency by recruiting CD8+ T cells. Overall, our data revealed a regulatory mechanism of the "don't eat me" signal and knockdown of HMMR for enhancing anti-PD-1 treatment.
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Antígeno CD47 , Carcinoma Hepatocelular , Receptores de Hialuronatos , Neoplasias Hepáticas , Fagócitos , Fagocitose , Animais , Humanos , Camundongos , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/genética , Antígeno CD47/metabolismo , Antígeno CD47/genética , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Quinase 1 de Adesão Focal/metabolismo , Quinase 1 de Adesão Focal/genética , Receptores de Hialuronatos/metabolismo , Receptores de Hialuronatos/genética , Evasão da Resposta Imune , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Camundongos Knockout , NF-kappa B/metabolismo , Fagócitos/metabolismo , Fagócitos/imunologia , Transdução de Sinais , Evasão Tumoral , Microambiente Tumoral/imunologiaRESUMO
Deposition of extracellular matrix (ECM) in the liver is an important feature of liver cirrhosis. Recovery from liver cirrhosis is physiologically challenging, partially due to the ECM in scar tissue showing resistance to cell-mediated degradation by secreted matrix metalloproteinases (MMPs). Here, a cell-mediated ECM-degradation screening system (CEDSS) in vitro is constructed for high-throughput searching for cells with tremendous degradation ability. ECM-degrading liver sinusoidal endothelial cells (dLSECs) are screened using CEDSS, which exhibit 17 times the ability to degrade collagen when compared to other cells. The degradation ability of dLSECs is mediated by the upregulation of MMP9. In particular, mRNA expression of MMP9 shows an 833-fold increase in dLSECs compared to normal endothelial cells (nLSECs), and MMP9 is regulated by transcription factor c-Fos. In vivo, single intrasplenic injection of dLSECs alleviates advanced liver fibrosis in mice, while intraperitoneal administration of liver-targeting peptide-modified dLSECs shows enhanced fibrosis-targeting effects. Degradative human umbilical vein endothelial cells (dHUVECs) prove their enhanced potential of clinical translation. Together, these results highlight the potential of ECM-degrading endothelial cells in alleviating advanced liver fibrosis, thus providing remarkable insights in the development of ECM-targeting therapeutics.
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Cicatriz , Metaloproteinase 9 da Matriz , Camundongos , Humanos , Animais , Metaloproteinase 9 da Matriz/metabolismo , Células Endoteliais/metabolismo , Cirrose Hepática/terapiaRESUMO
The corresponding mRNA vaccines Comirnaty (BNT162b2) and Spikevax (mRNA-1273) have been authorized for emergency use since the COVID-19 outbreak. Most clinical researches have also discovered that the mRNA vaccine is a revolutionary strategy for preventing and treating numerous diseases, including cancers. Unlike viral vectors or DNA vaccines, mRNA vaccines cause the body to directly produce proteins following injection. Delivery vectors and mRNAs that encode tumor antigens or immunomodulatory molecules work together to trigger an anti-tumor response. Before mRNA vaccines may be employed in clinical trials, a number of challenges need to be resolved. These include establishing effective and safe delivery systems, generating successful mRNA vaccines against diverse types of cancers, and proposing improved combination therapy. Therefore, we need to improve vaccine-specific recognition and develop mRNA delivery mechanisms. This review summarizes the complete mRNA vaccines' elemental composition and discusses recent research progress and future direction for mRNA tumor vaccines.
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COVID-19 , Neoplasias , Humanos , Vacina BNT162 , COVID-19/prevenção & controle , Vacinas Sintéticas/uso terapêutico , Vacinas de mRNA , Neoplasias/genética , Neoplasias/terapiaRESUMO
Herein, a base metal-enabled chemodivergent cyclization of propargylamines for the atom-economic construction of nitrogen heterocycles has been developed. Due to the different modes of activation of metal to propargylamine, copper-catalyzed 6-endo-dig cyclization generates functionalized 2-substitued quinoline-4-carboxylates, while iron-promoted cascade amino Claisen rearrangement, aromatization, and aza-Michael addition afford diverse 2-substituted indole-3-carboxylate derivatives. Excellent selectivity, broad functional group tolerance, mild conditions, and flexible late-stage functionalization illustrate the high efficiency and synthetic utility of this chemodivergent reaction.
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Neoadjuvant chemoimmunotherapy (NACI) has shown promise in the treatment of resectable esophageal squamous cell carcinoma (ESCC). The microbiomes of patients can impact therapy response, and previous studies have demonstrated that intestinal microbiota influences cancer immunotherapy by activating gut immunity. Here, we investigated the effects of intratumoral microbiota on the response of patients with ESCC to NACI. Intratumoral microbiota signatures of ß-diversity were disparate and predicted the treatment efficiency of NACI. The enrichment of Streptococcus positively correlated with GrzB+ and CD8+ T-cell infiltration in tumor tissues. The abundance of Streptococcus could predict prolonged disease-free survival in ESCC. Single-cell RNA sequencing demonstrated that responders displayed a higher proportion of CD8+ effector memory T cells but a lower proportion of CD4+ regulatory T cells. Mice that underwent fecal microbial transplantation or intestinal colonization with Streptococcus from responders showed enrichment of Streptococcus in tumor tissues, elevated tumor-infiltrating CD8+ T cells, and a favorable response to anti-PD-1 treatment. Collectively, this study suggests that intratumoral Streptococcus signatures could predict NACI response and sheds light on the potential clinical utility of intratumoral microbiota for cancer immunotherapy. SIGNIFICANCE: Analysis of intratumoral microbiota in patients with esophageal cancer identifies a microbiota signature that is associated with chemoimmunotherapy response and reveals that Streptococcus induces a favorable response by stimulating CD8+ T-cell infiltration. See related commentary by Sfanos, p. 2985.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Microbiota , Animais , Camundongos , Carcinoma de Células Escamosas do Esôfago/terapia , Carcinoma de Células Escamosas do Esôfago/patologia , Neoplasias Esofágicas/terapia , Linfócitos T CD8-Positivos , Imunoterapia , Microambiente TumoralRESUMO
Tumor therapies have entered the immunotherapy era. Immune checkpoint inhibitors have achieved tremendous success, with some patients achieving long-term tumor control. Tumors, on the other hand, can still accomplish immune evasion, which is aided by immune checkpoints. The majority of immune checkpoints are membrane glycoproteins, and abnormal tumor glycosylation may alter how the immune system perceives tumors, affecting the body's anti-tumor immunity. Furthermore, RNA can also be glycosylated, and GlycoRNA is important to the immune system. Glycosylation has emerged as a new hallmark of tumors, with glycosylation being considered a potential therapeutic approach. The glycosylation modification of immune checkpoints and the most recent advances in glycosylation-targeted immunotherapy are discussed in this review.
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Abnormal regulation of centrosome components can induce chromosome instability and tumorigenesis. Centrosomal protein 63 (CEP63) is a vital member for assembling centrosome. Yet, the involvement of CEP63 in cancer pathogenesis remains unclear. Here we identify CEP63 as an important mediator for RNA-binding proteins (RBPs) to facilitate regulation on their RNA targets in colorectal cancer (CRC). We demonstrate that CEP63 protein is upregulated in a large cohort of colorectal cancer tissues and predicts poor prognosis, and USP36 is identified for stabilizing CEP63 by enhancing its K48-dependent deubiquitination. CEP63 overexpression promotes the proliferation and tumor growth of CRC cells in vitro and in vivo. Furthermore, we find that CEP63 can promote cancer stem-like cell properties by enhancing YAP1 expression through binding with and inhibiting the K63-ubiquitylation degradation of RBP FXR1 in CRC cells. Importantly, we further verify that the KH domain of FXR1 is necessary for the interaction between CEP63 and FXR1. Moreover, microtube motor proteins can form a complex with CEP63 and FXR1 to mediate the regulation of FXR1 on RNA targets. Additionally, we also confirm that CEP63 can bind and regulate multiple RBPs. In conclusion, our findings unveil an unrecognized CEP63/RBPs/RNA axis that CEP63 may perform as an adapter facilitating the formation of RBPs complex to regulate RNA progression and discover the role of CEP63 involved in signal transduction and RNA regulation, providing potential therapeutic target for CRC patients.
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Neoplasias Colorretais , Proteínas de Ligação a RNA , Carcinogênese/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Centrossomo/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , RNA , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Ubiquitina Tiolesterase/metabolismo , Proteínas de Sinalização YAPRESUMO
Colorectal carcinoma (CRC) is the second most deadly cancer worldwide. Therapies that take advantage of DNA repair defects have been explored in various tumors but not yet systematically in CRC. Here, we found that Diphosphoinositol Pentakisphosphate Kinase 2 (PPIP5K2), an inositol pyrophosphate kinase, was highly expressed in CRC and associated with a poor prognosis of CRC patients. In vitro and in vivo functional studies demonstrated that PPIP5K2 could promote the proliferation and migration ability of CRC cells independent of its inositol pyrophosphate kinase activity. Mechanically, S1006 dephosphorylation of PPIP5K2 could accelerate its dissociation with 14-3-3 in the cytoplasm, resulting in more nuclear distribution. Moreover, DNA damage treatments such as doxorubicin (DOX) or irradiation (IR) could induce nuclear translocation of PPIP5K2, which subsequently promoted homologous recombination (HR) repair by binding and recruiting RPA70 to the DNA damage site as a novel scaffold protein. Importantly, we verified that S1006 dephosphorylation of PPIP5K2 could significantly enhance the DNA repair ability of CRC cells through a series of DNA repair phenotype assays. In conclusion, PPIP5K2 is critical for enhancing the survival of CRC cells via facilitating DNA HR repair. Our findings revealed an unrecognized biological function and mechanism model of PPIP5K2 dependent on S1006 phosphorylation and provided a potential therapeutic target for CRC patients.
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Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/patologia , Dano ao DNA , Reparo do DNA , Regulação Neoplásica da Expressão Gênica , Fosfotransferases (Aceptor do Grupo Fosfato)/metabolismo , Animais , Apoptose , Biomarcadores Tumorais/genética , Movimento Celular , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Fosfotransferases (Aceptor do Grupo Fosfato)/genética , Prognóstico , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The adenomatous polyposis coli (APC) gene plays a pivotal role in the pathogenesis of colorectal carcinoma (CRC) but remains a challenge for drug development. Long noncoding RNAs (lncRNAs) are invaluable in identifying cancer pathologies and providing therapeutic options for patients with cancer. Here, we identified a lncRNA (lncRNA-APC1) activated by APC through lncRNA microarray screening and examined its expression in a large cohort of CRC tissues. A decrease in lncRNA-APC1 expression was positively associated with lymph node and/or distant metastasis, a more advanced clinical stage, as well as a poor prognosis for patients with CRC. Additionally, APC could enhance lncRNA-APC1 expression by suppressing the enrichment of PPARα on the lncRNA-APC1 promoter. Furthermore, enforced lncRNA-APC1 expression was sufficient to inhibit CRC cell growth, metastasis, and tumor angiogenesis by suppressing exosome production through the direct binding of Rab5b mRNA and a reduction of its stability. Importantly, exosomes derived from lncRNA-APC1-silenced CRC cells promoted angiogenesis by activating the MAPK pathway in endothelial cells, and, moreover, exosomal Wnt1 largely enhanced CRC cell proliferation and migration through noncanonicial Wnt signaling. Collectively, lncRNA-APC1 is a critical lncRNA regulated by APC in the pathogenesis of CRC. Our findings suggest that an APC-regulated lncRNA-APC1 program is an exploitable therapeutic approach for the treatment of patients with CRC.