RESUMO
Communication between myeloid cells and epithelium plays critical role in maintaining intestinal epithelial barrier integrity. Myeloid cells interact with intestinal epithelial cells (IECs) by producing various mediators; however, the molecules mediating their crosstalk remain incompletely understood. Here, we report that deficiency of angiogenin (Ang) in mouse myeloid cells caused impairment of epithelial barrier integrity, leading to high susceptibility to DSS-induced colitis. Mechanistically, myeloid cell-derived angiogenin promoted IEC survival and proliferation through plexin-B2-mediated production of tRNA-derived stress-induced small RNA (tiRNA) and transcription of ribosomal RNA (rRNA), respectively. Moreover, treatment with recombinant angiogenin significantly attenuated the severity of experimental colitis. In human samples, the expression of angiogenin was significantly down-regulated in patients with inflammatory bowel disease (IBD). Collectively, we identified, for the first time to our knowledge, a novel mediator of myeloid cell-IEC crosstalk in maintaining epithelial barrier integrity, suggesting that angiogenin may serve as a new preventive agent and therapeutic target for IBD.
Assuntos
Mucosa Intestinal/metabolismo , Células Mieloides/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Ribonuclease Pancreático/metabolismo , Transdução de Sinais , Animais , Comunicação Celular/genética , Colite/induzido quimicamente , Colite/genética , Colite/metabolismo , Sulfato de Dextrana/toxicidade , Humanos , Mucosa Intestinal/patologia , Camundongos , Camundongos Knockout , Células Mieloides/patologia , Proteínas do Tecido Nervoso/genética , RNA Ribossômico/genética , RNA Ribossômico/metabolismo , Ribonuclease Pancreático/genéticaRESUMO
Metastasis of colorectal cancer (CRC) is the leading cause of CRC-associated mortality. Angiogenin (ANG), a member of the ribonuclease A superfamily, not only activates endothelial cells to induce tumor angiogenesis, but also targets tumor cells to promote cell survival, proliferation and/or migration. However, its clinical significance and underlying mechanism in CRC metastasis are still largely unknown. Here, we reported that ANG was upregulated in CRC tissues and associated with metastasis in CRC patients. We then revealed that ANG enhanced CRC growth and metastasis in both in vitro and in vivo systems. Intriguingly, we characterized a bunch of tRNA-derived stress-induced small RNAs (tiRNAs), produced through ANG cleavage, that was enriched in both CRC tumor tissues and highly metastatic cells, and functioned in ANG-promoted CRC metastasis. Moreover, higher level of a 5'-tiRNA from mature tRNA-Val (5'-tiRNA-Val) was observed in CRC patients and was correlated with tumor metastasis. Taken together, we propose that a novel ANG-tiRNAs-cell migration and invasion regulatory axis promotes CRC metastasis, which might be of potential target for CRC diagnosis and treatment.
Assuntos
Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , RNA de Transferência/biossíntese , Ribonuclease Pancreático/metabolismo , Regiões 5' não Traduzidas , Animais , Estudos de Casos e Controles , Movimento Celular/fisiologia , Neoplasias do Colo/irrigação sanguínea , Neoplasias do Colo/genética , Técnicas de Inativação de Genes , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos Nus , Camundongos SCID , Invasividade Neoplásica , Metástase Neoplásica , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , RNA de Transferência/genética , RNA de Transferência/metabolismo , Ribonuclease Pancreático/genética , Regulação para CimaRESUMO
Antimicrobial proteins contribute to host-microbiota interactions and are associated with inflammatory bowel disease (IBD), but our understanding on antimicrobial protein diversity and functions remains incomplete. Ribonuclease 4 (Rnase4) is a potential antimicrobial protein with no known function in the intestines. Here we find that RNASE4 is expressed in intestinal epithelial cells (IEC) including Paneth and goblet cells, and is detectable in human and mouse stool. Results from Rnase4-deficient mice and recombinant protein suggest that Rnase4 kills Parasutterella to modulate intestinal microbiome, thereby enhancing indoleamine-2,3-dioxygenase 1 (IDO1) expression and subsequently kynurenic and xanthurenic acid production in IECs to reduce colitis susceptibility. Furthermore, deceased RNASE4 levels are observed in the intestinal tissues and stool from patients with IBD, correlating with increased stool Parasutterella. Our results thus implicate Rnase4 as an intestinal antimicrobial protein regulating gut microbiota and metabolite homeostasis, and as a potential diagnostic biomarker and therapeutic target for IBD.
Assuntos
Microbioma Gastrointestinal , Homeostase , Doenças Inflamatórias Intestinais , Camundongos Endogâmicos C57BL , Animais , Feminino , Humanos , Masculino , Camundongos , Peptídeos Antimicrobianos/metabolismo , Colite/microbiologia , Colite/metabolismo , Colite/induzido quimicamente , Fezes/microbiologia , Microbioma Gastrointestinal/fisiologia , Doenças Inflamatórias Intestinais/microbiologia , Doenças Inflamatórias Intestinais/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Intestinos/microbiologia , Camundongos Knockout , Ribonucleases/metabolismoRESUMO
High spatial resolution, low background, and deep tissue penetration have made near-infrared II (NIR-II) fluorescence imaging one of the most critical tools for in vivo observation and measurement. However, the relatively short retention time and potential toxicity of synthetic NIR-II fluorophores limit their long-term application. Here, we report the use of infrared fluorescent proteins (iRFPs) as in vitro and in vivo NIR-II probes permitting prolonged continuous imaging (up to 15 months). As a representative example, iRFP713 is knocked into the mouse genome to generate a transgenic model to allow temporal and/or spatial expression control of the probe. To demonstrate its feasibility in a genuine diagnostic context, we adopt two liver regeneration models and successfully track the process for a week. The performance and monitoring efficacy are comparable to those of µCT and superior to those of indocyanine green dye. We are also able to effectively observe the pancreas, despite its deep location, under both physiological and pathological conditions. These results indicate that the iRFP-assisted NIR-II fluorescence system is suitable for monitoring various tissues and in vivo biological processes, providing a powerful noninvasive long-term imaging platform.
Assuntos
Fenômenos Biológicos , Imagem Óptica , Animais , Camundongos , Corantes Fluorescentes , Verde de IndocianinaRESUMO
Previous studies have indicated an association between the genetic variant in pre-miR-27a rs895819 with A->G transition and cancer risk; however, the results remain inconsistent and somehow conflicting in different cancers. Therefore, to obtain a more reliable conclusion, we performed an update meta-analysis by searching PubMed database or other databases. Odds ratio (ORs) and 95% confidence interval (CIs) were calculated to evaluate cancer risk. A total of 34 case-control studies involving 15,388 cases and 18,704 controls were included. The results showed that rs895819 was associated with an increased cancer risk (GG vs. AA/AG: OR = 1.15, 95% CI = 1.02-1.29). Furthermore, stratification analyses revealed an association of rs895819 with increased cancer risk among Asians (GG vs. AA: OR = 1.17, 95% CI = 1.01-1.36; GG vs. AA/AG: OR = 1.18, 95% CI = 1.03-1.35), but not Caucasians. Interestingly, the [G] allele of rs895819 was significantly associated with decreased risk of breast cancer (G vs. A: OR = 0.91, 95% CI = 0.86-0.97). However, rs895819 was associated with increased risk of colorectal cancer (GG vs. AA: OR = 1.56, 95% CI = 1.31-1.85; GG vs. AA/AG: OR = 1.53, 95% CI = 1.30-1.79; G vs. A: OR = 1.19, 95% CI = 1.09-1.30) and lung cancer (GG vs. AA/AG: OR = 1.43, 95% CI = 1.00-2.04). In addition, no association was found between rs895819 and risk of gastric cancer or esophageal cancer. In conclusion, our findings suggest distinct effects of rs895819 on risk of different cancers, and future well-designed studies with large samples are required to further validate our results.