Stress responsive miR-31 is a major modulator of mouse intestinal stem cells during regeneration and tumorigenesis.
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ABSTRACT:
SUBMITTER: Tian Y
PROVIDER: S-EPMC5584991 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:MicroRNA-mediated post-transcriptional regulation plays key roles in stem cell self-renewal and tumorigenesis. However, the in vivo functions of specific microRNAs in controlling mammary stem cell (MaSC) activity and breast cancer formation remain poorly understood. Here we show that miR-31 is highly expressed in MaSC-enriched mammary basal cell population and in mammary tumors, and is regulated by NF-?B signaling. We demonstrate that miR-31 promotes mammary epithelial proliferation and MaSC expansion at the expense of differentiation in vivo. Loss of miR-31 compromises mammary tumor growth, reduces the number of cancer stem cells, as well as decreases tumor-initiating ability and metastasis to the lung, supporting its pro-oncogenic function. MiR-31 modulates multiple signaling pathways, including Prlr/Stat5, TGF? and Wnt/?-catenin. Particularly, it activates Wnt/?-catenin signaling by directly targeting Wnt antagonists, including Dkk1. Importantly, Dkk1 overexpression partially rescues miR31-induced mammary defects. Together, these findings identify miR-31 as the key regulator of MaSC activity and breast tumorigenesis.
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Project description:This is a prospective-retrospective study to determine if the expression of the miRNA’s miR-31-3p and miR-31-5p are prognostic of patient outcomes or predictive of the benefit from anti-EGFR therapy in stage III Colon Cancer. The present study will utilize FFPE tumor samples collected from patients enrolled in the PETACC-8 study conducted by the Fédération Francophone de Cancérologie Digestive (FFCD). This phase 3 clinical trial prospectively randomized fully resected stage III colon cancer patients to receive adjuvant treatment with either FOLFOX-4 plus cetuximab or FLOFOX-4 alone.
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Project description:IntroductionPeriodontitis is a chronic inflammatory disease that causes alveolar bone loss. Diabetes is one of the most important factors contributing to periodontitis. Exosomes derived from mesenchymal stem cells (MSCs-Exo) have been reported to promote bone regeneration. This study aimed to examine the function and mechanism of exosomes derived from periodontal ligament stem cells (PDLSCs-Exo) in regulating periodontal regeneration in diabetic periodontitis.MethodsExosomes derived from normal-glucose-cultured PDLSCs (NG-PDLSCs-Exo) and high-glucose-preconditioned PDLSCs (HG-PDLSCs-Exo) were used. Their effects on RAW264.7 cells were investigated by TRAP staining and quantitative real time-polymerase chain reaction (qRT-PCR). The role of exosomal miR-31-5p in osteoclast differentiation was tested using qRT-PCR, double luciferase analysis, and Western blotting. We investigated the effects of these two types of PDLSCs-Exo on alveolar bone loss in vivo in mice with experimental periodontitis.ResultsPDLSCs-Exo were transferred to RAW264.7, and HG-PDLSCs-Exo inhibited osteoclast formation to a lesser extent than NG-PDLSCs-Exo. Further studies revealed the effect of PDLSCs-Exo on osteoclastogenesis via the miR-31-5p/eNOS signaling pathway. In mice with experimental periodontitis, PDLSCs-Exo reduced alveolar bone destruction and decreased the number of osteoclasts on the alveolar bone surface.ConclusionOur results suggest that exosomal miR-31-5p derived from PDLSCs regulates alveolar bone regeneration by targeting eNOS.
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Project description:The Wnt/?-catenin signaling pathway controls cellular proliferation in the intestines. In response to Wnt, ?-catenin transits into the nucleus and associates with members of the T-cell factor (TCF) family of transcription factors. ?-Catenin/TCF complexes bind Wnt responsive DNA elements (WREs) to activate target gene expression. The c-MYC proto-oncogene (MYC) is a direct target of ?-catenin/TCF complexes. We recently identified the MYC 3' WRE, which maps 1.4-kb downstream from the MYC transcription stop site. To investigate the role of the Myc 3' WRE in the intestines, we generated a mouse model with a germ line deletion of this element. The intestinal architecture was largely preserved in knockout mice; however, removal of the Myc 3' WRE compromised the crypt microenvironment. In comparison to wild-type intestines, knockout intestines contained an increased number of proliferative cells and a reduced number of differentiated cells comprising both absorptive and secretory lineages. Using a model of colitis, we found that knockout colons repaired more rapidly during the recovery period of the protocol. These results indicate that regulation of MYC expression through the Myc 3' WRE contributes to intestinal homeostasis. Furthermore, our study implicates MYC as an important regulator of intestinal regeneration following injury.
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Project description:Regulation of metabolic pathways plays an important role in controlling cell growth, proliferation, and survival. TIGAR acts as a fructose-2,6-bisphosphatase, potentially promoting the pentose phosphate pathway to produce NADPH for antioxidant function and ribose-5-phosphate for nucleotide synthesis. The functions of TIGAR were dispensable for normal growth and development in mice but played a key role in allowing intestinal regeneration in vivo and in ex vivo cultures, where growth defects due to lack of TIGAR were rescued by ROS scavengers and nucleosides. In a mouse intestinal adenoma model, TIGAR deficiency decreased tumor burden and increased survival, while elevated expression of TIGAR in human colon tumors suggested that deregulated TIGAR supports cancer progression. Our study demonstrates the importance of TIGAR in regulating metabolism for regeneration and cancer development and identifies TIGAR as a potential therapeutic target in diseases such as ulcerative colitis and intestinal cancer.
| S-EPMC3682186 | biostudies-literature
Project description:Ulcerative colitis (UC) features chronic, non-infectious inflammation of the colon. The risk of ulcerative colitis‑associated neoplasia (UCAN) increases in direct association with the duration of this disease. Whether miRNAs exert a regulatory effect on the pathogenesis of UCAN has remained to be elucidated. In the present study, differentially expressed genes (DEGs) and microRNAs (miRNAs/miRs) were identified using bioinformatics analysis of Gene Expression Omnibus datasets. Enrichment analyses were performed to determine the function of the DEGs. The target genes of key miRNAs were predicted using miRWalk. Validation of DEGs and miRNAs in patients with UC, UC with low‑grade dysplasia and UC with high‑grade dysplasia (UC‑HGD) was performed using reverse transcription‑quantitative PCR analysis. A total of 38 differentially expressed miRNAs and 307 mRNAs were identified from the profiles and miR‑31 was validated as being overexpressed in UCAN tissues, particularly in the UC‑HGD samples. Furthermore, special AT‑rich DNA‑binding protein 2 (SATB2) was validated as a target gene of miR‑31 and SATB2 expression was negatively correlated with miR‑31 expression. Therefore, miR‑31 is upregulated in UCAN and it may promote tumorigenesis through downregulation of SATB2.
| S-EPMC7646903 | biostudies-literature
Project description:Src, originally identified as an oncogene, is a membrane-anchored tyrosine kinase and the Src family kinase (SFK) prototype. SFKs regulate the signalling induced by a wide range of cell surface receptors leading to epithelial cell growth and adhesion. In the intestine, the SFK members Src, Fyn and Yes regulate epithelial cell proliferation and migration during tissue regeneration and transformation, thus implicating conserved and specific functions. In patients with colon cancer, SFK activity is a marker of poor clinical prognosis and a potent driver of metastasis formation. These tumorigenic activities are linked to SFK capacity to promote the dissemination and tumour-initiating capacities of epithelial tumour cells. However, it is unclear how SFKs promote colon tumour formation and metastatic progression because SFK-encoding genes are unfrequently mutated in human cancer. Here, we review recent findings on SFK signalling during intestinal homeostasis, regeneration and tumorigenesis. We also describe the key nongenetic mechanisms underlying SFK tumour activities in colorectal cancer, and discuss how these mechanisms could be exploited in therapeutic strategies to target SFK signalling in metastatic colon cancer.
| S-EPMC7464719 | biostudies-literature
Project description:The epithelial signaling pathways involved in damage and regeneration, and neoplastic transformation are known to be similar. We noted upregulation of argininosuccinate synthetase (ASS1) in hyperproliferative intestinal epithelium. Since ASS1 leads to de novo synthesis of arginine, an important amino acid for the growth of intestinal epithelial cells, its upregulation can contribute to epithelial proliferation necessary to be sustained during oncogenic transformation and regeneration. Here we investigated the function of ASS1 in the gut epithelium during tissue regeneration and tumorigenesis, using intestinal epithelial conditional Ass1 knockout mice and organoids, and tissue specimens from colorectal cancer patients. We demonstrate that ASS1 is strongly expressed in the regenerating and Apc-mutated intestinal epithelium. Furthermore, we observe an arrest in amino acid flux of the urea cycle, which leads to an accumulation of intracellular arginine. However, loss of epithelial Ass1 does not lead to a reduction in proliferation or increase in apoptosis in vivo, also in mice fed an arginine-free diet. Epithelial loss of Ass1 seems to be compensated by altered arginine metabolism in other cell types and the liver.
| S-EPMC8486827 | biostudies-literature
Project description:BackgroundColorectal cancer (CRC) remains the most common gastrointestinal cancer and a leading cause of cancer deaths worldwide, with most showing pathologies indicating the malignant transformation of early stage intestinal stem cells. The long non-coding RNA Meg3, which functions as a tumor suppressor, has been reported to be abnormal in multiple tumorigenesis events; however, the underlying mechanism by which Meg3 contributes to the malignant proliferation of colonic stem cells remains unclear.MethodsWe analyzed the expression levels of Meg3, miR-708, and SOCS3 in samples from Apc loss-of-function (Apcmin) mice and patients with CRC, particularly in colonic crypt cells. Apcmin mice and AMO/DSS-induced mice model (in vivo) and organoid culture system (in vitro) were used to explore the effect of the Meg3/miR-708/SOCS3 axis on tumorigenesis in the colon. In vitro, we performed RNApull-down, RNA immunoprecipitation, and luciferase reporter assays using DLD1 and RKO cell lines.FindingsThe Meg3/miR-708/SOCS3 signaling axis plays a critical role in the early stage of CRC development. Our data showed Meg3 levels negatively correlate with miR-708 levels both in clinical samples and in the Apcmin mouse model, which indicated that Meg3 acts as a competitive endogenous RNA (ceRNA) of miR-708. Then, miR-708 served as an oncogene, inducing neoplasia in both Apcmin mice and cultured colonic organoids. Put together, miR-708 appears to promote malignant proliferation of colonic stem cells by targeting SOCS3/STAT3 signaling.InterpretationThese data revealed that Meg3 sponges miR-708 to inhibit CRC development via SOCS3-mediated repression of the malignant proliferation of colonic stem cells. The Meg3/miR-708/SOCS3 signaling axis provides potential targets for the diagnosis and treatment of CRC, particularly early stage CRC.
| S-EPMC8692598 | biostudies-literature
Project description:BackgroundAs a distinctive type of head and neck cancers, nasopharyngeal carcinoma (NPC) is genesis from the clonal Epstein-Barr virus (EBV)-infected nasopharyngeal epithelial cells accumulated with multiple genetic lesions. Among the recurrent genetic alterations defined, loss of 9p21.3 is the most frequent early event in the tumorigenesis of EBV-associated NPC. In addition to the reported CDKN2A/p16, herein, we elucidated the role of a miRNA, miR-31 within this 9p21.3 region as NPC-associated tumor suppressor.MethodsThe expression and promoter methylation of miR-31 were assessed in a panel of NPC tumor lines and primary tumors. Its in vitro and in vivo tumor suppression function was investigated through the ectopic expression of miR-31 in NPC cells. We also determined the miR-31 targeted genes and its involvement in the growth in NPC.ResultsDownregulation of miR-31 expression was detected in almost all NPC cell line, patient-derived xenografts (PDXs) and primary tumors. Both homozygous deletion and promoter hypermethylation were shown to be major mechanisms for miR-31 silencing in this cancer. Strikingly, loss of miR-31 was also obviously observed in the dysplastic lesions of nasopharynx. Restoration of miR-31 in C666-1 cells inhibited the cell proliferation, colony-forming and migratory capacities. Dramatic reduction of in vitro anchorage-independent growth and in vivo tumorigenic potential were demonstrated in the stable clones expressing miR-31. Furthermore, we proved that miR-31 suppressed the NPC cell growth via targeting FIH1 and MCM2.ConclusionsThe findings provide strong evidence to support miR-31 as a new NPC-associated tumor suppressor on 9p21.3 region. The inactivation of miR-31 may contribute to the early development of NPC.
| S-EPMC4127521 | biostudies-literature