Secretory mucin 5AC promotes neoplastic progression by augmenting KLF4-mediated pancreatic cancer cell stemness
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA671675 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12888582_1.fastq.gz | Fastqsanger.gz | |||
| SRR12888582_2.fastq.gz | Fastqsanger.gz | |||
| SRR12888583_1.fastq.gz | Fastqsanger.gz | |||
| SRR12888583_2.fastq.gz | Fastqsanger.gz | |||
| SRR12888584_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 32 |
Similar Datasets
Project description:Pancreatic cancer (PC) is the third deadliest malignancy with a dismal five-year survival rate. The KrasG12D initiator mutation, present in 95% of the PC patients, leads to the development of pancreatic intraepithelial neoplasia (PanIN). The PanIN lesions, the most common precursor lesion of PC, exhibit de novo expression of mucins, which significantly contributes to PC pathobiology. The poor clinical outcome of PC warrants the identification of molecular player(s) that facilitate the progression of Kras-driven precursor lesions to invasive ductal carcinoma. Gel-forming mucin 5AC (MUC5AC) is one of the top differentially expressed genes in PC as compared to the normal pancreas. The expression of MUC5AC appears de-novo at PanIN-1A stage and elevates in tumor tissues, while remaining absent in the normal pancreas. To delineate the mechanistic contribution of Muc5ac in PC pathology, we genetically depleted Muc5ac in an autochthonous murine model (KrasG12D; Pdx-1cre, KC), which mirrors the early stages of PC. The onset of neoplastic growth and the progression of low-grade to high-grade PanIN lesions were significantly delayed in Muc5ac knockout (KrasG12D; Muc5ac-/-; Pdx-1cre, KCM) animals. We utilized high-throughput RNA seq. analysis to investigate the downstream molecular targets of Muc5ac-associated PC progression. Our study demonstrated that knockout of Muc5ac led to a significant decline in the genes associated with cancer stem cell (CSC) maintenance and epithelial-to-mesenchymal transition (EMT). The contribution of MUC5AC in CSC maintenance was validated via in vitro experiments, and tumor formation frequency using limiting dilution assay upon subcutaneous administration.
2020-10-25 | GSE160029 | GEO
Project description:Secreted mucin 5AC (MUC5AC) is the most abundantly overexpressed member of the mucin family during early pancreatic intraepithelial neoplasia stage I (PanIN-I) of pancreatic cancer. To comprehend the contribution of Muc5ac in pancreatic cancer pathology, we genetically ablated it in an autochthonous murine model (KrasG12D; Pdx-1cre, KC), which mirrors the early stages of pancreatic cancer development. Neoplastic onset and the PanIN lesion progression were significantly delayed in Muc5ac knockout (KrasG12D; Pdx-1 cre; Muc5ac-/-, KCM) animals with a 50% reduction in PanIN-2 and 70% reduction in PanIN-3 lesions compared with KC at 50 weeks of age. High-throughput RNA-sequencing analysis from pancreatic tissues of KCM animals revealed a significant decrease in cancer stem cell (CSC) markers Aldh1a1, Klf4, EpCAM, and CD133. Furthermore, the silencing of MUC5AC in human pancreatic cancer cells reduced their tumorigenic propensity, as indicated by a significant decline in tumor formation frequency by limiting dilution assay upon subcutaneous administration. The contribution of MUC5AC in CSC maintenance was corroborated by a significant decrease in tumor burden upon orthotopic implantation of MUC5AC-depleted pancreatic cancer cells. Mechanistically, MUC5AC potentiated oncogenic signaling through integrin αvβ5, pSrc (Y416), and pSTAT3 (Y705). Phosphorylated STAT3, in turn, upregulated Klf4 expression, thereby enriching the self-renewing CSC population. A strong positive correlation of Muc5ac with Klf4 and pSTAT3 in the PanIN lesions of KC mouse pancreas reinforces the crucial involvement of MUC5AC in bolstering the CSC-associated tumorigenic properties of Kras-induced metaplastic cells, which leads to pancreatic cancer onset and progression. SIGNIFICANCE: This study elucidates that de novo expression of MUC5AC promotes cancer cell stemness during Kras-driven pancreatic tumorigenesis and can be targeted for development of a novel therapeutic regimen.
| S-EPMC7990052 | biostudies-literature
Project description:Meningiomas are the most common primary tumors of the central nervous system. The genetic landscape of the most common subtype of meningioma involves mutation or copy loss of the NF2 gene in approximately 50% of cases. Other recurrent canonical somatic mutations are present in ~40% of sporadic meningiomas and are not defined by NF2 inactivation. These genes include TRAF7, AKT1, SMO, and KLF4, among others. Tumors with KLF4 and TRAF7 mutations share a unique secretory phenotype, which is characterized by glandular lumina with secretory globules, and tend to cause disproportional peritumoral edema, which can cause severe medical and neurological complications in pre- and post-operative management. The K409Q mutation in KLF4 is found in ~15% of meningiomas. The mutated allele KLF4K409Q is the same in all affected patients and occurs together with TRAF7 missense mutations. The contribution of the meningioma-specific KLF4 mutation to tumorigenesis and mechanism of action is unknown. Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) analysis was performed to investigate different DNA recognition sequences by ectopically expressed KLF4 and KLF4(K409Q) proteins in transiently transfected HEK293 cells.
2022-08-18 | GSE205920 | GEO
Project description:While growing in the human intestine, C. jejuni grows within the mucus layer. The largest constituents of this layer are the large mucin glycoproteins. A transcriptomic profile of C. jejuni NCTC11168 growing in a mucin-containing minimal medium seeks to describe the effect of the presence of mucin proteins on the transcriptome of C. jejuni. Microarray data was collected from three independent biological replicates and 9 technical replicates for each biological replicate.
2011-04-01 | E-GEOD-28295 | biostudies-arrayexpress
Project description:While growing in the human intestine, C. jejuni grows within the mucus layer. The largest constituents of this layer are the large mucin glycoproteins. A transcriptomic profile of C. jejuni NCTC11168 growing in a mucin-containing minimal medium seeks to describe the effect of the presence of mucin proteins on the transcriptome of C. jejuni.
2011-04-01 | GSE28295 | GEO
Project description:Klf4 is the zinc finger transcription factor indispensable for terminal maturation of epithelial tissues and part of group of proteins for the generation of pluripotent embryonic stem cells from differentiated tissues. No definitive in-vivo-function of Klf4 in the hematopoietic system has been established yet. We show here that Klf4 directly guides the transcriptional program for terminal differentiation of Ly-6Chigh monocytes. Klf4 suppresses transcripts of the interferon immune response and induces a proinflammatory cytokine transcriptional program. Concordantly, Klf4 hematopoietic deficiency in mice results in an enhanced Th1 but impaired Th17 immune response, and, consequently, those mice are resistant towards the induction of experimental autoimmune encephalitis (EAE). We here identify Klf4 is a transcription factor required for ontogenesis and function of Ly-6Chigh monocytes at the interface of innate and acquired immunity.
2012-07-31 | GSE11572 | GEO
Project description:Candida albicans is the most prevalent fungal pathogen of humans, causing a variety of diseases ranging from superficial mucosal infections to deep-seated systemic infections. Mucus, the gel that coats all wet epithelial surfaces, accommodates Candida albicans as part of the regular microbiome where C. albicans resides asymptomatically in healthy humans. Through a series of in vitro experiments combined with genome-wide transcriptional profiling, we show that mucin biopolymers, the main gel-forming constituents of mucus, induce a new oval-shaped morphology in C. albicans in which a range of genes related to adhesion, filamentation, and biofilm formation are down-regulated. We also show that corresponding phenotypes are suppressed, rendering Candida incapable of forming biofilms on a range of different synthetic surfaces and human epithelial cells. Our data suggests that mucins can manipulate Candida physiology and we hypothesize that they are key regulators for retaining Candida in the host-compatible, commensal state. 3 biological replicates grown in log phase in the presence and absence of mucin for 8 hours. Experiments were performed using RPMI 1640 (Gibco 31800-089) buffered with 165mM MOPS and supplemented with 0.2% NaHCO3 and 2% glucose with and without 0.5% mucin.
2014-03-11 | E-GEOD-55766 | biostudies-arrayexpress
Project description:Klf4 is the zinc finger transcription factor indispensable for terminal maturation of epithelial tissues and part of group of proteins for the generation of pluripotent embryonic stem cells from differentiated tissues. No definitive in-vivo-function of Klf4 in the hematopoietic system has been established yet. We show here that Klf4 directly guides the transcriptional program for terminal differentiation of Ly-6Chigh monocytes. Klf4 suppresses transcripts of the interferon immune response and induces a proinflammatory cytokine transcriptional program. Concordantly, Klf4 hematopoietic deficiency in mice results in an enhanced Th1 but impaired Th17 immune response, and, consequently, those mice are resistant towards the induction of experimental autoimmune encephalitis (EAE). We here identify Klf4 is a transcription factor required for ontogenesis and function of Ly-6Chigh monocytes at the interface of innate and acquired immunity. The following constructs were used: Mus musculus Klf4 full length, (ref|NM_010637.1) cDNA, Mus musculus cyclin-dependent kinase inhibitor 1A (P21) (Cdkn1a), cDNA (ref|NM_007669.3) were fused in frame to the modified oestrogen receptor ERT2 (Feil et al., 1997) and cloned into a retroviral vector (Mieg3) expressing the constructs together with eGFP after an internal ribosomal entry site . (Williams et al., 2000). For Klf4, a mutant comprinsing the zinc- finger domains only AA 393 M-bM-^@M-^S 474 (Klf4 dN) as well as a mutant comprising the entire protein except the zinc fingers AA 1-393 (Klf4-dC) were constructed and fused in frame to the modified oestrogen receptor. BM cells from 5-FU treated mice were infected with viral constructs, sorted for GFP expression (day8), plated in IMDM , 10% FCS, 2mM Gln, 1% P/S, supplemented with 50ng/ml rSCF, 100ng/ml TPO and 100ng/ml G-CSF and cultured for 72h (day8-day10). On day10 cells were stimulated with 4-OHT (1uM) for 16h. After that time, total RNA was isolated by Trizol method. Reference List: Feil,R., Wagner,J., Metzger,D., and Chambon,P. (1997). Regulation of Cre recombinase activity by mutated estrogen receptor ligand-binding domains. Biochem. Biophys. Res. Commun. 237, 752-757. Williams,D.A., Tao,W., Yang,F., Kim,C., Gu,Y., Mansfield,P., Levine,J.E., Petryniak,B., Derrow,C.W., Harris,C., Jia,B., Zheng,Y., Ambruso,D.R., Lowe,J.B., Atkinson,S.J., Dinauer,M.C., and Boxer,L. (2000). Dominant negative mutation of the hematopoietic-specific Rho GTPase, Rac2, is associated with a human phagocyte immunodeficiency. Blood 96, 1646-1654.
2012-07-30 | E-GEOD-11572 | biostudies-arrayexpress
Project description:Vascular smooth muscle cells (VSMCs) within atherosclerotic lesions undergo a phenotypic switching in a KLF4-dependent manner. Glycolysis plays important roles in transdifferentiation of somatic cells, however, it is unclear whether and how KLF4 mediates the link between glycolytic switch and VSMCs phenotypic transitions. Here, we show that KLF4 upregulation accompanies VSMCs phenotypic switching in atherosclerotic lesions. KLF4 enhances the metabolic switch to glycolysis through increasing PFKFB3 expression. Inhibiting glycolysis suppresses KLF4-induced VSMCs phenotypic switching, demonstrating that glycolytic shift is required for VSMCs phenotypic switching. Mechanistically, KLF4 upregulates expression of circCTDP1 and eEF1A2, both of which cooperatively promote PFKFB3 expression. TMAO induces glycolytic shift and VSMCs phenotypic switching by upregulating KLF4. Our study indicates that KLF4 mediates the link between glycolytic switch and VSMCs phenotypic transitions, suggesting that a previously unrecognized KLF4-eEF1A2/circCTDP1-PFKFB3 axis plays crucial roles in VSMCs phenotypic switching.
2022-11-09 | PXD038057 |
Project description:The oviducts contain high grade serous cancer precursors, which are M-NM-3-H2AXp and p53 mutation positive. Secretory cell outgrowths (SCOUTs) are associated with older age and serous cancer. We evaluated PAX2 expression in proliferating oviductal cells, normal mucosa, SCOUTs, Walthard cell nests, STINs and HGSCs. Non-ciliated cells in normal mucosa were PAX2 positive but became PAX2 negative in multilayered epithelium. PAX2 negative SCOUTs fell into two groups; Type I were secretory or secretory/ciliated with a M-bM-^@M-^\tubalM-bM-^@M-^] phenotype and were ALDH1 negative. Type II displayed a columnar to pseudostratified phenotype, with an EZH2,ALDH1, M-NM-2-catenin, Stathmin, LEF1, RCN1 and RUNX2 expression signature . This study, for the first time, links PAX2 negative with proliferating fetal and adult oviductal cells undergoing basal and ciliated differentiation and shows that this expression state is maintained in SCOUTs, STINs and HGSCs. All three entities can demonstrate a consistent perturbation of genes involved in potential tumor suppressor gene silencing (EZH2), transcriptional regulation (LEF1), regulation of differentiation (RUNX2) calcium binding (RCN1) and oncogenesis (Stathmin). This shared expression signature between benign and neoplastic entities links normal progenitor cell expansion to abnormal and neoplastic outgrowth in the oviduct and exposes a common pathway that could be a target of early prevention. 17 total samples are analyzed. 4 for TYPE 1 SCOUTs, 3 for TYPE 2 SCOUTs, 7 for paired normal epithelium, 3 for tumor
2014-09-20 | E-GEOD-58842 | biostudies-arrayexpress