LIN28B promotes cell invasion and colorectal cancer metastasis via CLDN1 and NOTCH3
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA981563 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24878500_1.fastq.gz | Fastqsanger.gz | |||
| SRR24878500_2.fastq.gz | Fastqsanger.gz | |||
| SRR24878501_1.fastq.gz | Fastqsanger.gz | |||
| SRR24878501_2.fastq.gz | Fastqsanger.gz | |||
| SRR24878502_1.fastq.gz | Fastqsanger.gz |
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Project description:The RNA-binding protein LIN28B is overexpressed in over 30% of patients with colorectal cancer (CRC) and is associated with poor prognosis. In the present study, we unravel a novel mechanism by which LIN28B regulates colonic epithelial cell-cell junctions and CRC metastasis. Using human CRC cells (DLD-1, Caco-2 and LoVo) with either knockdown or overexpression of LIN28B, we identified Claudin 1 (CLDN1) tight junction protein as a direct downstream target and effector of LIN28B. RNA immunoprecipitation revealed that LIN28B directly binds to and post-transcriptionally regulates CLDN1 mRNA. Furthermore, using in vitro assays and a novel murine model of metastatic CRC, we show that LIN28B-mediated CLDN1 expression enhances collective invasion, cell migration, and metastatic liver tumor formation. Bulk RNA-sequencing of the metastatic liver tumors identified NOTCH3 as a downstream effector of the LIN28B-CLDN1 axis. Additionally, genetic and pharmacologic manipulation of NOTCH3 signaling revealed that NOTCH3 was necessary for invasion and metastatic liver tumor formation. In summary, our results suggest that LIN28B promotes invasion and liver metastasis of CRC by post-transcriptionally regulating CLDN1 and activating NOTCH3 signaling. This discovery offers a promising new therapeutic option for metastatic CRC to the liver, an area where therapeutic advancements have been relatively scarce.
2023-09-14 | GSE234513 | GEO
Project description:Recently a consensus molecular subtype (CMS) classification of colorectal cancer (CRC) has been established that is based on the transcriptional rather than the genetic profile of an individual tumor and which may ultimately help to individualize CRC therapy. So far, however, the lack of appropriate animal models that faithfully recapitulate the different molecular subtypes impedes adequate preclinical testing of stratified therapeutic concepts. Here we demonstrate that constitutive AKT activation in intestinal epithelial cells markedly enhances colonic tumor invasion and metastasis in Trp53DIEC mice (Trp53ΔIECAktE17K) upon challenge with the carcinogen azoxymethane (AOM). Gene-expression profiling indicates that Trp53ΔIECAktE17K tumors closely resemble the human mesenchymal colorectal cancer subtype (CMS4), which is characterized by the poorest survival rate among the four consensus molecular subtypes of CRC. Trp53ΔIECAktE17K tumors are further characterized by a NOTCH pathway gene signature and a distinct cell autonomous upregulation of Notch3 in tumor epithelia while treatment of Trp53ΔIECAktE17K mice with a NOTCH3-inhibiting antibody reduces invasion and metastasis. Conversely, selective activation of NOTCH3 by overexpression of NOTCH3-IC in Akt wt tumor organoids strongly promotes development of metastasis in an orthotopic transplantation model. In CRC patients NOTCH3 expression correlates positively with tumor grading and the presence of lymph node as well as distant metastases and is specifically upregulated in CMS4 tumors. Therefore, we suggest NOTCH3 as a putative target for advanced CMS4 CRC patients.
2021-09-08 | PXD014778 | Pride
Project description:Recently a consensus molecular subtype (CMS) classification of colorectal cancer (CRC) has been established that is based on the transcriptional rather than the genetic profile of an individual tumor and which may ultimately help to individualize CRC therapy. So far, however, the lack of appropriate animal models that faithfully recapitulate the different molecular subtypes impedes adequate preclinical testing of stratified therapeutic concepts. Here we demonstrate that constitutive AKT activation in intestinal epithelial cells markedly enhances colonic tumor invasion and metastasis in Trp53DIEC mice (Trp53ΔIECAktE17K) upon challenge with the carcinogen azoxymethane (AOM). Gene-expression profiling indicates that Trp53ΔIECAktE17K tumors closely resemble the human mesenchymal colorectal cancer subtype (CMS4), which is characterized by the poorest survival rate among the four consensus molecular subtypes of CRC. Trp53ΔIECAktE17K tumors are further characterized by a NOTCH pathway gene signature and a distinct cell autonomous upregulation of Notch3 in tumor epithelia while treatment of Trp53ΔIECAktE17K mice with a NOTCH3-inhibiting antibody reduces invasion and metastasis. Conversely, selective activation of NOTCH3 by overexpression of NOTCH3-IC in Akt wt tumor organoids strongly promotes development of metastasis in an orthotopic transplantation model. In CRC patients NOTCH3 expression correlates positively with tumor grading and the presence of lymph node as well as distant metastases and is specifically upregulated in CMS4 tumors. Therefore, we suggest NOTCH3 as a putative target for advanced CMS4 CRC patients.
2020-07-29 | GSE136254 | GEO
Project description:Recently a consensus molecular subtype (CMS) classification of colorectal cancer (CRC) has been established that is based on the transcriptional rather than the genetic profile of an individual tumor and which may ultimately help to individualize CRC therapy. So far, however, the lack of appropriate animal models that faithfully recapitulate the different molecular subtypes impedes adequate preclinical testing of stratified therapeutic concepts. Here we demonstrate that constitutive AKT activation in intestinal epithelial cells markedly enhances colonic tumor invasion and metastasis in Trp53DIEC mice (Trp53ΔIECAktE17K) upon challenge with the carcinogen azoxymethane (AOM). Gene-expression profiling indicates that Trp53ΔIECAktE17K tumors closely resemble the human mesenchymal colorectal cancer subtype (CMS4), which is characterized by the poorest survival rate among the four consensus molecular subtypes of CRC. Trp53ΔIECAktE17K tumors are further characterized by a NOTCH pathway gene signature and a distinct cell autonomous upregulation of Notch3 in tumor epithelia while treatment of Trp53ΔIECAktE17K mice with a NOTCH3-inhibiting antibody reduces invasion and metastasis. Conversely, selective activation of NOTCH3 by overexpression of NOTCH3-IC in Akt wt tumor organoids strongly promotes development of metastasis in an orthotopic transplantation model. In CRC patients NOTCH3 expression correlates positively with tumor grading and the presence of lymph node as well as distant metastases and is specifically upregulated in CMS4 tumors. Therefore, we suggest NOTCH3 as a putative target for advanced CMS4 CRC patients.
2020-07-29 | GSE136218 | GEO
Project description:Colorectal cancer (CRC) remains a leading cause of cancer death, primarily due to metastatic spread. LIN28B, an RNA-binding protein overexpressed in 30% of CRCs, acts as an oncogene and promotes CRC metastasis. However, the mechanisms through which LIN28B drives these effects remain unclear. In this study, we genetically modified CRC cell lines to overexpress LIN28B, leading to enhanced activation of the PI3K/AKT pathway and increased metastatic potential in mice. We developed genetically engineered mouse models (GEMMs) with mutant PIK3CA that are the first to exhibit primary intestinal tumors progressing to liver metastases with an intact immune system. Pharmacological inhibition with the PI3Kα-specific inhibitor alpelisib effectively reduced migration and invasion in vitro, as well as metastasis in vivo. Treatment of CRC patient-derived organoids (PDOs) with alpelisib, the AKT inhibitor capivasertib, and/or the S6K inhibitor LY2584702 demonstrated the potential of pathway inhibition to impair tumor growth. Tissue microarrays from CRC patients further indicated that pathway activation correlates with disease progression. These findings underscore the critical role of the PI3K/AKT pathway in CRC metastasis and open new avenues in targeted inhibition and combination therapies in metastatic CRC (mCRC).
2025-06-07 | GSE269369 | GEO
Project description:The RNA-binding protein LIN28B is overexpressed in over 30% of patients with colorectal cancer (CRC) and is associated with poor prognosis. In the present study, we unraveled a potentially novel mechanism by which LIN28B regulates colonic epithelial cell-cell junctions and CRC metastasis. Using human CRC cells (DLD-1, Caco-2, and LoVo) with either knockdown or overexpression of LIN28B, we identified claudin 1 (CLDN1) tight junction protein as a direct downstream target and effector of LIN28B. RNA immunoprecipitation revealed that LIN28B directly binds to and posttranscriptionally regulates CLDN1 mRNA. Furthermore, using in vitro assays and a potentially novel murine model of metastatic CRC, we show that LIN28B-mediated CLDN1 expression enhances collective invasion, cell migration, and metastatic liver tumor formation. Bulk RNA sequencing of the metastatic liver tumors identified NOTCH3 as a downstream effector of the LIN28B/CLDN1 axis. Additionally, genetic and pharmacologic manipulation of NOTCH3 signaling revealed that NOTCH3 was necessary for invasion and metastatic liver tumor formation. In summary, our results suggest that LIN28B promotes invasion and liver metastasis of CRC by posttranscriptionally regulating CLDN1 and activating NOTCH3 signaling. This discovery offers a promising new therapeutic option for metastatic CRC to the liver, an area where therapeutic advancements have been relatively scarce.
| S-EPMC10443801 | biostudies-literature
Project description:The biological role and precise molecular mechanisms of Notch receptor 3 (NOTCH3) in the malignant progression of bladder cancer (BLCA) remain unclear. In this study, we found that NOTCH3 was significantly upregulated and associated with poor prognosis in BLCA patients. Functional experiments demonstrated that NOTCH3 knockdown inhibited BLCA cell proliferation, migration, invasion and significantly suppressed tumor growth and metastasis in vivo as well. Mechanically, chromatin immunoprecipitation and dual-luciferase reporter assays confirmed that NOTCH3 could promote the transcription of secreted phosphoprotein 1(SPP1), a potential downstream target gene of NOTCH3，by binding to the CSL elements in the SPP1 promoter. Moreover, we also found that targeting NOTCH3 inhibited BLCA growth and metastasis by suppressing the SPP1-PI3K/AKT axis. Our study highlights the critical role of NOTCH3-SPP1-PI3K/AKT axis in the malignant progression of BLCA, suggesting that NOTCH3 may be a potential therapeutic target for BLCA.
2024-11-27 | GSE279910 | GEO
Project description:Gene expression profiling of circulating tumor cells purified from human patients with pancreatic cancer led to identification of LIN28B as possible metastasis driver. Functional studies in model systems confirmed the importance of this pathway.
2020-03-01 | GSE144561 | GEO
Project description:Here, we examined the role of intestinal epithelial specific tumor suppressive function of 53. We provide evidence that p53 plays a dual role during carcinogen-induced tumorigenesis. At the initiation stage, p53 controls DNA damage and survival of initiated epithelia. In contrast, at later stages, loss of p53 is associated with the formation of an inflammatory microenvironment that is linked to epithelial mesenchymal transition, invasion and metastasis and the activation of NF-kappaB and Stat3. Thus, we propose a novel p53 controlled tumor suppressive function during the progression stage of colorectal cancer that is independent of its well-established role in cell cycle regulation, apoptosis and senescence. 6 samples were analyzed. We compared 3 wt colon tumor samples and 3 p53-knockout tumor samples.
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Project description:The survival rate of colorectal liver metastases remains low. Long noncoding lncRNAs is emerging as a novel class of master regulators of cell invasion and metastasis. In this study, analysis of the lncRNA expression dynamics in the colorectal liver metastases, primary colorectal tumor and normal tissues led to the identification of the metastasis-specific expression of a set of lncRNAs including CRLM1. CRLM1 inhibited apoptosis and promoted metastasis and invasion of colorectal cancer cells, and also promoted tumor growth in nude mice. CRLM1 weakly associated with chromatin regions of genes involved in cell adhesion and DNA damage, correlated with CRLM1-regulated gene expression bidirectionally. CRLM1 physically interacts with and promotes the nuclear localization of the metastasis protein hnRNPK. CRLM1 effectively promotes hnRNPK promoter occupancy, and co-regulate gene expression. These findings suggest a potential biomarker and druggable target for treatment of colorectal liver metastases.
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