LIS1 promotes perineural invasion by upregulating the serine metabolism in head and neck squamous carcinoma
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ABSTRACT:
PROVIDER: PRJNA1190471 | ENA |
REPOSITORIES: ENA
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Project description:LIS1 is a critical mediator of neuronal migration during brain development, and is strongly associated with malignant tumors. We found that LIS1 is highly expressed in HNSCC,which is releated to perineural infiltration(PNI) in HNSCC.To explore the mechanism of PNI, we silenced the LIS1 expression in HNSCC cells and dected the function of PNI.In a word,We sought to validate LIS1 as a key signaling molecule for PNI in HNSCC.
2025-01-01 | GSE282822 | GEO
Project description:Perineural invasion (PNI) is a mechanism of tumor dissemination that can provide a challenge to tumor eradication and that is correlated with poor survival. Squamous cell carcinoma, the most common type of head and neck cancer, has a high prevalence of PNI. This review provides an overview of clinical studies on the outcomes and factors associated with PNI in head and neck cancer and on findings on cancer-nerve crosstalk.
| S-EPMC6728584 | biostudies-other
Project description:To investigate the mechanisms of cancer cell migration during perineural invasion in pancreatic cancer, we injected fluorescently labelled MiaPaCA-2 cells in the sciatic nerves and collected the leader and lagger cells.
2023-03-31 | GSE207319 | GEO
Project description:Mutations in Lissencephaly 1 (LIS1) result in various human brain developmental diseases, such as changes in brain structure, lissencephaly, and epilepsy. RNA-sequencing data from on-chip organoids derived from human embryonic stem cells (hESCs) revealed significant changes in the expression of extracellular matrix (ECM) – related genes in LIS1+/- samples. This project examined the biomechanical properties of LIS1+/- mutated and healthy hESCs-derived cortical organoids. A rheological test using the pipette aspiration technique revealed that LIS1+/- cortical organoids are stiffer than control organoids. The increased stiffness of the LIS1+/- cortices was proportional to an increased expression of the nuclear mechano-sensing protein, Lamin A, highlighting the adverse cellular and nuclear changes underlying the stiffening of LIS1+/- organoids. To delineate the ECM composition associated with the stiffening effect in LIS1+/-, healthy and mutated hippocampal and cortical organoids were examined at the protein, mRNA, and miRNA levels. Whole RNA sequencing showed altered expression of multiple collagen-related pathways, including the 'collagens containing ECM' and the 'Collagen trimer' pathways. Differential mRNA expression has inversely correlated with the expression of their targeting miRNAs in the LIS1+/- organoids. This inverse miRNA-mRNA expression was most pronounced in genes associated with the ECM-receptor signalling pathway. At the protein level, the mutated hippocampal organoids showed unilateral, substantial increased expression of collagens and proteins involved in collagen synthesis, modification, and remodelling. Following a collagenolytic treatment with the catalytic domain of the MMP9 enzyme, the stiffness levels in the LIS1+/- organoids were reduced to control values. Overall, this work provides new information about the role of LIS1 in controlling collagen expression and the abnormal mechanical properties associated with mutation to the LIS1 gene in the development of the human cortex and hippocampus.
2025-01-25 | GSE228926 | GEO
Project description:BACKGROUND. Perineural invasion (PNI) is the dominant pathway for local invasion in prostate cancer. To date, only few studies have investigated the molecular differences between prostate tumors with PNI and those without it. METHODS. To evaluate the involvement of both microRNAs and protein-coding genes in PNI, we determined their genome-wide expression with a custom microRNA microarray and Affymetrix GeneChips in 50 prostate adenocarcinomas with PNI and 7 without it. In-situ hybridization and immunohistochemistry was used to validate candidate genes. RESULTS. Unsupervised classification of the 57 adenocarcinomas revealed two clusters of tumors with distinct global microRNA expression. One cluster contained all non-PNI tumors and a subgroup of PNI tumors. Significance analysis of microarray data yielded a list of microRNAs associated with PNI. At a false discovery rate (FDR) < 10%, 19 microRNAs were higher expressed in PNI tumors than in non-PNI tumors. The most differently expressed microRNA was miR-224. In-situ hybridization showed that this microRNA is expressed by perineural cancer cells. The analysis of protein-coding genes identified 34 transcripts that were differently expressed by PNI status (FDR <10%). These transcripts were down-regulated in PNI tumors. Many of those encoded metallothioneins and proteins with mitochondrial localization and involvement in cell metabolism. Consistent with the microarray data, perineural cancer cells tended to have lower metallothionein expression by immunohistochemistry than nonperineural cancer cells. CONCLUSIONS. Although preliminary, our findings suggest that alterations in microRNA expression, mitochondrial function, and cell metabolism occur at the transition from a non-invasive prostate tumor to a tumor with PNI. Keywords: Disease State analysis
2008-07-01 | GSE7055 | GEO
Project description:Perineural invasion (PNI) is a prominent characteristic of pancreatic ductal adenocarcinoma (PDAC) and indicates poor prognosis. The invasion of the surrounding nerves by pancreatic cancer cells not only provides route for metastasis but also contributes to neural remodeling and changes in the neuronal milieu that can profoundly influenced the microenvironment of pancreatic cancer. To investigate the downstream molecules associated with PNI, the experiment analyzed mRNA expression of 50 pairs of pancreatic ductal adenocarcinoma tissue and paired adjacent non-tumor tissue, among which 28 pairs of cases diagnosed with PNI by experienced pathologist. Results provide new insight into molecular basis for the influence of PNI on the microenvironment of pancreatic cancer.
2017-08-04 | GSE102238 | GEO
Project description:We found that genetic deletion of Lis1 (also known as Pafah1b1) in mouse liver led to increased lipid accumulation and inflammation in the liver. Further analysis revealed that loss of Lis1 led to endoplasmic reticulum (ER) stress and reduced triglyceride secretion. Attenuation of ER stress by tauroursodeoxycholic acid (TUDCA) diminished lipid accumulation in the Lis1 defecient hepatocytes. In addition, Golgi was disorganized in Lis1 deficient livers. These mutants exhibited increased hepatocyte ploidy and accelerated development of liver cancer when treated with DEN. Taken together, these findings suggest that Lis1 is involved in the development and progression of liver diseases from steatosis to liver cancer and provide a useful model for delineating the molecular pathways that lead to these diseases.
2018-02-15 | GSE108096 | GEO
Project description:Lissencephaly-1 (LIS1) is associated with neurodevelopmental diseases and is known to regulate the molecular motor cytoplasmic dynein activity. Here we show that LIS1 is essential for the viability of mouse embryonic stem cells (mESCs), and it governs the physical properties of these cells. LIS1 dosage substantially affects gene expression, and we uncovered an unexpected interaction of LIS1 with RNA and RNA-binding proteins, most prominently the Argonaute complex. We demonstrate that LIS1 overexpression partially rescued the extracellular matrix (ECM) expression and mechanosensitive genes conferring stiffness to Argonaute null mESCs. Collectively, our data transforms the current perspective on the roles of LIS1 in post-transcriptional regulation underlying development and mechanosensitive processes.
2023-05-04 | GSE198390 | GEO
Project description:Perineural invasion (PNI) is a pivotal prognostic factor in pancreatic cancer, associated with aggressive tumor behavior and adverse patient outcomes. Despite its recognized clinical impact, the molecular mechanisms underlying PNI are not well understood. In this study, we isolated perineural invasion-associated cancer-associated fibroblasts (pCAFs), which demonstrated a markedly enhanced capacity to promote neural invasion in pancreatic cancer compared to non-perineural invasion-associated CAFs (npCAFs). Utilizing single-cell, high-throughput sequencing, and metabolomics, we identified a significant upregulation of glycolysis in pCAFs, fostering a high-lactate tumor microenvironment conducive to cancer progression. pCAFs-derived lactate is absorbed by tumor cells, facilitating histone H3K18 lactylation. This epigenetic modification activates the transcription of neural invasion-associated genes such as L1CAM and SLIT1, thereby driving PNI in pancreatic cancer. Further exploration of metabolic reprogramming in pCAFs revealed enhanced acetylation of the glycolytic enzyme GAPDH, correlated with increased enzymatic activity and glycolytic flux. Targeting of GAPDH and lactylation modifications significantly inhibits neural invasion in a KPC mouse model. Clinical data suggested that high levels of H3K18 lactylation correlate with severe PNI and poorer patient prognosis. Our findings provide critical insights into the role of pCAFs in the PNI of pancreatic cancer, highlighting glycolytic reprogramming and lactate-driven histone modifications as potential therapeutic targets for PDAC.
2025-03-19 | GSE290654 | GEO