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Gene transcriptomics reveals that PAK5 regulates the pathogenesis of Esophageal Squamous Cell Carcinoma

ABSTRACT: Abstract Background Esophageal Squamous Cell Carcinoma (ESCC) is one of the leading causes of cancer death worldwide, especially in Asia. Because the early symptoms are not obvious, most patients are already in an advanced stage when diagnosed, which greatly limits the effectiveness of treatment and affects the patient's prognosis. Therefore, it is of great significance to explore the occurrence and development mechanism of ESCC and to search for effective biomarkers and therapeutic targets for improving patient prognosis. P21 activated protein kinase 5 (PAK5) belongs to the mitogen-activated protein kinase family, which has been extensively studied in recent years and is thought to play an important role in a variety of malignant tumors. PAK5 promotes tumor development by regulating processes such as cell cycle, cell migration and invasion. However, the specific role of PAK5 in ESCC and its potential mechanisms have not been fully elucidated. Methods We initially employed immunohistochemical techniques to assess PAK5 expression levels in ESCC tissue samples and compared these levels with those in normal esophageal tissues. Kaplan-Meier survival analysis was subsequently conducted to evaluate the correlation between PAK5 expression levels and patient survival in ESCC. To further investigate the functional role of PAK5 in ESCC cells, we constructed PAK5 overexpression (PAK5-OE) and PAK5 silencing (PAK5-si) ESCC cell models. The effects of PAK5 on cell proliferation, clonogenicity, migration, and invasion were assessed using CCK-8 assays, Cell Plate Cloning assays, and Transwell assays. Additionally, transcriptomic analyses were performed using mRNA sequencing techniques to identify downstream effector molecules and signaling pathways influenced by PAK5. Results The results showed that the expression of PAK5 in ESCC tissue was significantly higher than that in normal esophageal tissue, and high PAK5 level was closely associated with poor prognosis in ESCC patients. Functional experiments showed that PAK5 could significantly enhance the proliferation, clonal formation, migration and invasion of ESCC cells. Further transcriptomic analysis revealed multiple downstream genes and signaling pathways regulated by PAK5, particularly those related to cell cycle progression and anti-apoptosis. Most notably, this study found that PAK5 forms a new signaling axis by interacting with GAREM1, which is critical for maintaining the transfer behavior of ESCC cells.These findings underscore PAK5's tumorigenic potential in ESCC, positioning it as a promising prognostic marker and therapeutic target. Keywords: PAK5, Esophageal squamous cell carcinoma, GAREM1

ORGANISM(S): Homo sapiens

PROVIDER: GSE283031 | GEO | 2024/12/09

REPOSITORIES: GEO

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Project description:Background: Esophageal squamous cell carcinoma (ESCC) is a common invasive malignancy worldwide with poor clinical outcomes. Increasing amount of long non-coding RNAs (lncRNAs) have been reported to be involved in cancer development. However, lncRNAs that are functional in ESCC and the underlying molecular mechanisms remain largely unknown. Methods: Transcriptomic analysis was performed to identify dysregulated lncRNAs in ESCC tissue samples. The high expression of LINC00680 in ESCC was validated by RT-qPCR, and the oncogenic functions of LINC00680 was investigated by cell proliferation, colony formation, migration and invasion assays in ESCC cells in vitro and xenografts derived from ESCC cells in mice. RNA-seq, competitive endogenous RNA (ceRNA) network analysis, and luciferase reporter assays were carried out to identify LINC00680 target genes and the microRNAs (miRNAs) bound to LINC00680. Antisense oligonucleotides (ASOs) were used for in vivo treatment. Results: Transcriptome profiling revealed that a large number of lncRNAs was dysregulated in ESCC tissues. Notably, LINC00680 was highly expressed, and upregulation of LINC00680 was associated with large tumor size, advanced tumor stage, and poor prognosis. Functionally, knockdown of LINC00680 restrained ESCC cell proliferation, colony formation, migration, and invasion in vitro and inhibited tumor growth in vivo. Mechanistically, LINC00680 was found to act as a ceRNA by sponging miR-423-5p to regulate PAK6 (p21-activated kinase 6) expression in ESCC cells. The cell viability and motility inhibition induced by LINC00680 knockdown was significantly reversed upon PAK6 restoration and miR-423-5p inhibition. Furthermore, ASO targeting LINC00680 substantially suppressed ESCC both in vitro and in vivo. Conclusions: An oncogenic lncRNA, LINC00680, was identified in ESCC, which functions as a ceRNA by sponging miR-423-5p to promote PAK6 expression and ESCC. LINC00680/miR-423-5p/PAK6 axis may serve as promising diagnostic and prognostic biomarkers and therapeutic targets for ESCC.

Project description:Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers with high mortality rate. Smoking is one of the established risk factors of ESCC. However, there is limited data on molecular alterations associated with cigarette smoke exposure in esophageal cells. Understanding the effects of cigarette smoke on esophageal squamous epithelial cells at a molecular level would lead to a better understanding of the pathobiology of ESCC which has implications for identification of early biomarkers and therapeutic targets. To investigate the effect of cigarette smoke exposure, we developed a cell line model where Het1A cells (non-neoplastic human esophageal epithelial cells) were chronically treated with cigarette smoke condensate (CSC) for 2 months, 4 months, 6 months and 8 months. We carried out comparative proteomic, phosphoproteomic and whole exome sequencing analyses on CSC treated and untreated cells. Increased cell proliferation and invasion of Het1A cells was observed after chronic exposure to cigarette smoke. Using quantitative proteomic and phosphoproteomic analyses, we identified 56 proteins and 296 phosphoproteins that showed differential expression. Bioinformatics analysis of differentially expressed proteins and phosphoproteins showed enrichment of molecules involved in DNA damage response pathway. Whole exome sequencing (WES) of CSC treated and untreated cells also revealed mutations and copy number alterations in genes associated with DNA damage response. By correlating WES, proteomic and phosphoproteomic results, we observed potential loss of function in HMGN2 and MED1 that were reported as potential tumor suppressors and are known to play important role in DNA damage response. We also observed decreased expression of HMGN2 in tissue section of ESCC. Overexpression of HMGN2 and MED1 lead to decreased proliferative and invasive ability of CSC treated cells. These findings suggest that cigarette smoke affects genes and proteins associated with DNA damage response pathways which might play a vital role in development of ESCC.

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Gene transcriptomics reveals that PAK5 regulates the pathogenesis of Esophageal Squamous Cell Carcinoma

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