Integrated Transcriptomic-Proteomic Analysis Revealed the Diagnostic and Potential Therapeutic Targets of Colorectal Cancer
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE200076 | GEO | 2022/12/31
REPOSITORIES: GEO
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Project description:Integrated Transcriptomic-Proteomic Analysis Revealed the Diagnostic and Potential Therapeutic Targets of Colorectal Cancer
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Project description:Lung cancer is the leading cause of cancer-related death in the world. Non-small cell lung carcinomas (Non-SCLC) account for almost 80% of lung cancers, of which 40% were adenocarcinomas. For a better understanding of the molecular mechanisms behind the development and progression of lung cancer, particularly lung adenocarcinoma, we have used proteomics technology to search for candidate prognostic and therapeutic targets in pulmonary adenocarcinoma. The protein profile changes between human pulmonary adenocarcinoma tissue and paired surrounding normal tissue were analyzed using two-dimensional polyacrylamide gel electrophoresis (2-DE) based approach. Differentially expressed protein-spots were identified with ESI-Q-TOF MS/MS instruments. As a result, thirty two differentially expressed proteins (over 2-fold, p<0.05) were identified in pulmonary adenocarcinoma compared to normal tissues. Among them, two proteins (PKM2 and cofilin-1), significantly up-regulated in adenocarcinoma, were selected for detailed analysis. Immunohistochemical examination indicated that enhanced expression of PKM2 and cofilin-1 were correlated with the severity of epithelial dysplasia, as well as a relatively poor prognosis. Knockdown of PKM2 expression by RNA interference led to a significant suppression of cell growth and induction of apoptosis in pulmonary adenocarcinoma SPC-A1 cells in vitro, and tumor growth inhibition in vivo xenograft model (P<0.05). In addition, the shRNA expressing plasmid targeting cofilin-1 significantly inhibited tumor metastases and prolonged survival in LL/2 metastatic model. While additional works are needed to elucidate the biological significance and molecular mechanisms of these altered proteins identified in this study, PKM2 and cofilin-1 may serve as potential diagnostic and prognostic biomarkers, as well as therapeutic targets for pulmonary adenocarcinoma.
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Project description:Personalized cancer therapy targeting somatic mutations in patient tumors is increasingly being incorporated into practice. Other therapeutic vulnerabilities resulting from changes in gene expression due to tumor specific epigenetic perturbations are progressively being recognized. These genomic and epigenomic changes are ultimately manifest in the tumor proteome and phosphoproteome. We integrated transcriptomic, epigenomic, and proteomic/phosphoproteomic data to elucidate the cellular origins and therapeutic vulnerabilities of rhabdomyosarcoma (RMS). We discovered that alveolar RMS occurs further along the developmental program than embryonal RMS. We also identified deregulation of the RAS/MEK/ERK/CDK4/6, G2/M, and unfolded protein response pathways through our integrated analysis. Comprehensive preclinical testing revealed that targeting the WEE1 kinase in the G2/M pathway is the most effective approach in vivo for high-risk RMS.
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Project description:Identification and validation of NOL5A and RPS2 as potential therapeutic targets in colorectal cancer using a functional genomics approach. To identify potential therapeutic targets for colorectal cancer, we first assessed the functional and molecular consequences of RNAi mediated silencing of candidate genes derived from previously performed gene expression analyses. We then generated gene expression signatures after RNAi against HMGA1, RRM2, TACSTD2, RPS2, and NOL5A. To assess the consequences of silencing specific genes on global gene expression levels, triplicate transfections were independently performed. Cells for lyzed 48 hours or 72 hours after transfection (depending on the target gene), and total RNA was isolated for each transfection. For each sample, one array experiment was subsequently performed.
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Project description:Serine racemase (SRR) is an enzyme that catalyzes two reactions, the racemization and the dehydration of L-Ser and D-Ser and has been studied mainly in the fields of central nervous system. The function of SRR in cancer metabolism has not been elucidated. Here we show that SRR expression is upregulated in colorectal adenoma and adenocarcinoma lesions compared to non-neoplastic mucosa in human colorectal cancer specimens. Further analysis by using CRISPR/CRISPR-associated protein 9 system reveals that SRR enhances colorectal cancer cell proliferation via maintaining intracellular pyruvate and mitochondrial mass resulting in higher basal reactive oxygen species level, and has anti-apoptotic function.
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