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THE INTEGRATIVE GENOMIC AND FUNCTIONAL IMMUNOLOGICAL ANALYSES OF COLORECTAL CANCER INITIATING CELLS TO MODULATE STEMNESS PROPERTIES AND THE SUSCEPTIBILIY TO IMMUNE RESPONSES [RNA-Seq]

ABSTRACT: We conducted a the transcriptomic profile of CICs or FBS cell lines, upon treatment or not with immunomodulatory or epigenetic drugs or with miRNA modulators, using the QuantSeq 3’mRNA-Seq Library Prep Kit-FWD (Lexogen). Differentially expressed genes (DEGs) were assessed in CICs and FBS cell line pairs (#1076 and 1247) upon treatment with either miRNA-15a or -196a modulators (inhibitors or mimics) or immunomodulatory or epigenetic agents (HDACi, butyrate or IFN-γ + butyrate). Numerous DEGs were detected among the comparisons of the different treatments. In CICs, N= 176, 238, 131, 168, 1155, 1237 and 1368 DEGs were significantly (p<0.05) detected following their treatment with miR-15a mimic or inhibitor, miR-196a mimic or inhibitor, butyrate, HDACi or IFN-γ + butyrate, respectively. The results corroborated the role of miRNA-15a and miRNA-196a mimics and of epigenetic drugs as beneficial treatments to improve CRC-specific immune responses through mechanisms including TGF-β signaling downmodulation, HLA and APM upregulation and negative regulation of tumorigenic pathways.

ORGANISM(S): Homo sapiens

PROVIDER: GSE287597 | GEO | 2025/02/26

REPOSITORIES: GEO

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Project description:Hyperactivation of the PI3K/AKT pathway is observed in most NSCLCs, promoting proliferation, migration and resistance to therapy. AKT can be activated through several mechanisms that include loss of the negative regulator PTEN, activating mutations of the catalytic subunit of the positive regulator phosphatydil-inositol-3â phosphate kinase (PIK3CA) and/or mutations of AKT1 itself. However, whereas the effects of AKT activation on mRNAs and proteins in the cell are fairly clear, the role of miRNAs as downstream targets of activated PI3K/AKT signalling is still poorly defined so far. To identify miRNAs that are targets of constitutive signalling of PI3K/AKT in lung cancer cells, we performed miRNA profiling of human lung epithelial cells expressing active mutant AKT1 (E17K), active mutant PI3KCA (E545K) or that are silenced for PTEN. We identified 28 differentially expressed miRNAs (8 up-regulated, 20 down-regulated) that were common to BEAS-AKT1-E17K, BEAS-PIK3CA-E545K and BEAS-shPTEN cells. Among the 8 up-regulated miRNAs that were common to all the alterations, the miRNA most consistently up-regulated by activation of the PI3K/AKT pathway in BEAS-2B cells was miR-196a. The results reported here demonstrate that miR-196a acts as oncogene downstream the PI3K/AKT pathway, mediating the proliferative, pro-migratory and tumorigenic activity of this pathway in NSCLC cells by targeting FoxO1 and p27 expression. By adoptive expression of miR-196a in BEAS-2B cells, we demonstrated that miR-196a stimulates anchorage-dependent and -independent proliferation, migration and tumorigenicity in BEAS-2B cells. On the other hand, by use of antimir-196a in NCI-H460 cells to silence the endogenous expression of miR-196a, we demonstrate that miR-196a plays a pivotal role in mediating the stimulation of proliferation, migration and tumorigenicity induced by aberrant activation of PI3K/AKT signalling. Accordingly, we found that miR-196a was significantly overexpressed in human NSCLC-derived cell lines (n=6) and primary lung cancer samples (n=28). Finally, based on predicted binding sites for miR-196a by microRNA analysis software, we found that miR-196a affects protein levels of FoxO1 and p27 in NSCLC cells.

Dataset Information

THE INTEGRATIVE GENOMIC AND FUNCTIONAL IMMUNOLOGICAL ANALYSES OF COLORECTAL CANCER INITIATING CELLS TO MODULATE STEMNESS PROPERTIES AND THE SUSCEPTIBILIY TO IMMUNE RESPONSES [RNA-Seq]

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