GZ21T inhibits the growth of actinic keratoses in a UVB induced model of skin carcinogenesis
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE223986 | GEO | 2023/02/02
REPOSITORIES: GEO
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Project description:GZ21T inhibits the growth of actinic keratoses in a UVB induced model of skin carcinogenesis
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Project description:Actinic keratoses (AKs) are premalignant intraepidermal neoplasms that occur as a result of cumulative sun damage. AKs commonly relapse, and up to 16% undergo malignant transformation into cutaneous squamous cell carcinoma. There is a need for novel therapies that reduce the quantity and surface area of AKs as well as prevent malignant transformation to cutaneous squamous cell carcinomas. We recently showed that GZ17-6.02, an anticancer agent composed of curcumin, haramine, and isovanillin, inhibited the growth of H297.T cells. This study evaluated the efficacy of a topical formulation of GZ17-6.02, known as GZ21T, in a murine model of AK generated by exposing SKH1 mice to UVR. Treatment of mice with topical GZ21T inhibited the growth of AKs by decreasing both lesion count (P = 0.012) and surface area occupied by tumor (P = 0.002). GZ21T also suppressed the progression of AKs to cutaneous squamous cell carcinoma by decreasing the count (P = 0.047) and surface area (P = 0.049) of lesions more likely to represent cutaneous squamous cell carcinoma. RNA sequencing and proteomic analyses revealed that GZ21T suppressed several pathways, including MAPK (P = 0.025), phosphoinositide 3-kinase-protein kinase B (P = 0.04), HIF-1α (P = 0.016), Wnt (P = 0.025), insulin (P = 0.018), and ERBB (P = 0.016) signaling. GZ21T also upregulated the autophagy-promoting protein AMPK while suppressing proteins such as PD-L1, glutaminase, pAkt1 S473, and eEF2K.
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Project description:The risk of developing cutaneous squamous cell carcinoma (SCC) is markedly increased in organ transplant recipients (OTRs) compared to the normal population. Next to sun exposure, the immunosuppressive regimen is an important risk factor for the development of SCC in OTRs. Various gene mutations (e.g. TP53) and genetic alterations (e.g. loss of CDKN2A, amplification of RAS) have been found in SCCs. The aim of this genome-wide study was to identify pathways that are consistently involved in the formation of SCCs and their precursor lesions, actinic keratoses (AKs). To perform the analysis in an isogenic background, RNA and DNA were isolated from normal (unexposed) epidermis, benign AK, and SCC from each of 15 OTRs. Hierarchical cluster analysis of mRNA expression profiles showed SCC, AK and epidermal samples to separate into three distinct groups. Several thousand genes were differentially expressed between epidermis, AK and SCC; most upregulated in SCCs were genes related to hyperproliferation and stress markers, such as keratin 6 (KRT6), KRT16 and KRT17. Matching to oncogenic pathways revealed activation of downstream targets of RAS and cMYC in SCCs and of NFkappaB and TNF already in AKs.
2013-02-06 | GSE32628 | GEO
Project description:The risk of developing cutaneous squamous cell carcinoma (SCC) is markedly increased in organ transplant recipients (OTRs) compared to the normal population. Next to sun exposure, the immunosuppressive regimen is an important risk factor for SCC development in OTRs. Various gene mutations (e.g. TP53) and genetic alterations (e.g. CDKN2A loss, RAS amplification) have been found in SCCs. The aim of this study was to identify genomic alterations that are consistently involved in the formation of SCCs and their precursor lesions, actinic keratoses (AKs). To perform the analysis in an isogenic background, DNA was isolated from SCC and AK from each of 13 OTRs. Tumor samples and their matching normal control (peripheral blood) were analyzed on the Illumina HumanHap550V3_duo genotyping beadchips. In contrast to previous studies, genome-wide SNP analysis showed very few copy number variations in AKs and SCCs, and these variations had no apparent relationship with observed changes in mRNA expression profiles (GSE32628). Other molecular mechanisms, such as DNA methylation or miRNA alterations, may affect gene expression in SCCs of OTRs.
2013-02-06 | GSE32969 | GEO
Project description:The risk of developing cutaneous squamous cell carcinoma (SCC) is markedly increased in organ transplant recipients (OTRs) compared to the normal population. Next to sun exposure, the immunosuppressive regimen is an important risk factor for the development of SCC in OTRs. Various gene mutations (e.g. TP53) and genetic alterations (e.g. loss of CDKN2A, amplification of RAS) have been found in SCCs. The aim of this genome-wide study was to identify pathways that are consistently involved in the formation of SCCs and their precursor lesions, actinic keratoses (AKs). To perform the analysis in an isogenic background, RNA and DNA were isolated from normal (unexposed) epidermis, benign AK, and SCC from each of 15 OTRs. Hierarchical cluster analysis of mRNA expression profiles showed SCC, AK and epidermal samples to separate into three distinct groups. Several thousand genes were differentially expressed between epidermis, AK and SCC; most upregulated in SCCs were genes related to hyperproliferation and stress markers, such as keratin 6 (KRT6), KRT16 and KRT17. Matching to oncogenic pathways revealed activation of downstream targets of RAS and cMYC in SCCs and of NFkappaB and TNF already in AKs. Patients were selected from the group of OTRs that are regularly seen at the dermatology clinic of the Leiden University Medical Center. Patients with clinically suspected SCC were informed on the study and after informed consent was obtained, fresh frozen samples were obtained from SCCs (n=15), AKs (n=14) and NS (n=13). RNA was isolated and gene expression profiles were obtained using HumanWG-6 v2 Expression BeadChips (Illumina). The normalized expression data was analyzed for differences in expression between SCC, AK and NS, at single-gene level but also at geneset level.
2013-02-06 | E-GEOD-32628 | biostudies-arrayexpress
Project description:The risk of developing cutaneous squamous cell carcinoma (SCC) is markedly increased in organ transplant recipients (OTRs) compared to the normal population. Next to sun exposure, the immunosuppressive regimen is an important risk factor for SCC development in OTRs. Various gene mutations (e.g. TP53) and genetic alterations (e.g. CDKN2A loss, RAS amplification) have been found in SCCs. The aim of this study was to identify genomic alterations that are consistently involved in the formation of SCCs and their precursor lesions, actinic keratoses (AKs). To perform the analysis in an isogenic background, DNA was isolated from SCC and AK from each of 13 OTRs. Tumor samples and their matching normal control (peripheral blood) were analyzed on the Illumina HumanHap550V3_duo genotyping beadchips. In contrast to previous studies, genome-wide SNP analysis showed very few copy number variations in AKs and SCCs, and these variations had no apparent relationship with observed changes in mRNA expression profiles (GSE32628). Other molecular mechanisms, such as DNA methylation or miRNA alterations, may affect gene expression in SCCs of OTRs. Patients were selected from the group of OTRs that are regularly seen at the dermatology clinic of the Leiden University Medical Center. Patients with clinically suspected SCC were informed on the study and after informed consent was obtained, fresh frozen samples were obtained from SCCs (n=15, including 2 repeats) and AKs (n=11). Peripheral blood was taken as normal control. DNA was isolated and SNP profiles were obtained using HumanHap550V3_duo Genotyping BeadChips (Illumina). Both the log R ratio and the B allele frequency (BAF) were investigated to identify copy number alterations and loss of heterozygosity (LOH) The tumor DNA samples are from the same tumor samples as the RNA samples in GSE32628.
2013-02-06 | E-GEOD-32969 | biostudies-arrayexpress