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Dynamic alteration in miRNA and mRNA expression profiles at different stages of chronic arsenic exposure-induced carcinogenesis in a human cell culture model of skin cancer.

ABSTRACT: Chronic arsenic exposure causes skin cancer, although the underlying molecular mechanisms are not well defined. Altered microRNA and mRNA expression likely play a pivotal role in carcinogenesis. Changes in genome-wide differential expression of miRNA and mRNA at 3 strategic time points upon chronic sodium arsenite (As³⁺) exposure were investigated in a well-validated HaCaT cell line model of arsenic-induced cutaneous squamous cell carcinoma (cSCC). Quadruplicate independent HaCaT cell cultures were exposed to 0 or 100 nM As³⁺ for up to 28-weeks (wk). Cell growth was monitored throughout the course of exposure and epithelial-mesenchymal transition (EMT) was examined employing immunoblot. Differentially expressed miRNA and mRNA profiles were generated at 7, 19, and 28-wk by RNA-seq, followed by identification of differentially expressed mRNA targets of differentially expressed miRNAs through expression pairing at each time point. Pathway analyses were performed for total differentially expressed mRNAs and for the miRNA targeted mRNAs at each time point. RNA-seq predictions were validated by immunoblot of selected target proteins. While the As³⁺-exposed cells grew slower initially, growth was equal to that of unexposed cells by 19-wk (transformation initiation), and exposed cells subsequently grew faster than passage-matched unexposed cells. As³⁺-exposed cells had undergone EMT at 28-wk. Pathway analyses demonstrate dysregulation of carcinogenesis-related pathways and networks in a complex coordinated manner at each time point. Immunoblot data largely corroborate RNA-seq predictions in the endoplasmic reticulum stress (ER stress) pathway. This study provides a detailed molecular picture of changes occurring during the arsenic-induced transformation of human keratinocytes.

SUBMITTER: Banerjee M

PROVIDER: S-EPMC8241660 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Several studies have investigated miRNA and mRNA co-expression to identify regulatory networks at the transcriptional level. A typical finding of these studies is the presence of both negative and positive miRNA-mRNA correlations. Negative correlations are consistent with the expected, faster degradation of target mRNAs, whereas positive correlations denote the existence of feed-forward regulations mediated by transcription factors. Both mechanisms have been characterized at the molecular level, although comprehensive methods to represent miRNA-mRNA correlations are lacking. At present, genome-wide studies are able to assess the expression of more than 1000 mature miRNAs and more than 35,000 well-characterized human genes. Even if studies are generally restricted to a small subset of genes differentially expressed in specific diseases or experimental conditions, the number of potential correlations remains very high, and needs robust multivariate methods to be conveniently summarized by a small set of data.Nonparametric Kendall correlations were calculated between miRNAs and mRNAs differentially expressed in livers of patients with acute liver failure (ALF) using normal livers as controls. Spurious correlations due to the histopathological composition of samples were removed by partial correlations. Correlations were then transformed into distances and processed by multidimensional scaling (MDS) to map the miRNA and mRNA relationships. These showed: (a) a prominent displacement of miRNA and mRNA clusters in ALF livers, as compared to control livers, indicative of gene expression dysregulation; (b) a clustering of mRNAs consistent with their functional annotations [CYP450, transcription factors, complement, proliferation, HLA class II, monocytes/macrophages, T cells, T-NK cells and B cells], as well as a clustering of miRNAs with the same seed sequence; and (c) a tendency of miRNAs and mRNAs to populate distinct regions of the MDS plot. MDS also allowed to visualize the network of miRNA-mRNA target pairs.Different features of miRNA and mRNA relationships can be represented as thematic maps within the framework of MDS obtained from pairwise correlations. The symmetric distribution of positive and negative correlations between miRNA and mRNA expression suggests that miRNAs are involved in a complex bidirectional molecular network, including, but not limited to, the inhibitory regulation of miRNA targets.

Project description:Background The development of the ovaries is an important factor that affects egg production performance in geese. Ovarian development is regulated by genes that are expressed dynamically and stage-specifically. The transcriptome profile analysis on ovarian tissues of goose at different egg laying stages could provide an important basis for screening and identifying key genes regulating ovarian development. Results In this study, 4 ovary tissues at each breeding period of pre-laying (PP), laying (LP), and ceased-laying period (CP), respectively, with significant morphology difference, were used for RNA extraction and mRNAs, lncRNAs, and miRNAs comparison in Yili geese. CeRNA regulatory network was constructed for key genes screening. A total of 337, 1136, and 525 differentially expressed DE mRNAs, 466, 925, and 742 DE lncRNAs and 258, 1131 and 909 DE miRNAs were identified between PP and LP, between CP and LP, and between CP and PP groups, respectively. Functional enrichment analysis showed that the differentially expressed mRNAs and non-coding RNA target genes were mainly involved in the cell process, cytokine-cytokine receptor interaction, phagosome, calcium signaling pathway, steroid biosynthesis and ECM-receptor interaction. Differential genes and non-coding RNAs, PDGFRB, ERBB4, LHCGR, MSTRG.129094.34, MSTRG.3524.1 and gga-miR-145–5p, related to reproduction and ovarian development were highly enriched. Furthermore, lncRNA-miRNA-mRNA regulatory networks related to ovary development were constructed. Conclusions Our study found dramatic transcriptomic differences in ovaries of Yili geese at different egg-laying stages, and a differential lncRNA-miRNA-mRNA regulatory network related to cell proliferation, differentiation and apoptosis and involved in stromal follicle development were established and preliminarily validated, which could be regarded as a key regulatory pathway of ovarian development in Yili geese. Supplementary Information The online version contains supplementary material available at 10.1186/s12864-022-08774-4.

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Dynamic alteration in miRNA and mRNA expression profiles at different stages of chronic arsenic exposure-induced carcinogenesis in a human cell culture model of skin cancer.

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