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. 2016 Feb;10(2):303-16.
doi: 10.1016/j.molonc.2015.10.011. Epub 2015 Nov 3.

Differential expression of miRNAs in pancreatobiliary type of periampullary adenocarcinoma and its associated stroma

V Sandhu  1 , I M Bowitz Lothe  2 , K J Labori  3 , M L Skrede  4 , J Hamfjord  4 , A M Dalsgaard  4 , T Buanes  5 , G Dube  6 , M M Kale  7 , S Sawant  6 , U Kulkarni-Kale  6 , A-L Børresen-Dale  8 , O C Lingjærde  9 , E H Kure  10
Affiliations

Differential expression of miRNAs in pancreatobiliary type of periampullary adenocarcinoma and its associated stroma

V Sandhu et al. Mol Oncol. 2016 Feb.

Abstract

Periampullary adenocarcinomas can be of two histological subtypes, intestinal or pancreatobiliary. The latter is more frequent and aggressive, and characterized by a prominent desmoplastic stroma, which is tightly related to the biology of the cancer, including its poor response to chemotherapy. Whereas miRNAs are known to regulate various cellular processes and interactions between cells, their exact role in periampullary carcinoma remains to be characterized, especially with respect to the prominent stromal component of pancreatobiliary type cancers. The present study aimed at elucidating this role by miRNA expression profiling of the carcinomatous and stromal component in twenty periampullary adenocarcinomas of pancreatobiliary type. miRNA expression profiles were compared between carcinoma cells, stromal cells and normal tissue samples. A total of 43 miRNAs were found to be differentially expressed between carcinoma and stroma of which 11 belong to three miRNA families (miR-17, miR-15 and miR-515). The levels of expression of miRNAs miR-17, miR-20a, miR-20b, miR-223, miR-10b, miR-2964a and miR-342 were observed to be higher and miR-519e to be lower in the stromal component compared to the carcinomatous and normal components. They follow a trend where expression in stroma is highest followed by carcinoma and then normal tissue. Pathway analysis revealed that pathways regulating tumor-stroma interactions such as ECM interaction remodeling, epithelial-mesenchymal transition, focal adhesion pathway, TGF-beta, MAPK signaling, axon guidance and endocytosis were differently regulated. The miRNA-mRNA mediated interactions between carcinoma and stromal cells add new knowledge regarding tumor-stroma interactions.

Keywords: Bioinformatics and statistical analyses; Pathway analysis; Periampullary adenocarcinoma; Stromal reaction; Tumor microenvironment; Tumor-stroma interaction; miRNA/mRNA expression profiling.

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Figures

Figure 1
Figure 1
Analysis pipeline of the PA samples using miRNA and mRNA expression profiling.
Figure 2
Figure 2
2a) The figure shows the heatmap of all the samples with the column representing the samples and the row representing the miRNAs. The samples were clustered using the complete linkage method. Pearson's correlation coefficient and Spearman's rank correlation were used as a distance measure for miRNAs and samples, respectively. The heatmap shows the separation of carcinoma, stromal and normal samples based on expression levels of the most intrinsically variable miRNAs (n = 183). The carcinoma and stromal tissues clustered separately at P = 9.071e‐09 for Fisher's exact test. 2b) The figure shows the scatterplot of the first two principal components identified by the SPCA performed on all the samples and on 183 miRNAs with s.d > 0.8. The color and shape of the points refer to type of the tissues, and the x‐axis represents the first principal component and the y‐axis represents the second principal component of the samples.
Figure 3
Figure 3
The Venn diagram shows the numbers of differentially expressed miRNAs with respect to comparisons between carcinoma, stroma and normal tissues.
Figure 4
Figure 4
The boxplots show the relative expression of the eight most differentially expressed miRNAs in stroma (blue), carcinoma (red) and normal tissues (grey) at BH‐adjusted P < 0.05.
Figure 5
Figure 5
The figure shows the heatmap of the miRNAs and mRNAs associated with proliferation of the cells. 5a) The heatmap shows expression of the miRNA anti‐correlated to the proliferation genes in the carcinoma and stromal samples 5b) The heatmap shows expression of proliferation genes in the periampullary adenocarcinoma samples. 5c) The miRNA‐mRNA pairs anti‐correlated at adjusted P value < 0.05.
Figure 6
Figure 6
The figure shows the interaction between the miRNAs and mRNAs in the deregulated pathways in the stroma and carcinoma samples. 6a) The miRNA‐mRNA‐pathway network shows the miRNA and the targeted mRNAs in the deregulated pathways in the stromal samples. 6b) The miRNA‐mRNA‐pathway network shows the miRNA and the targeted mRNAs in the deregulated pathways in the carcinoma samples.
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References

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Further reading

    1. Web links
    1. Cancer registry of Norway: http://www.kreftregisteret.no/en/.
    1. miRbase: http://www.mirbase.org/ (release 21, June, 2014).
    1. miRNA.org: http://www.microrna.org/microrna/home.do (release August, 2010).
    1. miRTarBase: http://mirtarbase.mbc.nctu.edu.tw/ (Release 4.5, November 1, 2013).

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