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01.12.2018 | Research | Ausgabe 1/2018 Open Access

Molecular Cancer 1/2018

Novel evidence for a PIWI-interacting RNA (piRNA) as an oncogenic mediator of disease progression, and a potential prognostic biomarker in colorectal cancer

Zeitschrift:
Molecular Cancer > Ausgabe 1/2018
Autoren:
Wenhao Weng, Na Liu, Yuji Toiyama, Masato Kusunoki, Takeshi Nagasaka, Toshiyoshi Fujiwara, Qing Wei, Huanlong Qin, Haifan Lin, Yanlei Ma, Ajay Goel
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1186/​s12943-018-0767-3) contains supplementary material, which is available to authorized users.

Abstract

Background

Emerging evidence suggests that PIWI-interacting RNAs (piRNAs) may be important epigenetic regulators of gene expression in human cancers; however, their functional and clinical significance in colorectal cancer (CRC) remains unknown.

Methods

We performed piRNA expression profiling in paired cancer and normal tissues through small RNA-sequencing. The clinical significance of candidate piRNAs was investigated, and independently validated in 771 CRC patients from three independent cohorts. The biological function of piRNAs was characterized in cell lines, followed by identification and validation of downstream target genes in CRC tissues.

Results

We identified piR-1245 as a novel and frequently overexpressed noncoding RNA in CRC, and its expression significantly correlated with advanced and metastatic disease. Patients with high piR-1245 expression experienced significantly shorter overall survival, and multivariate analysis identified its expression to serve as an independent prognostic biomarker in CRC. Functionally, piR-1245 acts as an oncogene and promotes tumor progression, and gene expression profiling results identified a panel of downstream target-genes involved in regulating cell survival pathway. Based upon piRNA:mRNA sequence complementarity, we identified a panel of tumor suppressor genes (ATF3, BTG1, DUSP1, FAS,NFKBIA, UPP1, SESN2, TP53INP1 and MDX1) as direct targets of piR-1245, and successfully validated an inverse correlation between their expression and piR-1245 in CRC.

Conclusions

We for the first time have identified the role for a PIWI-interacting noncoding RNA, piR-1245, as a novel oncogene and a potential prognostic biomarker in colorectal cancer.
Zusatzmaterial
Additional file 1: Supplementary Methods. (DOCX 17 kb)
12943_2018_767_MOESM1_ESM.docx
Additional file 2: Table S1. Primers sequence. (DOCX 13 kb)
12943_2018_767_MOESM2_ESM.docx
Additional file 3: Figure S1. PIWIL1 and PIWIL4 are overexpressed in CRC A. Oncomine and Protein atlas database showed the mRNA and protein level of PIWIL1 and PIWIL4 are significantly overexpressed in CRC tissues compared to normal tissues. B. The representative IHC staining of PIWIL1 and PIWIL4 in CRC and normal tissues (provided by Protein atlas database). (TIFF 444 kb)
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Additional file 4: Figure S2. The expression level of candidate piRNAs in validation cohorts. The expression of piR-1245 and piR-26,525 were further confirmed in the Shanghai cohort (cohort I) and subsequently validated in the Okayama cohort (cohort II). piR-1245 was consistently overexpressed in cancer vs. normal tissues in each cohort. **P < 0.01, Wilcoxon paired test. (TIFF 100 kb)
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Additional file 5: Figure S3. The expression level of piR-1245 in different cancer type. The TCGA datasets showed piR-1245 is significantly up-regulated in tumor tissues compared to normal tissues in different types of cancer. **P < 0.01, Wilcoxon paired test. (TIFF 118 kb)
12943_2018_767_MOESM5_ESM.tif
Additional file 6: Figure S4. The expression level of Ki-67 in CRC cell lines treated with piR-1245 overexpression or inhibition. HCT116 and SW480 cells were transfected with piR-1245 antisense, RNA oligos or control oligos. The representative images showed expression of Ki67 was detected by immunofluorescence assay from different treatment groups. The overexpression of piR-1245 in HCT116 cells showed increased level of proliferation marker Ki-67, while inhibition of piR-1245 showed decreased level of Ki-67, compared to the control cells. (TIFF 193 kb)
12943_2018_767_MOESM6_ESM.tif
Additional file 7: Figure S5. Gene Ontology (GO) and disease functions of IPA analysis for the differential expressed genes in HCT116 treated with or without piR-1245 antisense treatment. Go annotation of top 10 enrichment pathways covering domains of biological processes, cellular components and molecular functions. The top 10 GO term enrichment analysis for up-regulated genes favored cell death or apoptosis, cell proliferation, protein metabolic process and protein, while the down-regulated genes were enriched for chromatin assembly and catalytic activity. IPA for the disease functions of piR-1245 in CRC showed that it correlates with cell death and survival. (TIFF 560 kb)
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Additional file 8: Figure S6. Prediction of piR-1245’s target by miRanda. The representative images showed the binding sites between piR-1245 and its targets. (TIFF 197 kb)
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Additional file 9: Figure S7. Prediction of piR-1245’s target by RNA22. The representative images showed the binding sites between piR-1245 and its targets. (TIFF 127 kb)
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Additional file 10: Table S2. The function of piR-1245 targets and their expression in CRC. (DOCX 17 kb)
12943_2018_767_MOESM10_ESM.docx
Literatur
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