Abstract
BackgroundWith persistent inconsistencies in colorectal cancer (CRC) miRNAs expression data, it is crucial to shift toward inclusion of a “pre-laboratory” integrated analysis to expedite effective precision medicine and translational research. Aberrant expression of hsa-miRNA-195 (miR-195) which is distinguished as a clinically noteworthy miRNA has previously been observed in multiple cancers, yet its role in CRC remains unclear.MethodsIn this study, we performed an integrated analysis of seven CRC miRNAs expression datasets. The expression of miR-195 was validated in The Cancer Genome Atlas (TCGA) datasets, and an independent validation sample cohort. Colon cancer cells were transfected with miR-195 mimic and inhibitor, after which cell proliferation, colony formation, migration, invasion, and dual luciferase reporter were assayed. Xenograft mouse models were used to determine the role of miR-195 in CRC tumorigenicity in vivo.ResultsFour downregulated miRNAs (hsa-let-7a, hsa-miR-125b, hsa-miR-145, and hsa-miR-195) were demonstrated to be potentially useful diagnostic markers in the clinical setting. CRC patients with a decreased level of miR-195-5p in tumor tissues had significantly shortened survival as revealed by the TCGA colon adenocarcinoma (COAD) dataset and our CRC cohort. Overexpression of miR-195-5p in DLD1 and HCT116 cells repressed cell growth, colony formation, invasion, and migration. Inhibition of miR-195-5p function contributed to aberrant cell proliferation, migration, invasion, and epithelial mesenchymal transition (EMT). We identified miR-195-5p binding sites within the 3’-untranslated region (3′-UTR) of the human yes-associated protein (YAP) mRNA. YAP1 expression was downregulated after miR-195-5p treatment by qRT-PCR analysis and western blot.ConclusionsFour downregulated miRNAs were shown to be prime candidates for a panel of biomarkers with sufficient diagnostic accuracy for CRC in a clinical setting. Our integrated microRNA profiling approach identified miR-195-5p independently associated with prognosis in CRC. Our results demonstrated that miR-195-5p was a potent suppressor of YAP1, and miR-195-5p-mediated downregulation of YAP1 significantly reduced tumor development in a mouse CRC xenograft model. In the clinic, miR-195-5p can serve as a prognostic marker to predict the outcome of the CRC patients.
Highlights
With persistent inconsistencies in colorectal cancer (CRC) miRNAs expression data, it is crucial to shift toward inclusion of a “pre-laboratory” integrated analysis to expedite effective precision medicine and translational research
We identified seven datasets that met the criteria listed in Methods (387 Colorectal cancer (CRC) samples and 386 paired adjacent normal tissue (PANT) samples; Additional file 5: Table S3)
One-sided tests revealed upregulated miRNAs in CRC compared with PANT (Additional file 6: Table S4) and downregulated ones in CRC compared with PANT (Additional file 7: Table S5)
Summary
With persistent inconsistencies in colorectal cancer (CRC) miRNAs expression data, it is crucial to shift toward inclusion of a “pre-laboratory” integrated analysis to expedite effective precision medicine and translational research. The 5year survival rate for localized stage CRC is 90%, whereas as CRC spreads to the regional lymph nodes or distant parts of the body, the 5-year survival rate plunges from 71% to 13% in the United States [2] These malignancies are ascribed to accumulation of genetic alterations, including dissemination of proto-oncogenes, losing or inactivating of tumor suppressor genes, and EMT, which lead to tumor evolution and progression [3,4,5,6,7]. Recent studies showed that YAP and its transcriptional coactivator with PDZ-binding motif (TAZ) function as a nexus on the crosstalk of multiple signaling pathways, and can be potential therapeutic targets as the chief downstream effectors of the Hippo pathway in a variety of cancers [11,12,13,14,15]. There have been few studies on miRNAs that regulate the oncogenic alterations in the Hippo signaling pathway
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