Abstract
Human colorectal cancer (CRC), characterized by its high morbidity and lethality, seriously threatens human health and lives. MicroRNA‐487b (miR‐487b) is currently reported to be aberrantly expressed in several tumors, but the detailed functions and underlying mechanisms of miR‐487b in CRC remain unclear. Here, we found that miR‐487b is downregulated in CRC cell lines and is markedly decreased in tumor specimens derived from CRC patients. MiR‐487b inhibits cell proliferation, migration and invasion and promotes the apoptosis of CRC cells in vitro. Statistical analysis of clinical samples indicates that miR‐487b may serve as a biomarker for early CRC diagnosis. Inverse correlations between the expression levels of MYC, SUZ12, and KRAS and that of miR‐487b exist in vitro and in CRC patient tissue specimens. Further experiments demonstrated the regulatory effects of miR‐487b on MYC, SUZ12, and KRAS, and the disruption of these genes partially restores the miR‐487b inhibitor‐induced phenotype. Additionally, miR‐487b promoter region is in a DNA hypermethylated condition and the DNA methyltransferase inhibitor 5‐aza‐2’‐deoxycytidine (5‐Aza) increases the levels of miR‐487b but suppresses the expression of MYC, SUZ12, and KRAS in a time‐ and concentration‐dependent manner in CRC cells. Collectively, miR‐487b is regulated by DNA methylation and it functions as a tumor suppressor in CRC mainly through targeting MYC, SUZ12, and KRAS. Our study provides insight into the regulatory network in CRC cells, offering a new target for treating CRC patients.
Highlights
Human colorectal cancer (CRC) is one of the most common digestive malignancies in the world
We demonstrated that endogenous miR‐487b inhibition is an advantageous condition for CRC cells to transfer from the epithelial phenotype to mesenchymal phenotype and acquire the capability to proliferate, migrate, and invade uncontrollably
In agreement with the MTT assay, colony amounts of the HCT116 cells were notably boosted with the transient transfection of the miR‐487b inhibitor compared with that in the negative control (NC) group, and vice versa in SW620 miR‐487b mimic/NC cells (Figure 1F). These findings demonstrate that miR‐487b can prevent the proliferation of CRC cells in vitro, as suggested by the data acquired from HCT116 and SW620 cells
Summary
Human colorectal cancer (CRC) is one of the most common digestive malignancies in the world. MicroRNAs (miRNAs) typically suppress translation or degrade transcripts via direct interactions with the complementary mRNA sequences in 3’‐untranslated regions (3’‐UTRs) during the posttranscriptional phase, and they participate in various biological processes, tumorigenesis.[4,5] Multiple miRNAs, functioning either as onco‐ miRs or tumor suppressors, are implicated in the regulatory networks of CRC development and progression to date.[6] In addition, aberrant expression of miRNAs in CRC may be attributed to the genetic or epigenetic alterations, such as DNA methylation and histone modification.[7,8] MiR‐487b, which was first identified as a negative regulator for acute ischemic stroke[9] and pulmonary fibrosis,[10] is currently reported to be involved in the modulation of several tumors, such as preventing pulmonary carcinogenesis[11] and serving as a favorable biomarker for prostate cancer.[12] Recently, miR‐487b was reported to play a role in regulating CRC tumorigenesis via directly targeting GRM3 and Kirsten rat sarcoma viral oncogene homolog (KRAS).[13,14] the function of miR‐487b in CRC and mechanism that accounts for the aberrant expression of miR‐487b in tumors are not fully elucidated. We identified miR‐487b as a CRC suppressor and provide a novel target for CRC diagnosis and therapy
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