Original articlemiR-125a-5p inhibits cell proliferation and induces apoptosis in colon cancer via targeting BCL2, BCL2L12 and MCL1
Introduction
MicroRNAs (miRNAs) are small non-coding RNAs that function as regulators of gene expression. Although detailed mechanism of action is not clear, miRNAs are believed to act primarily in a post-transcriptional manner through destabilization of mRNA transcripts and repression of translation [1]. A rapidly growing body of studies have demonstrated that miRNAs are involved in the regulation of numerous cellular processes, including metabolic homeostasis, cell proliferation and cell apoptosis [2]. Therefore, aberrant expression of miRNAs has become tightly associated with the pathogenesis of a variety of human diseases, among which are almost all types of cancers [3]. The roles miRNAs play in cancer development are rather complex, as miRNAs can either act as oncogenes by repressing target mRNAs of tumor suppressor genes, or as tumor suppressors by negatively regulating oncogene mRNAs [4].
MiR-125 is a family of miRNAs that have been shown to be involved in various cancer types. This miRNA family consists of three different miRNAs, namely miR-125a, miR-125b-1, and miR-125b-2, which are transcribed from distinct loci in the genome [5]. Intriguingly, the different members of miR-125 family appear to have contradicting functions in different types of cancer. Both miR-125a and miR-125b have been shown their tumor-suppressor properties in cancer types including bladder cancer [6], liver cancer [7], melanoma [8], ovarian cancer [9], breast cancer [10] and osteosarcoma [11]. In contrast, the members of miR-125 family, especially miR-125b, can also act as oncogene in several cancer types, including pancreatic cancer [12], prostate cancer [13], [14], breast cancer [15], and glioblastoma [16]. Adding to the complexity of contradicting roles that miR-125 plays in cancer development, the downstream target pathways regulated by miR-125 are even more diverse. MiR-125 family genes have been demonstrated to mediate the function of ETS1 gene [17], the ERBB2 and ERBB3 pathway [18], matrix metalloproteinase 11 (MMP11) and vascular endothelial growth factor A (VEGF-A) [7], [15], STARD13 [15], [17], and IL6R [19]. The controversial properties of the miR-125 family in different cancers suggest that miR-125 plays highly diverse functions in cancer initiation and progression, and that the underlying mechanisms on different cell context are likely distinct, therefore requiring careful investigation.
In this study, we demonstrated for the first time that miR-125a-5p was specifically down-regulated in colon cancer tissue. The tumor suppressor role of miR-125a-5p in colon cancer was further supported by the fact that overexpression of miR-125a-5p inhibited cell proliferation and induced apoptosis in colon cancer cell lines. We also confirmed that in colon cancer cells, anti-apoptotic genes BCL2, BCL2L12 and Mcl-1 were targets of miR-125a-5p, and they were down-regulated by miR-125a-5p overexpression. Furthermore, replenishment of BCL2, BCL2L12 and Mcl-1 in cells overexpressing miR-125a-5p could partially relieve the cell proliferation inhibition, indicating that miR-125a-5p inhibits cell proliferation and induces apoptosis in colon cancer via targeting BCL2, BCL2L12 and Mcl-1.
Section snippets
Ethics statement
This study was approved by the First Affiliated Hospital of Harbin Medical University. Clinic samples were authorized to be used in this research by the Ethics Committee of the First Affiliated Hospital of Harbin Medical University. Written consent was obtained from all participants. A total of 33 patients were enrolled in this study.
Clinical specimen collection
Colon cancer samples and adjacent normal tissues (at least 5 cm from the edge of tumor) were collected by the Department of General Surgery, the First Affiliated
miR-125a-5p is down-regulated in colon cancer tissues
In order to investigate the role of miR-125a-5p in colon cancer development, we first examined the levels of miR-125a-5p expression in colon cancer tissues from 23 patients. In the majority of these patients, we found that the expression of miR-125a-5p was significantly inhibited in colon cancer tissues compared to that in adjacent tissues by qRT-PCR analysis (Fig. 1A and B). Subsequently, we selected five commonly used colon cancer cell lines (SW620, SW480, CaCo2, HT24 and HCT116), and
Discussion
MicroRNA miR-125 has been implicated in the development of various kinds of cancer in multiple previous studies. However, the distinct functional properties of miR-125a and miR-125b have made it difficult to hypothesize a uniform theory as to how members in this microRNA family regulate cancer related molecular and cellular pathways. Even for the specific members in the family, the spectrum of the downstream target is rather broad. This situation warrants the requirement for careful
Conflicts of interest
All authors of this manuscript declares no conflicts of interest in the research.
Acknowledgement
This study was supported by Department of Health, Heilongjiang Province (2012-701).
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