Elsevier

Biomedicine & Pharmacotherapy

Volume 75, October 2015, Pages 129-136
Biomedicine & Pharmacotherapy

Original article
miR-125a-5p inhibits cell proliferation and induces apoptosis in colon cancer via targeting BCL2, BCL2L12 and MCL1

https://doi.org/10.1016/j.biopha.2015.07.036Get rights and content

Abstract

MicroRNAs (miRNAs) are small non-coding RNAs that function as regulators of gene expression. MiR-125 is a family of miRNAs that have been shown to be involved in various cancer types. In this study, for the first time, we showed that miR-125a-5p was specifically down-regulated in both colon cancer tissue and colon cancer cell lines. The tumor suppressor role of miR-125a-5p in colon cancer was supported by the observation that overexpression of miR-125a-5p inhibited cell proliferation and induced cell apoptosis in colon cancer cells. We also confirmed that in colon cancer cells, anti-apoptotic genes BCL2, BCL2L12 and Mcl-1 were direct targets of miR-125a-5p, and they were down-regulated by miR-125a-5p overexpression. Furthermore, restoration of BCL2, BCL2L12 and Mcl-1 expression in colon cancer cells could partially reverse the cell proliferation inhibition and apoptosis stimulation caused by miR-125a-5p overexpression, indicating that miR-125a-5p inhibits cell proliferation and induces apoptosis in colon cancer cells via targeting BCL2, BCL2L12 and Mcl-1.

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).

References (24)

  • M. Kappelmann et al.

    MicroRNA miR-125b controls melanoma progression by direct regulation of c-Jun protein expression

    Oncogene

    (2013)
  • K.D. Cowden Dahl et al.

    The epidermal growth factor receptor responsive miR-125a represses mesenchymal morphology in ovarian cancer cells

    Neoplasia

    (2009)
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