Original ArticlesmiR-206 functions as a novel cell cycle regulator and tumor suppressor in clear-cell renal cell carcinoma
Introduction
Renal cell carcinoma (RCC) accounts for 3% of adult malignancies and is the most lethal urological malignancy, with about 65,150 new cases and 13,680 deaths estimated for 2013 in the United States [1]. RCC can be histologically classified into several subtypes, among which Clear-cell renal cell carcinoma (ccRCC) is the most common, accounting for 70–80% of all [2]. Apart from surgical therapies, current targeted therapies have improved survival in patients with advanced disease but complete response occurs rarely [3]. Therefore, increased understanding of the underlying molecular biology of RCC is necessary to identify the clinical and molecular phenotype of response and resistance, and to uncover novel targets [4].
MicroRNAs (miRNAs) are an abundant class of small non-coding RNAs that suppress gene expression at the post-transcriptional level by blocking mRNA translation or degrading target mRNAs [5]. Increased studies have extended the function of miRNAs to both physiological and pathological conditions, including cancer [6]. Most current clinical trials are for the use of microRNAs as biomarkers for patient stratification, prognosis, and drug efficacy [7]. In addition to that, microRNAs is now under investigation as potential therapeutic agents for cancer. The first microRNA-based therapy specifically for cancer is MRX34: a synthetic miR-34a mimic loaded in liposomal nanoparticles, which is now is in a phase I clinical trial (NCT01829971) for primary liver cancer and liver metastases [8].
It is demonstrated that a pool of miRNAs is as well involved in RCC through modulating their target genes implicated in multiple biological processes. For example, oncogenic miR-185 which has been found to be significantly up-regulated in RCC and anti-correlated with the tumor suppressor gene PTEN [9]. Epithelial-mesenchymal transition-related microRNA-200s regulate molecular targets and pathways in renal cell carcinoma [10]. MicroRNA-218 inhibits cell migration and invasion in renal cell carcinoma through targeting caveolin-2 involved in focal adhesion pathway [11]. RCC is known to be characterized by the loss of the VHL gene. VHL-regulated miR-204 suppresses tumor growth through inhibition of LC3B-mediated autophagy in renal cell carcinoma [12].
Unfortunately, the underlying molecular biology of microRNAs in ccRCC pathogenesis remains largely unknown. So in this study we tried to systematically investigate the tumor suppressing microRNAs in ccRCC.
Section snippets
Clinical sample preparation
A total of 41 paired clear cell renal cell carcinoma and corresponding noncancerous tissues (NCT) were obtained sequentially from patients undergoing radical nephrectomy from the period of 2010–2014. The basic clinical characteristics of these patients were listed in Table S1. Corresponding noncancerous tissues were acquired at least 5 cm away from the tumor site. Tissues specimens were snap frozen in liquid nitrogen before protein and RNA extraction. The study protocol was approved by the
Screening for the novel tumor suppressing miRNA in ccRCC
We previously performed a comprehensive meta-analysis of miRNA expression profiles in RCC and identified a down-regulated miRNAs panel including 38 miRNAs that reported in at least three expression profiling studies [18]. Based on that, we selected 23 miRNAs to perform further experimental analysis, while other 15 miRNAs which had been reported functions in RCC elsewhere were excluded (Table 1).
To investigate the tumor suppressing effect of these 23 down-regulated miRNAs, we first transfected
Discussion
In our previously performed comprehensive meta-analysis of miRNA expression profiles in RCC, we identified a down-regulated miRNAs signature including 38 miRNAs that reported in at least three miRNA expression profiling studies. Some of these down-regulated miRNAs have been suggested as tumor suppressors in RCC, such as miR-200/141/429 family [19], [20], [21], miR-204 [12], [22] and miR-138 [23]. In this study, we focused on miR-206 because it had the greatest proliferation inhibitory effect on
Conclusions
In this study, we reviewed and analyzed the currently available miRNA expression profiles data of ccRCC and identified miR-206 as one of the most critical tumor-suppressing microRNA in ccRCC. In addition, miR-206 inhibited ccRCC cell proliferation through inducing cell cycle arrest by directly targeting cell cycle related gene CDK4, CDK9 and Cyclin D1. All these results suggested that miR-206 functioned as a novel cell cycle regulator and tumor suppressor in ccRCC and could be considered as a
Conflict of interest
The authors have declared no conflicts of interest.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (31372562, 81170650, 81270788, 81470935, 81402098, 81402105, 81402087), the National Major Scientific and Technological Special Project for Significant New Drugs Development (2012ZX09303018), the Chenguang Program of Wuhan Science and Technology Bereau (2013072304010833, 2015070404010199), and The National High Technology Research and Development Program 863 (2014AA020607), and the Natural Science Foundation of Hubei
References (30)
- et al.
Renal cell carcinoma
Lancet
(2009) MicroRNAs: genomics, biogenesis, mechanism, and function
Cell
(2004)- et al.
MicroRNAs in cancer: biomarkers, functions and therapy
Trends Mol. Med
(2014) - et al.
MicroRNA-218 inhibits cell migration and invasion in renal cell carcinoma through targeting caveolin-2 involved in focal adhesion pathway
J. Urol
(2013) - et al.
VHL-regulated MiR-204 suppresses tumor growth through inhibition of LC3B-mediated autophagy in renal clear cell carcinoma
Cancer Cell
(2012) - et al.
Cisplatin-induced epigenetic activation of miR-34a sensitizes bladder cancer cells to chemotherapy
Mol. Cancer
(2014) - et al.
Honokiol suppresses renal cancer cells' metastasis via dual-blocking epithelial-mesenchymal transition and cancer stem cell properties through modulating miR-141/ZEB2 signaling
Mol. Cells
(2014) - et al.
TRPM3 and miR-204 establish a regulatory circuit that controls oncogenic autophagy in clear cell renal cell carcinoma
Cancer Cell
(2014) - et al.
Cancer statistics, 2013
CA Cancer J. Clin
(2013) - et al.
The international society of urological pathology (ISUP) vancouver classification of renal neoplasia
Am. J. Surg. Pathol
(2013)
Considerations for personalised therapy in RCC
Nat. Rev. Urol
Oncomirs – microRNAs with a role in cancer
Nat. Rev. Cancer
First microRNA mimic enters clinic
Nat. Biotechnol
MicroRNA-185 suppresses tumor growth and progression by targeting the Six1 oncogene in human cancers
Oncogene
Epithelial-mesenchymal transition-related microRNA-200s regulate molecular targets and pathways in renal cell carcinoma
J. Hum. Genet
Cited by (60)
Epigenetically-regulated miR-30a/c-5p directly target TWF1 and hamper ccRCC cell aggressiveness
2022, Translational ResearchCitation Excerpt :Over the past few years, the impact of dysfunctional epigenetic mechanisms on cancer has been largely unveiled.9 Among such mechanisms, DNA promoter methylation and microRNA (miR) deregulated levels have been broadly associated with ccRCC onset and progression.10-12 MiRs are small (18–25 nucleotide-long) non-coding RNAs that regulate gene expression through a mechanism of RNA interference (RNAi).13
A novel miR-206/hnRNPA1/PKM2 axis reshapes the Warburg effect to suppress colon cancer growth
2020, Biochemical and Biophysical Research CommunicationsCitation Excerpt :Manipulating tumor-suppressive miRNAs expression providing a promising new therapeutic approach for cancer treatment. Accumulating evidence has indicated that decreased expression of miR-206 (serves as a tumor suppressor) was observed in different types of cancer cells [23]. So far, the role of miR-206 in CRC remains somehow controversial.
Bone marrow mesenchymal stem cell-derived exosomal miR-206 inhibits osteosarcoma progression by targeting TRA2B
2020, Cancer LettersCitation Excerpt :Further studies verified that miR-206 was expressed at low levels in osteosarcoma tissues and that overexpression of miR-206 could significantly inhibit the proliferation, migration, and invasion of osteosarcoma cells and promote their apoptosis by targeting TRA2B. Currently, an increasing number of studies have revealed that miR-206 is expressed at low levels in a variety of tumors, such as clear-cell renal cell carcinoma [20], head and neck squamous cell carcinoma [21], and triple-negative breast cancer [22]. Similarly, several studies have demonstrated that miR-206 is expressed at low levels in osteosarcoma tissues.
Sonodynamic Therapy Combined to 2-Deoxyglucose Potentiate Cell Metastasis Inhibition of Breast Cancer
2019, Ultrasound in Medicine and BiologyCitation Excerpt :Rock-ribbed injury of cell morphology is bound to affect cell adhesion, migration and invasion, which may inhibit tumor metastasis. Moreover, cell cycle progression reflects tumor proliferation to some degree (Xiao et al. 2016). Using PI staining, we discovered that samples from the SDT + 2 DG group predominantly stopped in the S phase.
- 1
These authors have contributed equally to this work.