miR‑106b‑5p promotes cell cycle progression of malignant melanoma by targeting PTEN10.3892/or.2023.8669

  • Authors:
    • Xu-Ε Chen
    • Pu Chen
    • Shan-Shan Chen
    • Ting Ma
    • Guang Shi
    • Ya Zhou
    • Ji Li
    • Liang Sheng
  • View Affiliations

  • Published online on: November 16, 2017     https://doi.org/10.3892/or.2017.6099
  • Pages: 331-337
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Abstract

This study investigated how miR‑106b‑5p/PTEN signaling affects the cell cycle of malignant melanoma (MM) cells. miR‑106b‑5p mRNA was identified with qRT‑PCR. Through transient transfection, miR‑106b‑5p or PTEN was upregulated and downregulated in MM cells. With such transfected cells, MTT assay, colony formation assay and flow cytometry were carried out to investigate the role of miR‑106b‑5p in cell cycle progression after the transfected cells were treated with reverse-regulation of miR‑106b‑5p or PTEN. Western blot analysis was used to quantify all proteins, and a luciferase reporter assay was carried out to validate miR‑106b‑5p targeting PTEN. miR‑106b‑5p mRNA was overexpressed in MM tissues and cell lines. MM cells with upregulated miR‑106b‑5p presented faster growth and shorter cell cycles, while those with knockdown of miR‑106b‑5p presented the opposite trend. PTEN was subject to post‑transcriptional regulation of miR‑106b‑5p. Based on such a finding, further exploration was carried out to investigate the interaction between cyclin D1 and P27Kip1, with the finding that miR‑106b‑5p can stimulate cyclin D1 and suppress P27Kip1 via the Akt/ERK pathway. The results of this study suggest that miR‑106b‑5p may be a promoter in MM progression, possibly by targeting PTEN and thus regulating the downstream cell‑cycle-related proteins and Akt/ERK pathway.

Introduction

Malignant melanoma (MM) is the deadliest skin cancer due to high aggressiveness and metastasis (1). Regardless of progress in understanding the initiation and progression of MM, patients with MM experience gloomy prospects, with a poor prognosis and a low 5-year survival rate of <15% (2,3). Currently, due to a lack of adequate treatment, overall survival remains without improvement, requiring more efforts for searching for effective therapeutic target (4).

MicroRNAs (miRNAs) have binding sites in the 3′-UTRs of their target gene and are capable of regulating expression of the target genes at the transcriptional level by degrading mRNA and suppressing mRNA translation (5,6). Accumulating evidence has shown that differentially expressed miRNAs participate in cancer progression via regulation of cell proliferation and the cell cycle (7). MicroRNA-106b (miR-106b) is also a well-accepted participant in the progression of such cancers as breast cancer, gastric cancer, prostate cancer and hepatocellular cancer (811). According to these studies, miR-106b upregulation is frequent in tumor progression, and such upregulation is involved in the development of invasiveness and metastasis. Moreover, miR-106b has been shown to be heavily involved in melanoma growth. It has been reported that suppression of miRNA-106b arrests the cell cycle at the G1 phase and results in blocked growth of melanoma cells via reactivation of p21/WAF1/Cip1 signaling (12), while overexpression of miR-106b relates to poor prognosis of cutaneous melanoma (13). Regretfully, there is a poor understanding of the effect of miR-106b on its target in MM progression.

In this study, the status of miR-106b in MM is identified, and the impact of miR-106b on cell cycle progression was investigated. Additionally, PTEN (phosphatase and tensin homolog), which plays important roles in many cellular processes, for example, cell growth, cell cycle progression, angiogenesis, migration and invasion (14), was validated as a direct target of miR-106b. It has been reported that miR-106b contributes to the development of cancer by targeting PTEN (15,16). Consistently, the expression of PTEN was negatively correlated with the expression of miR-106b in MM cell lines. This study further explored the interaction between miR-106b and the Akt/ERK pathway downstream of PTEN. This study reveals the working process of miR-106b in MM progression and provides a potential molecular therapeutic target for treatment of MM patients.

Materials and methods

Ethics statement

The present study was conducted under the approval and guidance of the Medical Ethics Committee of Guizhou Provincial People's Hospital. All patients included in this study provided written consent.

Cell culture

SK-MEL-1 and A-375 (Human MM cell lines; American Type Culture Collection) were incubated with Dulbecco's modified Eagle's medium (DMEM) (Gibco, USA). Human epidermal melanocytes (HEM) (Promocell) were cultured in melanocyte growth medium. Both media contained 10% fetal bovine serum and such cell culture was conducted at 37°C in 5% CO2 atmosphere.

Transient transfection

Cells were transfected with miR-106b-5p mimics, mimics control, miR-106b-5p inhibitors and inhibitor control (GenePharma, Shanghai, China). miR-106b-5p mimics: 5′-UAAAGUGCUGACAGUGCAGAU-3′; miR-106b-5p inhibitor: 5′-AUCUGCACUGUCAGCACUUUA-3′. Cells were cultured for 20 h before transfection and were transfected at a confluence of 70%. Oligonucleotides were transfected into MM cells with Lipofectamine 2000 (Invitrogen, Carlsbad, CA, USA). The oligonucleotides were diluted to a final concentration of 100 nM for transfection. PTEN vector was synthesized (RiboBio, Guangzhou, China).

Tissue specimens

Benign nevi (intradermal or congenital; n=18) or primary cutaneous melanoma (n=18) was collected from patients treated with resection at the Guizhou Provincial People's Hospital between January 2014 and December 2015. All patients were free from radiotherapy or chemotherapy before resection. All collected tissues were cultured with RNAlater reagent (Takara, Japan) at −80°C until use.

Quantitative real-time PCR (qRT-PCR)

Total-RNA was extracted (Takara PrimeScript™ RT reagent kit with gDNA Eraser; Takara). For quantification of miR-106b-5p, TaqMan microRNA assays (Applied Biosystems, Foster City, CA, USA) were adopted. SYBR Premix Ex Taq II (Takara) was adopted for qRT-PCR. The following forward and reverse primers (RiboBio) were used for PTEN: 5′-CACCTATTCCTCAGCCCTTAT-3′ and 5′-AACCCTCATTCAGACCTTCAC-3′; GAPDH: 5′-AATGGGCAGCCGTTAGGAAA-3′ and 5′-TGAAGGGGTCATTGATGGCA-3′; miR-106b-5p: 5′-CAAGTACCCACAGTGCGGT-3′ and 5′-CTCGCTTCGGCAGCACA-3′); and U6: 5′-CGCTTCGGCAGCACATATACTA-3′ and 5′-CGCTTCACGAATTTGCGTGTCA-3′. GAPDH and U6 were the internal reference. For calculation of the relative expression of target genes, the ΔΔCT method was used (14).

MTT assay, colony formation and flow cytometry

For the MTT assay, the transfected cells were cultured (5.0×103 cells/well) in 96-well plate and then observed for cell proliferation at 24, 48, 72 and 96 h after 4-h incubation with 20 µl of MTT (5 mg/ml) and the addition of 150 µl of DMSO. The optical density (OD) at 490 nm was used to determine the cell proliferation activity. Each well was verified with other similar 5 wells, and the test on each well was conducted three times. For colony formation assay, such transfected cells were incubated for 10 days in 6-well plates, and the formed colonies were treated with fixation and 5-min staining with 1% crystal violet (Sigma-Aldrich). Ten different fields were selected for colony counting, and such counting data was determined to be the average of the ten fields. For flow cytometry, cells were incubated (20 min at 37°C) with propidium iodide (PI) and RNase (2 µg/ml, Sigma, USA). A FACSort flow cytometer was used to identify cell population at the G1, S, and G2 phases (Becton-Dickinson, CA, USA). The count data were expressed as percentages and analyzed with the FlowJo 7.6 software.

Luciferase reporter assay

HEK293T cells received 1-day incubation in 24-well plates (1×105/well) before transfection. pGL3 Dual-Luciferase miRNA Target Expression Vector (Promega, USA) was synthesized with the predicted mutated (MUT) and wild-type (WT) miR-106b-5p target on the PTEN 3′-UTR. The vectors were transfected into cells using polyethylenimine (PEI; Sigma). After 48 h of transfection, the luciferase activity of the transfected cells was determined using Dual-Luciferase Reporter assay system (Promega). Experiments were repeated two additional times.

Western blot analysis

Total protein extraction was conducted with RIPA (Thermo Scientific, Rockford, IL, USA). The cells were rinsed with PBS, followed by solubilization in lysis buffer (1% Nonidet P-40) and then centrifugation (20,000 × g, 15 min at 4°C). Protein was measured for the concentration with bicinchoninic acid protein assay kit (Pierce Biotechnology) and then separated with sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and transferred to membranes. Such membranes were first hatched with a respective primary antibody against phosphorylated rabbit p-Akt, p-ERK1/2, total AKT, and total ERK1/2, anti-PTEN, anti-P27Kip1, anti-cyclin D1 or anti-GAPDH (Santa Cruz Biotechnology, Inc., Dallas, TX, USA or Cell Signaling Technology, Inc., Danvers, MA, USA) and then continuously incubated with a horseradish peroxidase-conjugated secondary antibody (Sigma). Target proteins were quantified using enhanced chemiluminescence (ECL) assay. The protein expression was normalized to GAPDH expression.

Statistical analysis

SPSS 22.0 (SPSS Inc., Chicago, IL, USA) was employed for data analysis, which was based on the mean ± standard deviations (SD) from repeated experiments. Data comparisons were made with t-test or one-way ANOVA. P<0.05 indicated statistical significance.

Results

miR-106b-5p is increased in MM tissues and cells

In light of qRT-PCR, miR-106b-5p greatly increased in the MM tissues in parallel with that in the nevi (Fig. 1A), similarly to SK-MEL-1 and A-375 cell lines in parallel with HEMs (Fig. 1B). This finding suggested that miR-106b-5p may relate to MM progression.

Interaction between miR-106b-5p and MM cell proliferation in vitro

As demonstrated by qRT-PCR, miR-106b-5p was obviously increased in SK-EML-1/miR-106b-5p mimic cells (a 100-nm dose), while remarkably downregulated in A-375/miR-106b-5p inhibitor cells compared with that in the control cells (P<0.05; Fig. 2A). As observed in the MTT and colony formation assay, by reference to their control cells, SK-EML-1/miR-106b-5p mimic cells had higher growth rates and formed more colonies. In contrast, A-375/miR-106b-5p inhibitor cells presented decreased growth capacity (Fig. 2B and C). From these results, it is believed that miR-106b-5p is a promoter for cell proliferation in MM progression.

Relation of miR-106b-5p to MM cell cycle progression in vitro

From the belief that upregulated miR-106b-5p stimulated proliferation of MM cells, an investigation was carried out to determine how miR-106b-5p impacts cell cycle progression. According to flow cytometry, there were fewer SK-MEL-1 cells with upregulated miR-106b-5p at the G1/G0 phase but more at S phase than the control cells. Conversely, A-375 cells with downregulation of miR-106b-5p, in comparison with the control cells, had a larger population at the G1/G0 phase and a small population at the S phase (Fig. 3A).

It is well accepted that cell cycle progression is driven forward by bondage between cyclins and CDKs. As detected with western blot assay (Fig. 3B), SK-MEL-1 cells with upregulated miR-106b-5p had higher cyclin D1 expression and lower p27Kip expression, while A-375 cells with downregulation of miR-106b-5p presented suppressed cyclin D1 and increased p27Kip1. In consideration of all these findings, it is reasonable to propose that miR-106b promotes cell cycle progression when it is upregulated but arrests cell cycle progression at the G0/G1 phase via regulation of cyclins and p27Kip.

miR-106b-5p directly targeted the PTEN 3′-UTR

It was predicted with TargetScan that miR-106b-5p can be linked to PTEN at the 3′-UTR (Fig. 4A). This prediction is consistent with previous studies on other cancers (16,17). Luciferase reporter analysis showed that in HEK293T cells, miR-106b-5p suppressed the luciferase activity of the PTEN WT reporter gene but not the MUT type, an indication that PTEN is subject to the direct regulation of miR-106b-5p (Fig. 4B). It was also observed that SK-EML-1 cells with raised miR-106b-5p had significantly lower PTEN at both the mRNA and protein levels, while A-375 cells with downregulation of miR-106b-5p exhibited higher PTEN mRNA and protein expression (all P<0.05; Fig. 4C). After transfection with pMD-PTEN or PTEN control in A-375 and SK-MEL-1 cells, cells that were transfected with pMD-PTEN had significantly upregulated PTEN (P<0.05; Fig. 4D). These findings suggested that miR-106b-5p directly targeted PTEN and affected cell activities via regulation of PTEN.

miR-106b-5p promotes Akt/ERK1/2 signaling by inhibiting PTEN in MM cells

The AKT/ERK1/2 signaling pathway is a major pathway in tumor growth (18) and is subject to dephosphorylation by PTEN (19,20). Interestingly, p27Kip1 and cyclin D1 are also under the regulation of PTEN (21,22). Based on the above facts, it was hypothesized that the Akt/ERK1/2 signaling pathway might play a role in the miR-106b-5p/PTEN-stimulating MM progression. Surprisingly, A-375 cells with downregulated miR-106b-5p and upregulated PTEN had decreased p-AKT expression and p-ERK1/2 expression, while the total-Akt expression and total-ERK1/2 expression in such cells remained unchanged (Fig. 5A and B). Concordantly, SK-EML-1 cells with upregulation of miR-106b-5p increased p-Akt expression, p-ERK1/2 expression, and total Akt, and total ERK1/2 in such cells remained in the original expression status (Fig. 5C). After being co-transfected with pMD-PTEN, SK-EML-1 cells with upregulation of miR-106b-5p had a reversed trend in Akt and ERK1/2 expression (Fig. 5C). Based on these findings, it is suggested that MM progression may be triggered by miR-106b-5p, activating the Akt/ERK signaling pathways via downregulation of PTEN.

Discussion

miRNAs might be potential therapeutic targets for their roles in regulating many tumor suppressor genes (23,24). Previous studies reported that miR-106b was differentially upregulated in several human cancers such as gastric cancer, breast cancer and glioma (2527). In agreement with those studies, our qRT-PCR results also showed that MM tissues and cell lines had increased miR-106b-5p. Accumulating evidence has shown that miR-106b-5p is closely correlated with tumor progression (11,28). However, miR-106b-5p has varied functions in tumor progression among the studies. One study defined miR-106b-5p as a promoter of the progression of esophageal neoplasms by suppressing its two target genes, p21 and Bim (29). Another study suggested that it was a tumor-suppressor in type II invasive endometrial cancer, and its direct interaction with TWIST could block the development of EMT, thus preventing tumor invasion and metastasis (30). This study asserts that miR-106b-5p has different biological functions in different tumors. Therefore, the present study sought to clarify how miR-106b-5p works in MM progression.

Control of the cell cycle machinery has a critical role in regulating cell proliferation and tumor growth of cancer cells. In our study, which deploys upregulation and knockdown strategies in the SK-EML-1 and A-375 cell lines, respectively, it was observed that A-375 cells with suppressed miR-106b-5p presented lower growth capacity. Additionally, less colony formation had more cells at the G0/G1 phase and less cells at the S phase, while SK-EML-1 cells with increased miR-106b-5p had the reverse trend. Thus, it is suggested that miR-106b-5p is capable of promoting cell cycle progression. Coincidently, Xiang et al found that suppression of miR-106b-5p blocked cell cycle progression at the G0/G1 phase and inhibited cell proliferation via knockdown of SETD2 (31). By contrast, Ivanovska et al found that, after being upregulated, miR-106b in cancer cells sped up cell cycle progression (32). Considering these findings, this study suggests that miR-106b-5 may accelerate MM progression and MM cell proliferation by shortening the cell cycle. From this point, the study progresses to explore the association between miR-106b-5p and cell cycle-related proteins and pathways.

To our knowledge, levels of cyclins and cyclin-dependent kinase (Cdk) inhibitors are tightly controlled during normal cell proliferation and are frequently dysregulated in cancerous cells. Uncontrolled cell division is triggered by activated cyclins binding to CDKs in the G1 phase, inevitably driving cells to the S phase. However, the cell cycle exit is controlled by two major classes of non-enzymatic CDK inhibitors (CDKIs) that directly interact with cyclin-CDK complexes: the INK4 and the CDK-inhibitory protein (CIP)/kinase-inhibitory protein (KIP) families (33). The CIP/KIP family comprises three proteins in mammals: p21cip1/waf1, p27Kip1, and p57Kip2. In melanoma, cyclin D1 is highly expressed, and downregulation of the CDK-inhibitor, p27Kip1, is associated with a poor prognosis (34). On this basis, this study further investigated the effect of miR-106b-5p on cyclin D1 and p27Kip1 during regulation of the cell cycle. Our results indicate that miR-106b-5p suppressed p27Kip1 and activated the cell cycle regulator cyclin D1. Such an impact of miR-106b-5p on p27Kip1 and cyclin D1 can be mediated by downregulation of miR-106b-5p. Therefore, it can be concluded that miR-106b-5p promotes cell cycle progression in MM by regulating cyclins and CDKs. As known, p27Kip1 and cyclin D1 are subject to transcriptional regulation by PTEN (35,36), and PTEN is a well-accepted anti-oncogene in human cancers, including melanoma (3739). It is predicated that PTEN can crosstalk to miR-106b-5p in its 3′-UTR. Using a luciferase reporter assay, we recognized that PTEN is a target gene of miR-106b-5p and found that PTEN was negatively regulated by miR-106b-5p. With upregulation of PTEN, the growth rate and cell cycle progression of MM cells were controlled.

It has been reported that the AKT/ERK1/2 signaling pathway is a crucial pathway in the development of tumor/cancer. Hydrogen sulfide promotes oral cancer cell proliferation through activation of the COX2/AKT/ERK1/2 axis (40), and miR-7 inhibits tumor metastasis and reverses EMT through AKT and ERK1/2 pathway inactivation by reducing EGFR expression in EOC cell lines. Meanwhile, the AKT/ERK1/2 signaling pathway is subject to dephosphorylation by PTEN (19,20). Therefore, miR-106b-5p is involved in the correlation between PTEN and Akt and ERK1/2 pathway. To address this argument, this study progresses to look into the relation of miR-106b-5p to Akt/ERK1/2 signaling pathway, finding that miR-106b-5p positively intensified phospho-AKT (p-AKT) and phosphor-ERK1/2, while the total Akt expression and total ERK1/2 expression remained unchanged. Such intensification is accepted in this study as evidence that MM progression may be triggered by miR-106b-5p activating PTEN/Akt/ERK signaling pathways.

There are limitations to this study. First, miR-106b-5p should have been studied in relation to the clinicopathological features of MM. Second, miR-106b-5p promoting cell cycle progression should be further validated in an in vivo study. Future studies can adequately investigate the aforementioned limitations. This study summarily argues that miR-106b-5p is frequently differentially increased in both MM tissues and MM cell lines and closely relates to cell cycle progression via targeting PTEN and the Akt/ERK1/2 signaling pathway. Therefore, miR-106b-5p constitutes an oncogene in MM progression and a potential target for cellular therapy.

Acknowledgements

The authors would like to acknowledge the helpful comments on this manuscript that were provided by the reviewers.

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Chen X, Chen P, Chen S, Ma T, Shi G, Zhou Y, Li J and Sheng L: miR‑106b‑5p promotes cell cycle progression of malignant melanoma by targeting PTEN10.3892/or.2023.8669. Oncol Rep 39: 331-337, 2018
APA
Chen, X., Chen, P., Chen, S., Ma, T., Shi, G., Zhou, Y. ... Sheng, L. (2018). miR‑106b‑5p promotes cell cycle progression of malignant melanoma by targeting PTEN10.3892/or.2023.8669. Oncology Reports, 39, 331-337. https://doi.org/10.3892/or.2017.6099
MLA
Chen, X., Chen, P., Chen, S., Ma, T., Shi, G., Zhou, Y., Li, J., Sheng, L."miR‑106b‑5p promotes cell cycle progression of malignant melanoma by targeting PTEN10.3892/or.2023.8669". Oncology Reports 39.1 (2018): 331-337.
Chicago
Chen, X., Chen, P., Chen, S., Ma, T., Shi, G., Zhou, Y., Li, J., Sheng, L."miR‑106b‑5p promotes cell cycle progression of malignant melanoma by targeting PTEN10.3892/or.2023.8669". Oncology Reports 39, no. 1 (2018): 331-337. https://doi.org/10.3892/or.2017.6099