Tumor suppressor function of miR‑129‑5p in lung cancer

  • Authors:
    • Ge Li
    • Jiahang Xie
    • Jiuhui Wang
  • View Affiliations

  • Published online on: April 12, 2019     https://doi.org/10.3892/ol.2019.10241
  • Pages: 5777-5783
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Abstract

Lung cancer causes severe health problems worldwide and, in China, besides being the principal cause of mortality among urbanites, it is the second leading cause of mortality in the rural population, preceded by hepatocellular carcinoma. Between 80 and 85% of lung cancer is classified as non‑small cell lung cancer (NSCLC). The high mobility group box 1 (HMGB1) protein serves an important function in the tumor microenvironment and antitumor response, and may be targeted by microRNA (miR). In the present study, miR‑129‑5p was identified to target HMGB1 and miR‑129‑5p exhibited low expression levels in NSCLC tissues. Overexpression of miR‑129‑5p inhibited cell proliferation and promoted cell apoptosis. In conclusion, the results of the present study suggested the inhibitory function of miR‑129‑5p and revealed a novel therapeutic target for further investigation.

Introduction

Lung cancer is the leading cause of cancer-associated mortality in China (1). Two major types of lung cancer exist: Non-small cell lung cancer (NSCLC), which accounts for between 80 and 85% of lung cancer cases, and small cell lung cancer (SCLC), which accounts for between 10 and 15% of lung cancer cases (2). NSCLCs include adenocarcinoma, large cell carcinoma, bronchioloalveolar carcinoma and squamous cell carcinoma (3,4).

It has been reported that the high mobility group box 1 (HMGB1) protein is involved in the immune response of tumors (5). The HMGB1 protein was first identified as a highly conserved nuclear protein that serves a pivotal function in chromatin organization and transcriptional regulation (6,7). In addition, HMGB1 also serves important functions in the immune response (8). Preclinical data revealed that dying tumor cells emit certain danger molecular signals, known as damage-associated molecular patterns (DAMPs) (914). In brief, DAMPs are intracellular sequestered biomolecules that evade recognition by the immune system under normal physiological conditions (15). However, under conditions of cellular stress or injury, these molecules are actively secreted by stressed immune cells or released from dying cells, and trigger a non-infectious inflammatory response (16). HMGB1 is a typical DAMP biomolecule, as HMGB1 is released from dying cells and can trigger an immune response (17). A previous study demonstrated that, during chemotherapy or radiotherapy, HMGB1 was released from dying cells and stimulated dendritic cells (DCs) via Toll-like receptor 4 (TLR4) (5). DCs require signaling through TLR4 and its adaptor myeloid differentiation primary response 88 (MyD88) for efficient processing and cross-presentation of antigens from dying tumor cells (5).

MicroRNAs (miRNAs/miRs) serve multiple functions, including promoting cellular proliferation and apoptosis, in the pathogenesis of lung cancer (1824). HMGB1 may be a target for miRNAs. A previous study demonstrated that miR-218 is able to suppress cell proliferation and invasion, and promotes the apoptosis of pancreatic cancer cells by targeting HMGB1 (25).

In the present study, the function of miR-129-5p in lung cancer was examined and it was demonstrated that miR-129-5p targets HMGB1. The results of the present study may provide novel insights into the molecular mechanism for lung cancer progression.

Patients and methods

Tissue samples

A total of 10 NSCLC tissue samples were collected from The Pulmonary Department at Sichuan Cancer Center (Chengdu, China). Of the ten patients included in the study, 4 were male and 6 were female, with a mean age of 60 years (range, 43–77 years). The 10 NSCLC tissue samples were collected between January 2011 and May 2012. The exclusion criteria was any patient who had been diagnosed with another type of cancer. The protocol for the collection and use of human tissues in the present study was evaluated and approved by the Ethics Committee of Sichuan Cancer Hospital (Chengdu, China). All patients enrolled in the present study provided written informed consent, and all specimens were handled and blinded as required by the legal standards of China. All NSCLC tissue samples were evaluated and confirmed by a senior pathologist at Sichuan Cancer Center. The clinical information are presented in Table I.

Table I.

Characteristics of the 10 patients with non-small cell lung cancer.

Table I.

Characteristics of the 10 patients with non-small cell lung cancer.

Patient numberAge, yearsSexTNM stage
  165FemaleI
  255FemaleII
  356FemaleII
  443FemaleIII
  559MaleIII
  650MaleIV
  756MaleIII
  877FemaleIV
  966MaleII
1073FemaleII
Cell culture

The NSCLC cell lines A549 and SPC-A-1 were obtained from the Cell Bank of Sichuan University (Sichuan, China). All cells were cultured in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum (Gibco; Thermo Fisher Scientific, Inc., Waltham, MA, USA) at 37°C in a humidified incubator with 5% CO2.

Detection of miR-129-5p in tissues and cells

The levels of miR-129-5p in tissues and cells were determined using the reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Briefly, the total RNA from the tissue samples or A549 and SPC-A-1 cells was extracted using TRIzol® reagent, according to the manufacturer's protocol (Invitrogen; Thermo Fisher Scientific, Inc.). The corresponding cDNA was obtained using the reverse transcription kit (cat. no. 12574018, Thermo Fisher Scientific. Inc.). The expression of miR-129-5p was determined using TaqMan miRNA assay (Applied Biosystems; Thermo Fisher Scientific, Inc.). The thermocycling conditions were as follows: 95°C for 5 min, 40 cycles of 95°C for 15 sec, 58°C for 30 sec and 74°C for 30 sec. U6 small nuclear RNA was used as an internal loading control. RT-qPCR analysis was performed on an ABI 7900HT instrument (Applied Biosystems; Thermo Fisher Scientific, Inc.). The relative expression levels were calculated with the 2−ΔΔCq method (26). The primers were synthesized and tested by the Sangon Biotech Co., Ltd. (Shanghai, China) (2730). The following primer sequences were used: miR-129-5p forward, 5′-GGGGGCTTTTTGCGGTCTGG-3′ and reverse, 5′-AGTGCGTGTCGTGGAGTC-3; and U6 forward, 5′-CTCGCTTCGGCAGCACA-3′ and reverse, 5′-AACGCTTCACGAATTTGCGT-3′.

Overexpression and downregulation of miR-129-5p in NSCLC cells

The miR-129-5p levels in the A549 and SPC-A-1 cells were increased and decreased by miR-129-5p mimic and miR-129-5p antisense oligonucleotide (ASO), respectively. The miR-129-5p mimic and were purchased from Sangon Biotech Co., Ltd. Prior to transfection with 500 ng mimic or ASO, the cells were cultured overnight (1×106 cells/well) at 37°C. The cell transfection was performed using Lipofectamine® 2000 (Invitrogen; Thermo Fisher Scientific, Inc.), according to the manufacturer's protocol. The sequences of miR-129-5p mimic and miR-129-5p ASO were as follows: miR-129-5p mimic, 5′-GGAUCUUUUUGCGGUCUGGGCUUGCUGUUCCUCUCAACAGUAGUCAGGAAGCCCUUACCCCAAAAAGUAUCU-3′, and miR-129-5p ASO, 5′-CCUAGAAAAACGCCAGACCCGAACGACAAGGAGAGUUGUCAUCAGUCCUUCGGGAAUGGGGUUUUUCAUAGAAA-3′.

Cell proliferation assay

Cell proliferation was assessed using the MTT assay. Briefly, A549 and SPC-A-1 cells were seeded into 96-well plates at a density of 5×105 cells/well. The MTT reagent was added to the medium at a final concentration of 0.1 mg/ml. A total of 100 µl DMSO was added to each well to dissolve the formazan. The optical density was determined using a microplate reader at 570 nm.

Cell apoptosis analysis

A549 or SPC-A-1 cell suspensions (5×105 cells/ml) and Annexin V-FITC (Abcam, Shanghai, China) binding buffer was prepared. An Annexin V-FITC Apoptosis Detection kit (cat. no. APOAF-20TST; Sigma-Aldrich; Merck KGaA, Darmstadt, Germany) was used according the manufacturer's protocol. Annexin V-fluorescein isothiocyanate (FITC; 0.5 mg/ml) was added to the cell mixture and incubated at room temperature for 15 min. Subsequently, propidium iodide (PI; 0.1 µg/ml; Abcam) was added for 5 min at room temperature, and samples were analyzed on a fluorescence-activated cell sorting analyzer instrument using the 488 nm excitation wavelength (argon-ion laser or solid state laser) and emission detected was at 530 nm (green, FITC) and 575–610 nm (orange, PI) (28). Data were analyzed with BD FACSuite™ software (23–12943; BD Biosciences, San Jose, CA, USA).

Prediction of the possible targets of miR-129-5p

TargetScan software (www.targetscan.org) was used to predict the possible targets of miR-129-5p.

Dual-luciferase reporter assays

A549 cells were seeded at 1×105 cells/well and serum-starved for 6 h pre-transfection. The 3′-untranslated region (3′-UTR) of HMGB1 and mutated controls were cloned and inserted into a reporter plasmid (500 ng) and the pGL3-control (100 ng) (Promega Corporation, Madison, WI, USA). miR-129-5p mimics were then transfected into A549 cells containing wild-type or mutant 3′-UTR plasmids with Lipofectamine 2000. Cells were harvested and luciferase activity was analyzed after 24 h using the Dual-Luciferase Reporter assay system (Promega Corporation). Luciferase activity was normalized to Renilla luciferase activity. Mutants of HMGB1 3′-UTR were generated using a Site-Directed Mutagenesis kit (Promega Corporation).

Western blotting

A549 cells were frozen and lysed in lysis buffer (150 mM NaCl, 50 mM Tris/HCl, 1% Triton X-100 and 0.1% SDS) with protease inhibitors cocktail (cat. no. ab65621; Abcam). Protein concentration was determined using a BCA protein assay (cat. no. ab146331; Abcam). Subsequently, 20 µg total protein from the cell lysate was loaded onto a 10% SDS-PAGE gel. The protein was then transferred to PVDF membrane and the membrane was blocked with 5% milk for 1 h at room temperature. For the HMGB1 western blot analysis, anti-HMGB1 antibodies (cat. no. ab79823; Abcam) were used at a dilution of 1:1,000 at 4°C overnight. β-actin was used as an internal reference (cat. no. ab179467; 1:1,000; Abcam). The membrane was then incubated with horseradish peroxidase-conjugated anti-rabbit IgG (1:2,000; cat. no. ab150077; Abcam) at room temperature for 2 h. Proteins were detected by Enhanced Chemiluminescence Western Blotting Detection Reagents (GE Healthcare, Little Chalfont, UK). Images were analyzed using ImageJ 1.8.0 software (National Institutes of Health, Bethesda, MD, USA).

Statistical analysis

All experiments were performed three times. Results are presented as the mean ± standard deviation. A two-tailed Student's t-test was used to analyze the mean value between two groups; One-way analysis of variance was used to test the mean value among three or more groups with post hoc contrasts by Student-Newman-Keuls test. P<0.05 was considered to indicate a statistically significant difference. All calculations were performed using SPSS software (version 16.0; SPSS, Inc., Chicago, IL, USA).

Results

miR-129-5p is expressed at low levels in lung cancer tissues

First, the miR-129-5p expression levels in 10 NSCLC tissue samples and their corresponding normal adjacent tissue samples were analyzed using RT-qPCR. Tumor tissue samples exhibited lower miR-129-5p levels compared with their corresponding normal adjacent tissues (Fig. 1A). The mean expression levels of miR-129-5p in all 10 tumor tissue samples and normal tissue samples were determined, and were revealed to be significantly lower in tumor tissue samples compared with in normal tissue samples (Fig. 1B). These results suggest that miR-129-5p may exhibit a tumor suppressor function in NSCLC.

Overexpression of miR-129-5p inhibits cell proliferation and promotes cell apoptosis

To investigate the function of miR-129-5p in vitro, the levels of miR-129-5p in A549 and SPC-A-1 cells were analyzed using RT-qPCR, normal lung tissues were used as control. A549 and SPC-A-1 cells expressed significantly lower levels of miR-129-5p compared with normal tissues (Fig. 2A). Additionally, miR-129-5p mimic was transfected into A549 and SPC-A-1 cells, and it was identified that the miR-129-5p mimic effectively upregulated the miR-129-5p levels in A549 and SPC-A-1 cells (Fig. 2B). As the miR-129-5p mimic was able to increase the miR-129-5p level in vitro, cell proliferation following transfection with the miR-129-5p mimic was determined, and it was identified that the upregulation of miR-129-5p inhibited cell proliferation in A549 and SPC-A-1 cells (Fig. 2C). The effect of the miR-129-5p mimic on cell apoptosis was investigated and transfection of the miR-129-5p mimic was identified to increase the rate of apoptosis (Fig. 2D).

Downregulation of miR-129-5p promotes cell proliferation

miR-129-5p ASO was transfected into A549 and SPC-A-1 cells to decrease the miR-129-5p levels. The miR-129-5p levels in A549 and SPC-A-1 cells 24 h after miR-129-5p ASO transfection revealed that miR-129-5p were significantly inhibited by miR-129-5p ASO (Fig. 3A). Additionally, cell proliferation was determined using the MTT assay and it was identified that miR-129-5p ASO transfection significantly increased cell proliferation (Fig. 3B).

miR-129-5p inhibits HMGB1 expression in lung cancer cells

HMGB1 is an important immune factor and one of the genes targeted by miR-129-5p (1,68). The present study identified the binding site of miR-129-5p on the HMGB1 gene using TargetScan software (Fig. 4A). To confirm whether miR-129-5p targeted HMGB1, a mutant of the 3′-UTR of HMGB1 was generated and the mutant and wild-type versions were cloned into luciferase reporter plasmids. The miR-129-5p mimic and mutant version were co-transfected into A549 cells. At 24 h later, it was identified that the miR-129-5p mimic decreased the luciferase values of the 3′UTR of HMGB1 (wild-type version), but not that of the mutated version of the 3′UTR of HMGB1 (Fig. 4B). Furthermore, the miR-129-5p mimic was transfected into A549 cells and, 48 h later, the HMGB1 protein levels were evaluated using western blot analysis. The results identified that the miR-129-5p mimic inhibited HMGB1 protein expression (Fig. 4C).

Discussion

The present study investigated the function of miR-129-5p in NSCLC and identified that miR-129-5p exhibited tumor suppressor activity against NSCLC via HMGB1. The function of miR-129-5p has previously been investigated in various types of cancer. In gastric cancer, miR-129-5p was identified to be downregulated and involved in the migration and invasion of gastric cancer cells by targeting interleukin-8 (31). In laryngeal cancer, the upregulation of miR-129-5p inhibited laryngeal cancer cell proliferation, invasiveness and migration by affecting signal transducer and activator of transcription 3 expression (32), and in breast cancer, miR-129-5p attenuates irradiation-induced autophagy and decreases radioresistance of breast cancer cells by targeting HMGB1 (33). The results also indicated that miR-129-5p serves a function as an inhibitor of tumor growth.

HMGB1 may activate and induce the maturation of DCs (34). Accordingly, HMGB1 is one of the links between tumor cells and the immune system of the host (35). Recent studies have identified that, in NSCLC, DCs are in contact with tumor cells (36), and tumor-infiltrating lymphocytes (TILs) are observed in the peritumoral zones (37). HMGB1 produced by tumor cells recruits DCs, which associate with an increased number of TILs (38). Furthermore, HMGB1 may be released from dying cells and stimulate DCs (5). DCs required signaling through TLR4 and its adaptor MyD88 for the efficient processing and cross-presentation of antigens from dying tumor cells (5). We hypothesize that HMGB1 may serve an important function in the immune response against tumors and therefore represents a potential immune therapy target in cancer. Accordingly, miR-129-5p may serve a function in the NSCLC immune therapy via HMGB1.

A limitation of the present study was that only ten NSCLC tissue samples were analyzed. The number of patients involved in the study limited the patient survival analysis. Therefore, a larger number of patients should be included in further investigations.

In conclusion, the results of the present study revealed the suppressive function of miR-129-5p in NSCLC and offer a novel therapeutic target for the treatment of NSCLC that is worthy of further investigation.

Acknowledgements

The authors wish to thank Dr Tao Huang (Department of Cancer, West China Hospital, Chengdu, China) for discussion

Funding

No funding was received.

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Authors' contributions

GL collected patient data and performed the cell experiments. JX performed reverse transcription-quantitative polymerase chain reaction analysis, western blotting and other molecular experiments. JW contributed to the study design and manuscript writing.

Ethics approval and consent to participate

The protocol for the collection and use of human tissues in the present study was evaluated and approved by the Ethics Committee of Sichuan Cancer Hospital. All patients enrolled in the present study provided written informed consent, and all specimens were handled and blinded as required by the legal standards of China.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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APA
Li, G., Xie, J., & Wang, J. (2019). Tumor suppressor function of miR‑129‑5p in lung cancer. Oncology Letters, 17, 5777-5783. https://doi.org/10.3892/ol.2019.10241
MLA
Li, G., Xie, J., Wang, J."Tumor suppressor function of miR‑129‑5p in lung cancer". Oncology Letters 17.6 (2019): 5777-5783.
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Li, G., Xie, J., Wang, J."Tumor suppressor function of miR‑129‑5p in lung cancer". Oncology Letters 17, no. 6 (2019): 5777-5783. https://doi.org/10.3892/ol.2019.10241