Cellular Physiology and Biochemistry

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Propofol Inhibits Proliferation, Migration, Invasion and Promotes Apoptosis Through Down-Regulating miR-374a in Hepatocarcinoma Cell Lines

Liu S.-Q.a · Zhang J.-L.a · Li Z.-W.a · Hu Z.-H.a · Liu Z.a · Li Y.b

Author affiliations

aDepartment of Anesthesiology, Henan Provincial People’s Hospital, Zhengzhou University, Zhengzhou, China
bDepartment of Clinical Laboratory, Henan Provincial People’s Hospital, Zhengzhou University, Zhengzhou, China

Corresponding Author

Yi Li

Dept. of Clin. Lab., Henan Provincial People’s Hospital, Zhengzhou University No. 7,

Weiwu Road, Zhengzhou, Henan 450003 (China)

E-Mail yilili1220@sina.com

Key Words: Hepatocellular carcinomaPropofolmiR-374aWnt/β-cateninPI3K/AKT

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Cell Physiol Biochem 2018;49:2099–2110
https://doi.org/10.1159/000493814

Abstract

Background: Propofol is a commonly used anaesthetic with controversial effects on cancer cells. We aimed to explore the functional roles of propofol in hepatocellular carcinoma (HCC) cells as well as the underlying mechanisms. Methods: HepG2 and SMMC-7721 cells were used in this study. Firstly, the effects of propofol on cell viability, migration, invasion, apoptosis, and involved proteins were assessed by Cell Counting Kit-8 assay, Transwell assay, flow cytometry assay and Western blot analysis, respectively. Subsequently, alteration of miR-374a after stimulation of propofol was analyzed by qRT-PCR. miR-374a was overexpressed and the alteration of proteins in the Wnt/β-catenin and PI3K/AKT pathways was detected by Western blot analysis. The downstream factor of miR-374a was finally studied. Results: Propofol inhibited cell viability, migration and invasion but promoted apoptosis of HepG2 and SMMC-7721 cells. Meanwhile, cyclinD1, matrix metalloproteinase (MMP)-2 and MMP-9 were down-regulated while Bax/Bcl-2, cleaved caspase-3 and cleaved caspase-9 were up-regulated by propofol. Then, miR-374a level was reduced by propofol. Expression of Wnt3a, β-catenin, p-PI3K and p-AKT was decreased by propofol, whereas these decreases were reversed by miR-374a overexpression. Finally, TP53 was proven to be target of miR-374a in HepG2 cells. Conclusion: Propofol inhibited cell proliferation, migration and invasion while promoted cell apoptosis of HepG2 and SMMC-7721 cells through inhibiting the Wnt/β-catenin and PI3K/ AKT pathways via down-regulation of miR-374a. Besides, miR-374a affected propofol-treated HepG2 cells by targeting TP53.

© 2018 The Author(s). Published by S. Karger AG, Basel

Introduction

Liver cancer, a fatal malignant tumor that is most commonly relative to virus infection, is the second leading cause of cancer-related death worldwide which leads to 745 thousand deaths annually all over the world [1, 2]. Hepatocellular carcinoma (HCC) resulting in high morbidity and mortality is categorized into primary liver cancer and accounts for 90% of all cases with primary liver cancer [3]. On account of the high prevalence of hepatitis B virus-induced hepatitis, HCC in China accounts for > 50% of world’s burden [4, 5]. Modern therapeutic strategies such as surgery, chemotherapy, radiotherapy and biotherapy have been applied for the treatments of HCC, however, the outcome remains unsatisfactory [6]. The poor prognosis and high prevalence make the exploration of effective treatments for HCC become a hotspot.

Propofol (2, 6-diisopropylphenol) is an intravenous anesthetic that is commonly used for short-term sedation [7]. Numerous literatures have reported the immunomodulatory action of propofol, especially for anti-inflammatory property [8, 9]. In addition, mounting evidence has stated propofol exerts neuroprotection against focal cerebral ischemia in animal models [10, 11]. Recently, the functional roles of propofol in diverse cancer types are identified to be controversial. Cell proliferation and invasion of gastric cancer cells are suppressed by propofol [12]. Conversely, cell proliferation and migration of breast cancer cells are promoted by propofol via down-regulation of p53 and activation of Nrf2 pathway [13]. Thus, precise investigation with respect to explore the role of propofol in a specific cancer is of great importance.

MicroRNAs (miRNAs/miRs) are small, non-coding RNAs that post-transcriptionally participate in regulation of gene expression [14]. Numerous miRNAs are reported to be non-physiologically expressed in HCC, acting as oncogenic or antitumor factor [15, 16]. A previous literature has reported that propofol could inhibit osteosarcoma cell proliferation and invasion by modulating miR-143 expression [17]. Another study also illustrated that cell viability and apoptosis of lung cancer cells were repressed by propofol through up-regulating miR-486 [18]. Therefore, the effects of propofol on physiological activity of cells may be related to its modulation on miRNAs. In our study, the functional roles of propofol in cell proliferation, migration, invasion and apoptosis of HCC cells including HepG2 and SMMC-7721 cells, as well as the potentially associated miRNAs, were thoroughly studied. Moreover, the involved signaling pathways were also explored.

Materials and Methods

Cell culture and treatments

Human HCC cell lines HepG2 and SMMC-7721 were obtained from the Cell Bank of the Chinese Academy of Sciences (Shanghai, China). Cells were maintained in Dulbecco’s modified Eagle’s medium (DMEM; Gibco, Waltham, MA, USA) containing 10% fetal bovine serum (FBS; Invitrogen, Carlsbad, CA, USA) in a humidified incubator at 37°C with a gas mixture of 5% CO2 and 95% air. When monolayer cultures reached confluency, cells were subcultured using the Trypsin (0.05%; Gibco). For stimulation of propofol, cells were incubated in culture medium containing diverse doses of propofol (0-20 μg/mL; Sigma, St. Louis, MO, USA) for 48 h [19-21].

Cell Counting Kit-8 (CCK-8) assay

Cell viability was tested by using a CCK-8 purchased from Dojindo Molecular Technologies (Gaithersburg, MD, USA). In brief, cells (1 × 103 cells/well) were seeded into 96-well plates and maintained at 37°C for 48 h. Then, 10 μL of CCK-8 solution was added into each well, and cells were cultured for additional 1 h at 37°C. Absorbance at 450 nm was read by using a Microplate Reader (Bio-Rad, Hercules, CA, USA).

Migration and invasion assay

Cell migration and invasion were measured by Transwell migration/invasion assay, which was performed by using cell culture inserts carrying a membrane with 8 μm pores in 24-well plates (BD Biosciences, San Jose, CA, USA). Briefly, 5.0 × 104 cells in 200 μL low serum DMEM medium (0.1% FBS) were plated into the upper compartment, whereas 600 μL DMEM supplemented with 10% FBS was added to the lower compartment. For Transwell migration assay, cells were incubated at 37°C for 20 h. For Transwell invasion assay, the inserts were pre-coated with Matrigel (30 μg/insert; BD Biosciences) and the invasive procedure was lasted for 24 h at 37°C. Then, cells on the upper surface of the filter were removed by a cotton swab carefully. Migratory/invasive cells on the lower side of the filter were stained with 0.1% crystal violet, and then cells in five randomly chosen fields were counted under a microscope (Olympus Optical, Tokyo, Japan).

Apoptosis assay

Cell apoptosis was determined by staining with fluorescein isothiocynate (FITC)-conjugated Annexin V and propidium iodide (PI). Briefly, cells were trypsinized, washed with phosphate buffered saline (PBS), and resuspened in binding buffer. After being labeled by Annexin V-FITC and PI from the FITC Annexin V/Dead Cell Apoptosis Kit (Thermo Scientific, Waltham, MA, USA) following the recommendation of manufacturer. Labeled cells were analyzed using a flow cytometry (FACSCalibur, BD Biosciences) with FlowJo software (Tree Star, San Carlos, CA, USA).

Construction of recombined plasmids and cell transfection

Scramble miRNAs and miR-374a mimic were synthesized by GenePharma Co. (Shanghai, China). Full-length TP53 sequences were amplified and ligated into pcDNA3.1 plasmid (Invitrogen, Carlsbad, CA, USA), and the recombined plasmid was referred to as pc-TP53. miRNAs, pcDNA3.1 or pc-TP53 were transfected into cells with the help of the Lipofectamine 3000 reagent (Invitrogen) according to the manufacturer’s protocol.

Luciferase reporter assay

Wide-type (WT) TP53 3’ untranslated region (3’UTR) containing the putative miR-374a binding site or a mutant sequence was inserted into the downstream of the firefly luciferase gene in the pmirGLO Dual-Luciferase miRNA Target Expression Vector (Promega Corporation, Fitchburg, WI, USA). The reconstructed plasmids were designated as TP53-WT and TP53-MUT. HEK-293T cells co-transfected with miR-374a mimic (scramble miRNA) and TP53-WT (TP53-MUT) were collected at 48 h post-transfection, and luciferase activity was analyzed using the Dual-Luciferase Reporter Assay System (Promega Corporation). Luciferase activity values were normalized to that of the Renilla luciferase internal control.

Quantitative reverse transcription PCR (qRT-PCR)

As recommendation of supplier, total RNA of cells was extracted using Trizol reagent (Invitrogen). Then, 500 ng of RNA was reverse transcribed into cDNA by using the Taqman MicroRNA Reverse Transcription Kit (Applied Biosystems, Foster City, CA, USA). The reaction condition was 16°C for 30 min, 42°C for 30 min followed by 85°C for 5 min. The following real-time PCR was performed with 50 ng cDNA as template using a Taqman Universal Master Mix II (Applied Biosystems) to analyze the expression of miR-374a. The thermal cycling parameters were 50°C for 2 min, 95°C for 10 min, and 40 cycles of 95°C for 15 s and 60°C for 1 min. The Power SYBR® Green RNA-to-CTTM 1-Step Kit (Applied Biosystems) was used for determination of TP53 mRNA levels, according to the manufacturer’s instructions. The relative expression was calculated according to the 2-ΔΔCt method [22]. U6 and GAPDH were acted as the internal controls for miR-374a and TP53 mRNA, respectively.

Western blot analysis

Proteins were extracted in RIPA lysis buffer (Beyotime, Shanghai, China) with the presence of protease inhibitors (Applygen Technologies Inc., Beijing, China). After quantification with the BCATM Protein Assay Kit (Pierce, Appleton, WI, USA), proteins (30 μg/lane) were loaded and separated by SDS-PAGE. Then, proteins in the gels were transferred into polyvinylidene difluoride (PVDF) membranes, followed by blockage with 5% non-fat milk. Membranes were incubated with each antibody against cyclinD1 (ab134175), matrix metalloproteinase (MMP)-2 (ab97779), MMP-9 (ab73734), mammalian B cell lymphoma-2 (Bcl-2; ab194583), Bcl-2-associated X protein (Bax; ab32503), cleaved caspase-3 (ab2302), cleaved caspase-9 (ab2324), Wnt3a (ab81614), β-catenin (ab6302), phosphatidylinositol-3-kinase (PI3K; ab135952), phospho-PI3K (p-PI3K; ab182651), TP53 (ab131442), β-actin (ab8227) (all Abcam, Cambridge, UK), AKT (#9272) or phospho-AKT (p-AKT; #9271) (both Cell Signaling Technology, Beverly, MA, USA) at 4°C overnight. After rinsing, membranes were incubated with secondary antibodies marked by horseradish peroxidase (ab97051 and ab205719, Abcam) for 1 h at room temperature. After rinsing again, proteins in the membranes were visualized by chemiluminescence (ECL) system (Amersham Biosciences, Piscataway, New Jersey, USA).

Statistical analysis

All experiments were repeated three times. The results were presented as the mean ± SD. Statistical analysis was performed using Graphpad Prism 5 software (GraphPad, San Diego, CA, USA). The P-values were calculated using the one-way analysis of variance (ANOVA) or Student’s t-test. A P < 0.05 was considered as a significant difference.

Results

Propofol inhibits cell proliferation of HepG2 and SMMC-7721 cells

The effects of propofol on cell viability were measured by CCK-8 assay in both HepG2 and SMMC-7721 cells. When compared to the 0 μg/mL group (control), cell viability was significantly reduced by propofol at 5 μg/mL (P < 0.05), 10 μg/mL (P < 0.01) and 20 μg/mL (P < 0.001; Fig. 1A) doses. However, the effects of 1 μg/mL propofol on cell viability were non-significant compared to the control. Considering the cell viability was reduced to almost 50% when cells were incubated with 10 μg/mL propofol, the concentration of propofol in subsequent experiments was 10 μg/mL. Meanwhile, the protein expression of cyclinD1 was obviously down-regulated as the increasing of the propofol concentration (Fig. 1B). As the first protein synthesized in the G1 phase, cyclinD1 acts a crucial role in cell cycle progression from G0/G1 phase to S phase [23]. Therefore, the down-regulation of cyclinD1 induced by propofol indicated an anti-proliferative role. Results indicated that cell proliferation was reduced by propofol in HepG2 and SMMC-7721 cells.

Fig. 1.

Propofol inhibits cell viability of HepG2 and SMMC-7721 cells. Cells were stimulated with propofol under diverse concentrations (0, 1, 5, 10, 20 μg/mL) at 37°C for 48 h. Cells under 0 μg/mL propofol were acted as the control. A. Cell viability by a Cell Counting Kit-8 assay. B. Expression of cyclinD1 by Western blot analysis. Data are presented as the mean ± SD of at least three independent experiments. *, P< 0.05; **, P< 0.01; ***, P< 0.001.

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Propofol suppresses cell migration and invasion of HepG2 and SMMC-7721 cells

Then, the influences of propofol on migration and invasion of HepG2 and SMMC-7721 cells were tested by the Transwell assays. As compared to the control group, migration (Fig. 2A) and invasion (Fig. 2B) of HepG2 and SMMC-7721 cells were markedly decreased by propofol (all P < 0.05). Extracellular matrix (ECM) comprises complex components, including fibronectin and laminin, which are essential for the attachment of cells to the structural skeleton [24]. MMPs are the most extensive ECM degrading enzymes that can degrade all important components of ECM [25]. Due to the specificity for degradation of the basement membrane, MMP-2 and MMP-9 are two most essential MMPs and had been reported to be correlated with cell migration and invasion of HCC cells [26]. Further Western blot analysis showed the protein expression of MMP-2 and MMP-9 was observably down-regulated after stimulation of propofol (Fig. 2C). Results described above illustrated that migration and invasion of HepG2 and SMMC-7721 cells were reduced by propofol.

Fig. 2.

Propofol suppresses cell migration and invasion of HepG2 and SMMC-7721 cells. Cells were stimulated with 10 μg/mL propofol at 37°C for 48 h. Non-treated cells were acted as the control. A. Cell migration by Transwell migration assay. B. Cell invasion by Transwell invasion assay. C. Expression of MMP-2 and MMP-9 by Western blot analysis. Data are presented as the mean ± SD of at least three independent experiments. *, P< 0.05. MMP, matrix metalloproteinase.

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Propofol promotes cell apoptosis of HepG2 and SMMC-7721 cells

Next, the impacts of propofol on apoptosis of HepG2 and SMMC-7721 cells were tested by flow cytometry assay. In Fig. 3A, percentage of apoptotic cells was significantly elevated by treatment with propofol, as compared with the control group (both P < 0.01). Cell apoptosis is regulated by the Bcl-2 family and caspase family proteins [27, 28]. In brief, elevated ratio of Bax/Bcl-2 induces mitochondrial outer membrane permeabilization (MOMP) and release of pro-apoptotic proteins [29]. Then, caspase-9 and caspase-3 are cleaved in turns, resulting in the hallmarks of the cell apoptosis [27]. The following results of Western blot analysis showed that Bcl-2 level was decreased whereas levels of Bax, cleaved caspase-3 and cleaved caspase-9 were increased by propofol (Fig. 3B). Results described above stated that cell apoptosis of HepG2 and SMMC-7721 cells were promoted by propofol.

Fig. 3.

Propofol promotes cell apoptosis of HepG2 and SMMC-7721 cells. Cells were stimulated with 10 μg/ mL propofol at 37°C for 48 h. Non-treated cells were acted as the control. A. Percentage of apoptotic cells by flow cytometry assay. B. Expression of apoptosis-associated proteins by Western blot analysis. Data are presented as the mean ± SD of at least three independent experiments. **, P< 0.01. Bcl-2, mammalian B cell lymphoma-2; Bax, Bcl-2-associated X protein.

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miR-374a is down-regulated by propofol in HepG2 and SMMC-7721 cells

To explore whether miR-374a was involved in the modulation of propofol, the expression of miR-374a was determined by qRT-PCR. As compared to the 0 μg/mL group (control), miR-374a levels in the 5 μg/mL groups (both P < 0.05) and 10 μg/mL groups (P < 0.05 or P < 0.01) were significantly lower than the control group in HepG2 (Fig. 4A) and SMMC-7721 (Fig. 4B) cells. However, the alteration of miR-374a level after treatments with 1 μg/mL propofol was non-significant. Those data illustrated that propofol down-regulated miR-374a expression in HepG2 and SMMC-7721 cells.

Fig. 4.

MicroRNA (miR)-374a is down-regulated by propofol in HepG2 and SMMC-7721 cells. Cells were stimulated with propofol under diverse concentrations (0, 1, 5, 10 μg/mL) at 37°C for 48 h. Cells under 0 μg/ mL propofol were acted as the control. Expression of miR-374a in HepG2 (A) and SMMC-7721 (B) cells was measured by quantitative reverse transcription PCR. Data are presented as the mean ± SD of at least three independent experiments. *, P< 0.05; **, P< 0.01.

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Propofol inhibits the Wnt/β-catenin and PI3K/AKT pathways through down-regulating miR-374a

The possible regulatory mechanisms of propofol in HepG2 and SMMC-7721 cells were investigated. After cell transfection, expression of miR-374a was remarkably up-regulated by transfection with miR-374a mimic compared with the scramble group (both P < 0.01), which indicated that miR-374a was successfully overexpressed by transfection with miR-374a mimic (Fig. 5A). Then, expression of key kinases in the Wnt/β-catenin and PI3K/AKT pathways was assessed. In Fig. 5B, expression of Wnt3a and β-catenin was down-regulated by propofol, whereas the down-regulation was reversed by overexpression of miR-374a. Likewise, phosphorylation of PI3K and AKT was reduced by propofol while the reduction could be reversed by overexpression of miR-374a (Fig. 5C). Taken together, these results indicated that propofol inhibited the Wnt/β-catenin and PI3K/AKT pathways through down-regulating miR-374a in HepG2 and SMMC-7721 cells.

Fig. 5.

Propofol inhibits the Wnt/β-catenin and PI3K/AKT pathways through down-regulating microRNA (miR)-374a. Cells were transfected with scramble miRNAs and miR-374a mimic, respectively. Non-treated cells were acted as the control. A. Expression of miR-374a by quantitative reverse transcription PCR. Cells transfected with scramble miRNAs or miR-374a and non-transfected cells were stimulated with 10 μg/ mL propofol at 37°C for 48 h. Non-treated cells were acted as the control. Expression of key kinases in the Wnt/β-catenin (B) and PI3K/AKT pathways (C) was assessed by Western blot analysis. Data are presented as the mean ± SD of at least three independent experiments. **, P< 0.01. PI3K, phosphatidylinositol-3-kinase; p-, phospho.

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TP53 might be a downstream factor of miR-374a in propofol-treated cells

Finally, the possible downstream facotr of miR-374a in HepG2 and SMMC-7721 cells was studied to elucidate the regulatory mechanism of propofol. By using the online TargetScan software, TP53 was predicated to be a target of miR-374a and the complementary sequences were shown in the Fig. 6A. Luciferase reporter assay showed that transfection with miR-374a mimic could significantly reduce luciferase activity in TP53-WT-transfected cells (P < 0.05), while it could not alter luciferase activity in TP53-MUT-transfected cells. In the meantime, mRNA and protein expression levels of TP53 were markedly down-regulated by miR-374a overexpression (P < 0.01, Fig. 6B). Results suggested that TP53 might be a target gene of miR-374a. In Fig. 6C, mRNA and protein expression of TP53 was remarkably up-regulated in cells transfected with pc-TP53 compared with pc-DNA3.1-transfected cells (P < 0.001), indicating TP53 was overexpressed successfully after transfection with pc-TP53. Following results illustrated that effects of miR-374a overexpression on HepG2 cells were reversed by TP53 overexpression, showing significant reduction of cell viability (P < 0.01, Fig. 6D), down-regulation of cyclinD1 (Fig. 6E), decrease of migration and invasion (both P < 0.01, Fig. 6F-6G), down-regulation of MMP-2 and MMP-9 (Fig. 6H), increase of apoptotic cells (P < 0.01, Fig. 6I), and down-regulation of Bcl-2 as well as up-regulation of Bax, cleaved caspase-3 and cleaved caspase-9 (Fig. 6J). Results illustrated that miR-374a could affect propofol-treated cells through down-regulating TP53.

Fig. 6.

TP53 is a target gene of miR-374a. HEK-293T cells were co-transfected with TP53-WT (TP53-MUT) and miR-374a mimic (scramble miRNA). A. Complementary sequences between miR-374a and TP53 3’UTR and luciferase activity by luciferase reporter assay. HepG2 cells were transfected with scramble miRNAs or miR-374a mimic, and non-treated cells were acted as the control. B. Expression of TP53 by quantitative reverse transcription PCR and Western blot analysis. HepG2 cells were transfected with pcDNA3.1 or pcDNA3.1. C. Expression of TP53 by quantitative reverse transcription PCR and Western blot analysis. Transfected or untransfected HepG2 cells were treated with 10 μg/mL propofol at 37°C for 48 h. Non-treated cells were acted as control. D. Cell viability by a Cell Counting Kit-8 assay. E. Expression of cyclinD1 by Western blot analysis. F. Cell migration by Transwell migration assay. G. Cell invasion by Transwell invasion assay. H. Expression of MMP-2 and MMP-9 by Western blot analysis. I. Percentage of apoptotic cells by flow cytometry assay. J. Expression of apoptosis-associated proteins by Western blot analysis. Data are presented as the mean ± SD of at least three independent experiments. *, P< 0.05; **, P< 0.01; ***, P< 0.001. miR/miRNA, microRNA; 3’UTR, 3’ untranslated region; MMP, matrix metalloproteinase; Bcl-2, mammalian B cell lymphoma-2; Bax, Bcl-2-associated X protein.

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Discussion

HCC is a lethal cancer with increasing incidence and poor prognosis. Innovative and effective drugs are of great importance for the treatments of HCC. In our study, we focused on the effects of propofol, a commonly used anaesthetic, on HCC cells. Interestingly, propofol acted as an anti-tumor factor in both HepG2 and SMMC-7721 cells, showing decreased cell proliferation, migration and invasion while increased cell apoptosis. The level of miR-374a was down-regulated by propofol, and further experiments illustrated that propofol inhibited the Wnt/β-catenin and PI3K/AKT pathways through down-regulating miR-374a. Besides, TP53 was proven to be target of miR-374a, and miR-374a could affect propofol-treated cells through down-regulating TP53.

Overwhelming numbers of studies focused on the significant effects of propofol on tumor cells. In lung cancer cells, propofol exerts inhibitory effects on cell viability and inductive effects on cell apoptosis [18]. In C6 glioma cells, propofol inhibits invasion and proliferation [30]. In esophageal squamous cell carcinoma cells, propofol inhibits cell migration and invasion through down-regulating Sex-determining region Y-box 4 (SOX4) [31]. Consistent with the results described above, in our study, propofol suppressed cell viability, migration and invasion but promoted cell apoptosis in both HepG2 and SMMC-7721 cells.

To support the influence of propofol on HepG2 and SMMC-7721 cells, the alteration of proteins associated with proliferation, migration, invasion and apoptosis after propofol stimulation was also assessed. As an important protein in proliferation, down-regulation of cyclinD1 induced by DYC-279 is accompanied by inhibited proliferation of HepG2 cells [32]. Melittin exerts an anti-proliferative role in HepG2 cells through PTEN-induced down-regulation of histone deacetylase 2 (HDAC2) and cyclinD1 [33]. Therefore, down-regulation of cyclinD1 also indicated an anti-proliferative role of propofol. Expression of MMP-2 and MMP-9 was down-regulated by propofol in esophageal squamous cell carcinoma cells, along with inhibited migration and invasion [31]. Invasion of glioma cells was inhibited by propofol, along with down-regulation of MMP-2 [34]. Herein, significant down-regulation of MMP-2 and MMP-9 was observed in propofol-treated cells, supporting an anti-migratory and anti-invasive role of propofol. A previous study has reported that Bcl-2 level was decreased while levels of Bax and cleaved casapse-3 were increased in response to propofol, which was consistent with the results of apoptosis [35]. Herein, the alteration of proteins related to apoptosis after propofol treatments was consistent with the previous literature, supporting the pro-apoptotic role of propofol.

miR-374a has been reported as an oncogene in diverse tumor types, including HCC [36, 37]. In the literature by He et al., miR-374a could promote osteosarcoma cell proliferation through down-regulating FOXO1 expression [38]. Meanwhile, propofol has been reported to up-regulate FOXO1 expression in a dose-dependent manner [39]. Hence, we hypothesized there might be potential correlation between miR-374a and propofol. In our study, the expression of miR-374a was significantly down-regulated by propofol, verifying the hypothesis described above.

Activation of the Wnt/β-catentin and PI3K/AKT pathways is frequently observed in HCC [40, 41]. Moreover, propofol has been reported to inhibit hepatocellular carcinoma growth and invasion through the Wnt/β-catenin pathway [21]. To reveal the underlying mechanisms of the propofol-associated modulation, the alteration of the Wnt/β-catentin and PI3K/AKT pathways was further explored. In our study, these two signaling cascades were inhibited in propofol-treated cells, suggesting these two pathways were involved in the modulation of propofol. Furthermore, the propofol-induced inhibition of the Wnt/β-catentin and PI3K/ AKT pathways was reversed by miR-374a overexpression, illustrating that propofol might inhibit the Wnt/β-catentin and PI3K/AKT pathways through down-regulating miR-374a.

To enrich the regulatory mechanism of propofol, the downstream factor of miR-374a had been explored since miRNAs commonly functioned through repressing expression of target genes [42]. TP53 mutation is one of the common genetic alterations in HCC, suggesting the critical role of TP53 in HCC [43]. Restoration of TP53 has been reported to suppress growth of HCC in vitro and in vivo [44]. Therefore, the interaction between miR-374a and TP53 was further studied among those predicted targets. Results in this study illustrated that up-regulation of TP53 after propofol-induced down-regulation of miR-374a might be a rational regulatory mechanism in propofol-treated cells.

Conclusion

In conclusion, propofol was identified to inhibit cell proliferation, migration and invasion of HepG2 and SMMC-7721 cells. Cell apoptosis of these two cell lines was promoted via the mitochondrial- and caspase-dependent pathways. miR-374a was down-regulated by propofol, and the Wnt/β-catentin and PI3K/AKT pathways were inhibited by propofol via down-regulating miR-374a. Besides, TP53 was proven to be a target of miR-374a. Our study provides an innovatively regulatory mechanism about the propofol in HCC cells and points out a novel direction for the treatment of HCC. More experiments performed in vivo are needed to prove the regulatory mechanism in the future.

Disclosure Statement

The authors declare that no potential conflicts of interest exist.


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  17. Ye Z, Jingzhong L, Yangbo L, Lei C, Jiandong Y: Propofol inhibits proliferation and invasion of osteosarcoma cells by regulation of microRNA-143 expression. Oncol Res 2013; 21: 201-207.
  18. Yang N, Liang Y, Yang P, Yang T, Jiang L: Propofol inhibits lung cancer cell viability and induces cell apoptosis by upregulating microRNA-486 expression. Braz J Med Biol Res 2017; 50:e5794.
  19. Zhang Y, Wang X, Wang Q, Ge H, Tao L: Propofol depresses cisplatin cytotoxicity via the inhibition of gap junctions. Mol Med Rep 2016; 13: 4715-4720.
  20. Zhang J, Zhang D, Wu GQ, Feng ZY, Zhu SM: Propofol inhibits the adhesion of hepatocellular carcinoma cells by upregulating microRNA-199a and downregulating MMP-9 expression. Hepatobiliary Pancreat Dis Int 2013; 12: 305-309.
  21. Ou W, Lv J, Zou X, Yao Y, Wu J, Yang J, Wang Z, Ma Y: Propofol inhibits hepatocellular carcinoma growth and invasion through the HMGA2-mediated Wnt/beta-catenin pathway. Exp Ther Med 2017; 13: 2501-2506.
  22. Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001; 25: 402-408.
  23. Wang X, Guo H, Liu W, Yang C, Yang L, Wang D, Wang X: Effects of siRNA-Mediated Knockdown of HDAC1 on the Biological Behavior of Esophageal Carcinoma Cell Lines. Medical Science Monitor : Int Med J Exp Clin Res 2016; 22: 1291-1296.
  24. Brown GT, Murray GI: Current mechanistic insights into the roles of matrix metalloproteinases in tumour invasion and metastasis. J Pathol 2015; 237: 273-281.
  25. Egeblad M, Werb Z: New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2002; 2: 161-174.
  26. Wang YH, Sui XM, Sui YN, Zhu QW, Yan K, Wang LS, Wang F, Zhou JH: BRD4 induces cell migration and invasion in HCC cells through MMP-2 and MMP-9 activation mediated by the Sonic hedgehog signaling pathway. Oncol Lett 2015; 10: 2227-2232.
  27. Brentnall M, Rodriguez-Menocal L, De Guevara RL, Cepero E, Boise LH: Caspase-9, caspase-3 and caspase-7 have distinct roles during intrinsic apoptosis. BMC Cell Biol 2013; 14: 32.
  28. Aouacheria A, Baghdiguian S, Lamb HM, Huska JD, Pineda FJ, Hardwick JM: Connecting mitochondrial dynamics and life-or-death events via Bcl-2 family proteins. Neurochem Int 2017; 109: 141-161.
  29. Moldoveanu T, Follis AV, Kriwacki RW, Green DR: Many players in BCL-2 family affairs. Trends Biochem Sci 2014; 39: 101-111.
  30. Wang X-y, Li Y-l, Wang H-y, Zhu M, Guo D, Wang G-l, Gao Y-t, Yang Z, Li T, Yang C-y, Chen Y-m: Propofol inhibits invasion and proliferation of C6 glioma cells by regulating the Ca2+ permeable AMPA receptor-system xc– pathway. Toxicol In vitro 2017; 44: 57-65.
  31. Zhou C-l, Li J-j, Ji P: Propofol Suppresses Esophageal Squamous Cell Carcinoma Cell Migration and Invasion by Down-Regulation of Sex-Determining Region Y-box 4 (SOX4). Medical Science Monitor : Int Med J Exp Clin Res 2017; 23: 419-427.
  32. Junyan P, Shujuan Y, Shulin G, Yan C, Xia X: The Antitumor Effect of DYC-279 on Human Hepatocellular Carcinoma HepG2 Cells. Pharmacol. 2016; 97: 177-183.
  33. Zhang H, Zhao B, Huang C, Meng XM, Bian EB, Li J: Melittin restores PTEN expression by down-regulating HDAC2 in human hepatocelluar carcinoma HepG2 cells. PLoS One 2014; 9:e95520.
  34. Xu J, Xu W, Zhu J: Propofol suppresses proliferation and invasion of glioma cells by upregulating microRNA-218 expression. Mol Med Rep 2015; 12: 4815-4820.
  35. Wang H, Zhang S, Zhang A, Yan C: Propofol Prevents the Progression of Malignant Pheochromocytoma In vitro and In vivo. Dna. Cell Biol 2018; 37: 308-315.
  36. Liu F, Yuan JH, Huang JF, Yang F, Wang TT, Ma JZ, Zhang L, Zhou CC, Wang F, Yu J, Zhou WP, Sun SH: Long noncoding RNA FTX inhibits hepatocellular carcinoma proliferation and metastasis by binding MCM2 and miR-374a. Oncogene 2016; 35: 5422-5434.
  37. Li H, Chen H, Wang H, Dong Y, Yin M, Zhang L, Wei J: MicroRNA-374a Promotes Hepatocellular Carcinoma Cell Proliferation by Targeting Mitogen-Inducible Gene-6 (MIG-6). Oncol Res 2017; 10.3727/096504017x1 5000784459799.
  38. He W, Feng L, Xia D, Han N: MiR-374a promotes the proliferation of human osteosarcoma by downregulating FOXO1 expression. Int J Clin Exp Med 2015; 8: 3482-3489.
  39. Zhao D, Li Q, Huang Q, Li X, Yin M, Wang Z, Hong J: Cardioprotective effect of propofol against oxygen glucose deprivation and reperfusion injury in H9c2 cells. Oxid Med Cell Longev 2015; 2015: 184938.
  40. Shen G, Jia H, Tai Q, Li Y, Chen D: miR-106b downregulates adenomatous polyposis coli and promotes cell proliferation in human hepatocellular carcinoma. Carcinogenesis 2013; 34: 211-219.
  41. Janku F, Kaseb AO, Tsimberidou AM, Wolff RA, Kurzrock R: Identification of novel therapeutic targets in the PI3K/AKT/mTOR pathway in hepatocellular carcinoma using targeted next generation sequencing. Oncotarget 2014; 5: 3012-3022.
  42. Das S, Kohr M, Dunkerly-Eyring B, Lee DI, Bedja D, Kent OA, Leung AK, Henao-Mejia J, Flavell RA, Steenbergen C: Divergent Effects of miR-181 Family Members on Myocardial Function Through Protective Cytosolic and Detrimental Mitochondrial microRNA Targets. J Am Heart Assoc 2017; 6:e004694.
  43. Goh AM, Coffill CR, Lane DP: The role of mutant p53 in human cancer. J Pathol 2011; 223: 116-126.
  44. He X, Liu F, Yan J, Zhang Y, Yan J, Shang H, Dou Q, Zhao Q, Song Y: Trans-splicing repair of mutant p53 suppresses the growth of hepatocellular carcinoma cells in vitro and in vivo. Sci Rep 2015; 5: 8705.

Author Contacts

Yi Li

Dept. of Clin. Lab., Henan Provincial People’s Hospital, Zhengzhou University No. 7,

Weiwu Road, Zhengzhou, Henan 450003 (China)

E-Mail yilili1220@sina.com

Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: December 21, 2017
Accepted: September 18, 2018
Published online: September 26, 2018
Issue release date: October 2018

Number of Print Pages: 12
Number of Figures: 6
Number of Tables: 0

ISSN: 1015-8987 (Print)
eISSN: 1421-9778 (Online)

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  16. Xie K-L, Zhang Y-G, Liu J, Zeng Y, Wu H: MicroRNAs Associated With HBV Infection And HBV-related HCC. Theranostics 2014; 4: 1176-1192.
  17. Ye Z, Jingzhong L, Yangbo L, Lei C, Jiandong Y: Propofol inhibits proliferation and invasion of osteosarcoma cells by regulation of microRNA-143 expression. Oncol Res 2013; 21: 201-207.
  18. Yang N, Liang Y, Yang P, Yang T, Jiang L: Propofol inhibits lung cancer cell viability and induces cell apoptosis by upregulating microRNA-486 expression. Braz J Med Biol Res 2017; 50:e5794.
  19. Zhang Y, Wang X, Wang Q, Ge H, Tao L: Propofol depresses cisplatin cytotoxicity via the inhibition of gap junctions. Mol Med Rep 2016; 13: 4715-4720.
  20. Zhang J, Zhang D, Wu GQ, Feng ZY, Zhu SM: Propofol inhibits the adhesion of hepatocellular carcinoma cells by upregulating microRNA-199a and downregulating MMP-9 expression. Hepatobiliary Pancreat Dis Int 2013; 12: 305-309.
  21. Ou W, Lv J, Zou X, Yao Y, Wu J, Yang J, Wang Z, Ma Y: Propofol inhibits hepatocellular carcinoma growth and invasion through the HMGA2-mediated Wnt/beta-catenin pathway. Exp Ther Med 2017; 13: 2501-2506.
  22. Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001; 25: 402-408.
  23. Wang X, Guo H, Liu W, Yang C, Yang L, Wang D, Wang X: Effects of siRNA-Mediated Knockdown of HDAC1 on the Biological Behavior of Esophageal Carcinoma Cell Lines. Medical Science Monitor : Int Med J Exp Clin Res 2016; 22: 1291-1296.
  24. Brown GT, Murray GI: Current mechanistic insights into the roles of matrix metalloproteinases in tumour invasion and metastasis. J Pathol 2015; 237: 273-281.
  25. Egeblad M, Werb Z: New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2002; 2: 161-174.
  26. Wang YH, Sui XM, Sui YN, Zhu QW, Yan K, Wang LS, Wang F, Zhou JH: BRD4 induces cell migration and invasion in HCC cells through MMP-2 and MMP-9 activation mediated by the Sonic hedgehog signaling pathway. Oncol Lett 2015; 10: 2227-2232.
  27. Brentnall M, Rodriguez-Menocal L, De Guevara RL, Cepero E, Boise LH: Caspase-9, caspase-3 and caspase-7 have distinct roles during intrinsic apoptosis. BMC Cell Biol 2013; 14: 32.
  28. Aouacheria A, Baghdiguian S, Lamb HM, Huska JD, Pineda FJ, Hardwick JM: Connecting mitochondrial dynamics and life-or-death events via Bcl-2 family proteins. Neurochem Int 2017; 109: 141-161.
  29. Moldoveanu T, Follis AV, Kriwacki RW, Green DR: Many players in BCL-2 family affairs. Trends Biochem Sci 2014; 39: 101-111.
  30. Wang X-y, Li Y-l, Wang H-y, Zhu M, Guo D, Wang G-l, Gao Y-t, Yang Z, Li T, Yang C-y, Chen Y-m: Propofol inhibits invasion and proliferation of C6 glioma cells by regulating the Ca2+ permeable AMPA receptor-system xc– pathway. Toxicol In vitro 2017; 44: 57-65.
  31. Zhou C-l, Li J-j, Ji P: Propofol Suppresses Esophageal Squamous Cell Carcinoma Cell Migration and Invasion by Down-Regulation of Sex-Determining Region Y-box 4 (SOX4). Medical Science Monitor : Int Med J Exp Clin Res 2017; 23: 419-427.
  32. Junyan P, Shujuan Y, Shulin G, Yan C, Xia X: The Antitumor Effect of DYC-279 on Human Hepatocellular Carcinoma HepG2 Cells. Pharmacol. 2016; 97: 177-183.
  33. Zhang H, Zhao B, Huang C, Meng XM, Bian EB, Li J: Melittin restores PTEN expression by down-regulating HDAC2 in human hepatocelluar carcinoma HepG2 cells. PLoS One 2014; 9:e95520.
  34. Xu J, Xu W, Zhu J: Propofol suppresses proliferation and invasion of glioma cells by upregulating microRNA-218 expression. Mol Med Rep 2015; 12: 4815-4820.
  35. Wang H, Zhang S, Zhang A, Yan C: Propofol Prevents the Progression of Malignant Pheochromocytoma In vitro and In vivo. Dna. Cell Biol 2018; 37: 308-315.
  36. Liu F, Yuan JH, Huang JF, Yang F, Wang TT, Ma JZ, Zhang L, Zhou CC, Wang F, Yu J, Zhou WP, Sun SH: Long noncoding RNA FTX inhibits hepatocellular carcinoma proliferation and metastasis by binding MCM2 and miR-374a. Oncogene 2016; 35: 5422-5434.
  37. Li H, Chen H, Wang H, Dong Y, Yin M, Zhang L, Wei J: MicroRNA-374a Promotes Hepatocellular Carcinoma Cell Proliferation by Targeting Mitogen-Inducible Gene-6 (MIG-6). Oncol Res 2017; 10.3727/096504017x1 5000784459799.
  38. He W, Feng L, Xia D, Han N: MiR-374a promotes the proliferation of human osteosarcoma by downregulating FOXO1 expression. Int J Clin Exp Med 2015; 8: 3482-3489.
  39. Zhao D, Li Q, Huang Q, Li X, Yin M, Wang Z, Hong J: Cardioprotective effect of propofol against oxygen glucose deprivation and reperfusion injury in H9c2 cells. Oxid Med Cell Longev 2015; 2015: 184938.
  40. Shen G, Jia H, Tai Q, Li Y, Chen D: miR-106b downregulates adenomatous polyposis coli and promotes cell proliferation in human hepatocellular carcinoma. Carcinogenesis 2013; 34: 211-219.
  41. Janku F, Kaseb AO, Tsimberidou AM, Wolff RA, Kurzrock R: Identification of novel therapeutic targets in the PI3K/AKT/mTOR pathway in hepatocellular carcinoma using targeted next generation sequencing. Oncotarget 2014; 5: 3012-3022.
  42. Das S, Kohr M, Dunkerly-Eyring B, Lee DI, Bedja D, Kent OA, Leung AK, Henao-Mejia J, Flavell RA, Steenbergen C: Divergent Effects of miR-181 Family Members on Myocardial Function Through Protective Cytosolic and Detrimental Mitochondrial microRNA Targets. J Am Heart Assoc 2017; 6:e004694.
  43. Goh AM, Coffill CR, Lane DP: The role of mutant p53 in human cancer. J Pathol 2011; 223: 116-126.
  44. He X, Liu F, Yan J, Zhang Y, Yan J, Shang H, Dou Q, Zhao Q, Song Y: Trans-splicing repair of mutant p53 suppresses the growth of hepatocellular carcinoma cells in vitro and in vivo. Sci Rep 2015; 5: 8705.
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2018, Vol.49, No. 6

October 2018

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31 August 2021. The article has been retracted. The retraction statement can be viewed at the link above.
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