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ORIGINAL ARTICLE
Year : 2017  |  Volume : 13  |  Issue : 2  |  Page : 246-251

In vitro activity of probiotic Lactobacillus reuteri against gastric cancer progression by downregulation of urokinase plasminogen activator/urokinase plasminogen activator receptor gene expression


1 Department of Medical Biotechnology, School of Allied Medicine, Iran University of Medical Sciences; Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
2 Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran

Date of Web Publication23-Jun-2017

Correspondence Address:
Reza Nekouian
Department of Medical Biotechnology, School of Allied Medicine, Iran University of Medical Sciences, Tehran
Iran
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.204897

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 > Abstract 

Background: Gastric cancer (GC) is the third leading cause of cancer death, and most patients represent metastatic phenotype at the time of diagnosis. Urokinase plasminogen activator (uPA) system is well known for its critical roles in cancer cells invasion since uPA/uPA receptor (uPAR) overexpresses in several cancers. Subsequently, suppression of uPA/uPAR gene expression improves patients overall survival and prevents cancer progression.
Objectives: The aim of the current study was to investigate possible effects of live Lactobacillus reuteri as a probiotic in inhibition of GC cells proliferation and invasion.
Materials and Methods: Human gastric adenocarcinoma epithelial cell line (AGS) cells were treated with different ratios of live L. reuteri and were incubated for 24, 48, and 72 h. Viability of cancer cells was measured with 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide assay, and the effects of L. reuteri on uPA/uPAR gene expression were assessed by real-time polymerase chain reaction.
Results: Our results showed that L. reuteri inhibits cell proliferation significantly in dose-dependent manner. Expressions of uPA and uPAR were downregulated followed by co-incubation of AGS cells and live L. reuteri compared to untreated-based line level.
Conclusion: This study provides strong support in the role of L. reuteri in suppression of GC cell invasion by downregulation of pathways which is involved in extracellular matrix degradation such as uPA and uPAR.

Keywords: Gastric cancer, Lactobacillus reuteri, urokinase plasminogen activator, urokinase plasminogen activator receptor


How to cite this article:
Rasouli BS, Ghadimi-Darsajini A, Nekouian R, Iragian GR. In vitro activity of probiotic Lactobacillus reuteri against gastric cancer progression by downregulation of urokinase plasminogen activator/urokinase plasminogen activator receptor gene expression. J Can Res Ther 2017;13:246-51

How to cite this URL:
Rasouli BS, Ghadimi-Darsajini A, Nekouian R, Iragian GR. In vitro activity of probiotic Lactobacillus reuteri against gastric cancer progression by downregulation of urokinase plasminogen activator/urokinase plasminogen activator receptor gene expression. J Can Res Ther [serial online] 2017 [cited 2022 Dec 3];13:246-51. Available from: https://www.cancerjournal.net/text.asp?2017/13/2/246/204897


 > Introduction Top


Statistics have shown that gastric cancer (GC) is the third leading cause of cancer death worldwide.[1] Although GC incidence rate declined in recent last years,[2],[3] the 5-year survival rate of this neoplasm is <25% with regional variations.[4],[5] It is noteworthy that most GC patients are diagnosed in advanced stages and its concomitant of local invasion and metastasis.[6] Based on molecular interactions, the key element for cancer invasion and metastasis is alteration in extracellular matrix (ECM) and basement membranes, which was accomplished by coordinated operation of proteolytic enzymes including serine proteinase and metalloproteinase, their receptors and inhibitors.[7],[8]

Urokinase plasminogen activator (uPA) system belongs to serine proteinase family which have been known for its critical role in cancer progression as well as other physiological processes such as wound healing, tissue remodeling, and angiogenesis.[9],[10] uPA, uPA receptor (uPAR), plasminogen activator inhibitor-1 and -2 constitute uPA system, convert plasminogen to its active form, plasmin.[11] Moreover, activation of uPA system mediated matrix metalloproteinase (MMP) proteolytic activity, and also trigger the cascade of ECM destruction.[10] According to recent investigations, unrestrained expressions of uPA and uPAR have been demonstrated in cancers including breast, colon, gastric, prostate, and lung, which are mostly associated with metastatic behavior.[12],[13] However, there is an accumulating body of evidence which shows that uPA and uPAR expressions were induced by Helicobacter pylori infection as a Class I carcinogen in GC.[7] As a result, reduction of uPA and uPAR expression not only exhibit promising result in inhibition of ECM degradation, and disruption of cancer cell invasion afterward, but also could abrogate angiogenesis and cell proliferation due to its pivotal contribution in intracellular signaling pathways.[8],[14],[15]

It was shown that probiotics named Lactobacillus and Bifidobacterium and their products seem to play an effective role in GC risk reduction. In addition, their antiproliferative and antitumorigenic activities against cancer cells are known to play a key role in human health.[16] Probiotics are administered as dietary supplements and potential chemoprevention agents which are able to change cancer risks through different processes.[17] They act as followings: (1) binding and degradation of potential diet-induced carcinogens, (2) effect on cell proliferation in neoplastic conditions, (3) production of antitumorigenic and antimutagenic compounds, (4) increase of anti-inflammatory actions, (5) protection of gastric mucosa, and (6) competitive action toward growth and adhesion of pathogen bacteria.[18],[19] However, there are no strong evidence regarding molecular interactions and pathways which probiotics could interfere with cancer invasion and metastasis.

The main aim of the present study was to determine whether Lactobacillus reuteri enabled to prevent cancer metastasis by downregulation of uPA and uPAR gene expression in AGS cell line (human gastric adenocarcinoma cells). Our hypothesis is based on previous evidence supported that L. reuteri is one of the most common inhabitants of stomach,[20] and its anti-inflammatory effect is well characterized.[21] In addition, studies have shown that L. reuteri can promote eradication rate of H. pylori infection with production of antibacterial agents and its antioxidative potential also being reported.[20],[22] In another study, also, it indicated that L. reuteri could produce molecule with antitumor necrosis factor α (TNFα) activity.[23],[24] These reasons intensified the need for studying more about L. reuteri as a preventive agent in GC invasion.


 > Materials and Methods Top


Bacterial strain and culture condition

Freeze-dried L. reuteri (PTCC 1655) was obtained from the Iranian Research Organization Science and Technology and grown in MRS Broth (Ibresco, Tehran, Iran) at 37°C for 24 h under aerobic condition. Bacteria were subcultured three times before use.

Cell line and growth condition

Human gastric adenocarcinoma cells (AGS, NCBI: C131) were purchased from the National Cell Bank, Pasteur Institute of Iran. AGS cells were grown in Ham's F12 (Atocel, Graz, Austria) supplemented with 10% heat-inactivated fetal bovine serum FBS (Atocel, Graz, Austria) and 1% penicillin/streptomycin/amphotericin B mixture (Atocel, Graz, Austria). Cells were maintained in a humidified incubator of 5% CO2 at 37°C. Trypsin 0.5%/ethylenediaminetetraacetic acid (Atocel, Graz, Austria) were used for detachment of the cells.

Preparation of live bacteria cells for the treatment

First, we have to find whether the bacteria can grow in cell media. Therefore, approximately 1.5 × 108 L. reuteri cells were inoculated to complete cell culture media (Ham's F12 supplemented with 10% FBS) to monitor L. reuteri growth in this condition, which were assessed by spectroscopy at OD600nm and the pH changes of culture media.

Live bacteria cells were harvested by centrifuging at 5000 ×g for 15 min from liquid culture at exponential growth phase. Precipitated cells were washed twice by phosphate-buffered saline (PBS) (Atocel, Graz, Austria), and then the pellets were solved in an antibiotic-free cell culture media consisting of Ham's F12 supplemented with 10% FBS. L. reuteri live cells were diluted to the concentration of 1.5 × 108 CFU/ml (OD600nm = 0.1) and were added to AGS cell media. The final ratios of AGS cells to live bacteria cells were 1:10, 1:100, and 1:1000, respectively.

3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide assay

Antiproliferative effects of L. reuteri were measured through 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide (MTT) assay, which is based on reduction of tetrazolium MTT via metabolically active cells, in which 1 × 104 were placed into 96-well plates and incubated for 24 h. Thereafter, medium was replaced with antibiotic-free medium, containing different concentration of live bacteria cells, corresponding to the ratios of AGS cells to L. reuteri of 1:10, 1:100, and 1:1000, respectively, which were done in triplicate and incubated for 24 h, 48 h, and 72 h.

Subsequently, 5 mg of MTT powder (Atocel, Graz, Austria) was solved in 1 ml of PBS, and 10 μl of MTT solution was added to each well containing 100 μl cultured media, and then the plate was returned to cell culture incubator for 4 h. 200 μl of 0.04 mol/L hydrochloric acid (Merck, Darmstadt, Germany) in isopropanol (Merck, Darmstadt, Germany) was used to solubilize purple formazan crystals. Absorbance in each well was measured at 570 nm using a microtiter plate reader (BioRad, California, USA). Blank and control wells contained medium and untreated cells, respectively. The experiments were repeated three times for each concentration. The viability percentage of AGS cells was calculated according to the following equation:

Viability (%) = (Absorbance in treated wells/absorbance in control wells) × 100.

RNA isolation, complementary DNA synthesis, and relative quantification of gene expression

AGS cells were grown in T25 flasks (SPL Life Sciences Co., Korea). Incubated cancer cells were treated to achieve final ratios of 1:10, 1:100, and 1:1000 of AGS cells to live bacteria overnight, respectively. Subsequently, all treated cells were incubated for 24, 48, and 72 h in a humidified atmosphere of 5% CO2 at 37°C.

Total RNA was isolated by TRI Reagent according to the manufacturer's instruction (Sigma-Aldrich, Missouri, USA). The RNA concentration was quantified by NanoDrop One (Thermo Fisher Scientific, Inc., USA), and 500 ng of RNA was reverse transcribed using PrimeScript RT Reagent Kit (TaKaRa, Tokyo, Japan). Real-time polymerase chain reaction (PCR) was performed using RealQ Plus 2x Master Mix Green low ROX (Ampliqon, Odense, Denmark), complementary DNA as a template, and specific gene primers [Table 1]. The specificity of primers is shown in [Figure 1]. Reactions were run on a Rotor-Gene Q (Qiagen, Hilden, Germany) each reaction were run three times. PCR conditions are as follows: initial denaturation step 95°C for 10 min, 40 cycles of denaturation at 95°C for 15 s, annealing at 57°C for 45 s for uPA, 59°C for 45 s for uPAR, and 60°C for 30 s for glyceraldehyde 3 phosphate dehydrogenase (GAPDH), and final extension at 72°C for 20 s. GAPDH served as the endogenous control, and the assays were analyzed using 2−ΔΔCT method to calculate fold change values of uPA and uPAR messenger RNA (mRNA) expression.
Table 1: Primers used in real-time polymerase chain reaction

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Figure 1: Two percent agarose gel of polymerase chain reaction products. A 100 bp ladder; 1: Urokinase plasminogen activator; 2: Glyceraldehyde 3 phosphate dehydrogenase; 3: Urokinase plasminogen activator receptor

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Statistical analysis

The data were expressed as mean standard deviation. The group differences were evaluated using analysis of variance followed by Turkey's comparison test which was run by GraphPad Prism 6 (GraphPad Prism software Inc., Califorina, USA). P< 0.05 was considered statistically significant.


 > Results Top


Confirmation of Lactobacillus reuteri growth in Ham's F12 media

Within 72 h of incubation, the OD600nm increased from 0.121 to 0.298 and the pH decreased from 7.2 to 6 [Table 2]. These alterations indicated that the bacteria could grow in this condition.
Table 2: Lactobacillus reuteri growth in cell culture media

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Lactobacillus reuteri reduced AGS cells proliferation

Antiproliferative effects of L. reuteri based on MTT assay are shown in [Figure 2], which corresponds 24, 48, and 72 h of incubation. It was found that L. reuteri displayed no significant inhibitory effects within 24 h incubation at different concentrations, i.e., conversely, significant differences were observed in different concentrations of treated cells compared to control cells at 48 and 72 h. Co-incubation of L. reuteri and AGS cells up to 72 hours illustrated tangible antiproliferative effects and the results showed the higher percentage of L. reuteri, the more inhibition of AGS. The ratios of 1:10, 1:100, and 1:1000 showed 74.4%, 66.7%, and 40.8% of inhibition in proliferative cancer cells, respectively.. Moreover, the statistical analysis indicated that no significant differences were detected between all tested incubation time in each ratio. However, viability of AGS cells reduced significantly (P < 0.0001) with increasing L. reuteri concentration.
Figure 2: Effect of different concentrations of live Lactobacillus reuteri on AGS cells proliferation after 24, 48, and 72 h. Data are expressed as the mean ± standard deviation of three experiments. ***The significant values (P < 0.0001)

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Urokinase plasminogen activator and urokinase plasminogen activator receptor messenger RNA expression

Expression of uPA and uPAR mRNA was assessed after 24, 48, and 72 h of co-incubation of AGS cells and different concentrations of L. reutri cells by real-time PCR assay. Our results showed downregulation of uPA and uPAR expression, which are shown in [Figure 3] and [Figure 4], respectively. The expressions of uPA and uPAR were decreased significantly (P < 0.0001) in AGS cells which were exposed to L. reuteri for 24, 48, and 72 h in comparison to untreated cells. In contrast, slight differences were observed in different incubation time of AGS and L. reuteri cells. Although uPA/uPAR expression was decreased coincide with increasing L. reuteri concentration, no significant differences were found between them. It could be noted that the greatest reduction in uPA and uPAR gene expression was 1.78- and 2.43-fold, respectively.
Figure 3: Effect of different concentrations of live Lactobacillus reuteri on urokinase plasminogen activator expression following 24, 48, and 72 h co-incubation with AGS cells. Data are expressed as the mean ± standard deviation of three experiments. ***The significant values (P < 0.0001)

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Figure 4: Effect of different concentrations of live Lactobacillus reuteri on urokinase plasminogen activator receptor expression following 24, 48, and 72 h co-incubation with AGS cells. Data are expressed as the mean ± standard deviation of three experiments. ***The significant values (P < 0.0001)

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 > Discussion Top


In the current investigation, we used live L. reuteri as a probiotic due to their effects on promotion of H. pylori eradication rate and reduction of inflammation.[25],[26] Previous studies applied heat killed cells or different fractions of probiotics such as cytoplasm, metabolite, and peptidoglycan as well as cell wall.[27],[28] Live L. reuteri cells as the most common bacteria in stomach have anti-adhesive activity against pathogens.[20],[29] These results suggested that live L. reuteri cells might be an appropriate candidate for counteracting GC progression. Our results indicated L. reuteri grow in cell media within 72 h incubation [Table 2], which confirm that L. reuteri activation during treatment of cancer cells. Notably, reduction of pH following incubation may result in production of short-chain fatty acid (SCFA), which showed inhibitory effects against cancer cells.[30] Kahouli et al. findings demonstrated that different strains of L. reuteri produced optimal doses of SCFA in cell culture conditioned media.[30] Considering results in [Table 2], by elongation time of incubation, bacterial growth and decline in pH could be determined. The decline in pH might be co-related to the production of the metabolite containing SCFA by the bacteria itself which has been mentioned in different researches. One of the conclusion which could be drawn from this part of observation is that as the amount of metabolite like SCFA increased due to the increase in the number of bacteria the death of cells increased, although we did not measure the amount of SCFA in our research.

While several anticancer activities have been ascribed to probiotics, the present study evaluated antiproliferative effect of L. reuteri on AGS cells. Our experiment implied that L. reuteri inhibits cancer cells proliferation in a concentration-dependent manner [Figure 1], which may cause by increasing in SCFA production. However, production of SCFA was not measured in this investigation. According to previous studies, inhibitory effect of L. reuteri on cancer cells growth is mainly due to SCFA production, although it should be considered that we used live L. reuteri which produced other metabolite that could enhance this effect.[30]

Probiotics prevent cancer progression through inducing different apoptotic pathways. Previous literature revealed that L. reuteri exerts antiproliferative effects via suppression of nuclear factor-kappaB (NF-κB)-dependent gene products and TNF.[31] Similar antiproliferative effects of probiotics were also reported by Nami et al.[32] and Orlando et al.[17] The former observed that viability of AGS, MCF-7, HT-29, and HeLa cancer cells was reduced by Lactobacillus plantarum 5BL supernatant, and also highest antiproliferative effect was seen on Hela cells. The latter demonstrated that live cells or heat killed of two strains Lactobacillus paracasei IMPC2.1 and Lactobacillus rhamnosus. GG prevents proliferation of DLD-1 and HGC-27 cells and indicated that either both live and heat-killed bacteria showed antiproliferative effects. Despite numerous investigations in this context, it is not possible to compare these results with previous studies, because of variation in cell lines and bacterial concentrations.

It has been extensively accepted that uPA and uPAR act in modulation of cancer progression.[33] In addition, much evidence supports their correlation with metastatic phenotype of cancers.[34] For instance, Pan et al. showed an increase in AGS cells invasion following overexpression of uPA, caused by semaphorin 5A.[35] A significant association between uPAR expression and depth of tumor was seen in bone marrow and peripheral blood of GC patients, and the importance of uPAR expression in determination of cancer recurrence was also reported.[36]

Previous studies revealed that downregulation of uPA and uPAR gene expression provides new approach in inhibition of cancer invasion and improved patients overall survival.[37],[38] Yang et al. results indicated that phenethyl isothiocyanate (a component of cruciferous vegetables) could prevent dissemination of tumor cells via reduction of protein relevant to migration and metastasis such as uPA, MMP-2, MMP-9, and Cox-2.[39] Triptolide, an herbal extract, exerts its anti-invasive effects by suppression of uPAR mRNA and protein in human GC AGS cells.[40] As a result, we studied the effects of L. reuteri on uPA and uPAR gene expression. Our experiments showed that L. reuteri live cells caused a significant reduction in uPA and uPAR [Figure 2] and [Figure 3]. Although different incubation times and ratios of L. reuteri were examined in this study, no significant differences were seen between them. Based on previous studies, we proposed that casual role of L. reuteri in downregulation of NF-κB and Cox-2 might be involved in reduction of uPA/uPAR gene expression.[31] Unfortunately, there are no compatible data in this context, to the best of our knowledge, because it is the first report about L. reuteri contribution in reduction of gene expression involved in cancer metastasis. In spite of this fact, Soltan Dallal et al. showed that probiotics suppress Caco-2 cell invasion capacity using invasion assay.[41] Yang et al. also demonstrated that pretreatment of GC cells (MKN-45) by Lactobacillus acidophilus inhibited H. pylori induces NF-κB production and also IκBα stabilization as an anti-inflammation response, considering that NF-κB inactivation result in uPA suppression.[42]


 > Conclusion Top


Our outcomes suggested that L. reuteri could show beneficial effects via inhibition of cancer cells proliferation. It is also noteworthy that L. reuteri be able to reduce uPA and uPAR gene expression which are involved in cancer metastasis. Despite positive results obtained from this study, further experiments are needed to elucidate the precise molecular pathways underlined by L. reuteri. In addition, the main reason of aforementioned effects is unknown, and investigation of the effects of dead L. reuteri cells and their metabolite on GC invasion are proposed for future experiments. In addition, it is vital to study these effects in in vivo models, to understand L. reuteri activity against GC metastasis since they may interact differently in this condition.

Financial support and sponsorship

The study was supported by the Iran University of Medical Sciences, grant number “93-02-31-24682.”

Conflicts of interest

There are no conflicts of interest.

 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2]


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