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 Table of Contents  
ORIGINAL RESEARCH
Year : 2021  |  Volume : 13  |  Issue : 5  |  Page : 493-498

Downregulation of MTA-1, complex of CDK2–cyclin E, and NF-kB expressions as a molecular target therapy of oral Burkitt’s lymphoma cells mediated by sense KIP-1 and antisense SKP-2


1 Department of Oral Medicine, Faculty of Dentistry, Universitas Gadjah Mada, Yogyakarta, Indonesia
2 Department of Biomaterial, Faculty of Dentistry, Universitas Gadjah Mada, Yogyakarta, Indonesia
3 Faculty of Dentistry, Muhammadiyah University of Yogyakarta, Yogyakarta, Indonesia
4 Faculty of Dentistry, Muhammadiyah University of Surakarta, Surakarta, Indonesia

Date of Submission14-Dec-2020
Date of Decision18-Jun-2021
Date of Acceptance26-Aug-2021
Date of Web Publication11-Oct-2021

Correspondence Address:
Dr. Supriatno
Department of Oral Medicine, Faculty of Dentistry, Universitas Gadjah Mada, Bulaksumur, Caturtunggal, Kec. Depok, Kabupaten Sleman, Daerah Istimewa, Yogyakarta.
Indonesia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JIOH.JIOH_350_20

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  Abstract 

Aim: To examine the decreased of metastatic associated protein-1 (MTA-1), complex of cyclin-dependent kinase-2 (CDK2)–cyclin E, and nuclear factor-kappa beta (NF-kB) expression as a molecular target therapy of oral Burkitt’s lymphoma (Raji) cells mediated by oligonucleotides KIP-1 sense (KIP-1 S) and SKP-2 antisense (SKP-2 AS). Materials and Methods: In the study, the pure laboratory experimental with posttest only control group design was confirmed. The MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide] assay was performed to evaluate the suppression of cell growth. The chemotactic migration activity was carried out by Boyden chamber assay. Activation of MTA-1, NF-kB, cyclin E, CDK2, SKP-2, KIP-1, and α-tubulin was investigated by Western blot analysis. Apoptosis cells were analyzed by caspase-3 and caspase-9. Results: The growth inhibition and chemotactic migration activity of KIP-1 S and SKP-2 AS cells were significantly inhibited when compared with the scrambled control (SC) cells. Interestingly, Raji-KIP-1 S has potentially greater cell growth and migrated chemotactic suppression than SKP-2 AS. Induction of cell apoptosis was confirmed in KIP-1 S and SKP-2 AS proofed by increasing the activation of caspase-3 and caspase-9. Decreased level of MTA-1, NF-kB, cyclin E, CDK2, SKP-2, and increased level of KIP-1 protein were detected in KIP-1 S- and SKP-2 AS-treated cells. Conclusion: KIP-1 S and SKP-2 AS have strong antitumor activity on the oral Burkitt’s lymphoma cells through downregulation of MTA-1, CDK2–cyclin E complex, and NF-kB expression. However, KIP-1 S had a stronger antitumor activity than SKP-2 AS targeting these molecules could represent a promising new therapeutic approach for this type of tumor.

Keywords: Burkitt’s Lymphoma Cells, CDK2–cyclin E Complex, KIP-1 S, MTA-1, NF-kB, SKP-2 AS


How to cite this article:
Supriatno, Irnawati D, Medawati A, Entin Yuletnawati S. Downregulation of MTA-1, complex of CDK2–cyclin E, and NF-kB expressions as a molecular target therapy of oral Burkitt’s lymphoma cells mediated by sense KIP-1 and antisense SKP-2. J Int Oral Health 2021;13:493-8

How to cite this URL:
Supriatno, Irnawati D, Medawati A, Entin Yuletnawati S. Downregulation of MTA-1, complex of CDK2–cyclin E, and NF-kB expressions as a molecular target therapy of oral Burkitt’s lymphoma cells mediated by sense KIP-1 and antisense SKP-2. J Int Oral Health [serial online] 2021 [cited 2021 Dec 6];13:493-8. Available from: https://www.jioh.org/text.asp?2021/13/5/493/327866


  Introduction Top


The treatment strategy using sense and antisense oligonucleotides is based on the natural event of the expression process of a gene. Transfection of sense and antisense aims to ensure that specific mRNA sequences that carry genetic messages can be bound complementary by artificial sense or antisense so that the ribosome complex can or cannot be read, so that new gene products are formed or not formed.[1],[2] It was reported that induced biologically active proteins that produce new proteins with highly selective methods in increasing the function of these proteins can be performed by transfection of sense or antisense oligonucleotides because sense and antisense are protein targets of the immune system.[3] Therapy with sense or antisense transfection can selectively inhibit certain genes related to certain functions or diseases.[4]

Kinase inhibitor protein-1 (KIP-1) is a negative regulator and inhibitor of the cyclin E/cyclin-dependent kinase-2 (CDK2) complex, which was first identified during the transforming growth factor beta (TGF-β)-induced G1 phase.[5] KIP-1 also plays a role as a prognostic factor of several types of malignancies in the human body. Loss of KIP-1 expression has implications for increasing the aggressiveness and progression of cancer cells.[6] Meanwhile, S-phase kinase-associated protein-2 (SKP-2) is one of the co-activators of KIP-1 and functions as a positive regulator of the cell cycle. SKP-2 has the opposite role to KIP-1. Overexpression of SKP-2 was detected resulting in a poor prognosis and increased aggressiveness of cancer cells.[7] It was reported that SKP-2 −/− (knockout) showed a significant increase in apoptosis and inhibition of tumor growth in experimental animals.[8] In this study, we transfected KIP-1 and SKP-2 with oligonucleotides sense and antisense, and inserted them into Burkitt’s lymphoma (BL) cells. The purpose of the study was to analyze the mechanism responsible for KIP-1 S- and SKP-2 AS-mediated growth inhibition of oral BL (Raji) cells through suppression of metastatic associated protein-1 (MTA-1), CDK2–cyclin E complex, and nuclear factor-kappa beta (NF-kB) proteins.


  Materials and Methods Top


Cells and cell culture

BL (Raji) cells (ATCC CCL-86) were incubated in Dulbecco’s modified Eagle’s medium (DMEM, Sigma, St. Louis, Missouri) supplemented with 10% fetal calf serum (FCS, MoregateBioTech, Bulimba, Australia), 100 μg/mL streptomycin, and 100 U/mL penicillin (Invitrogen, Carlsbad, California). The cultures were incubated at 37°C with 5% CO2 in a 95% humidified atmosphere.[3]

Sense and antisense experiments

Two oligonucleotides for SKP-2 and two oligonucleotides for KIP-1 containing phosphorothioate backbones (Fasmac Co., Kanagawa, Japan) were synthesized as follows: antisense (AS), 5′-TCCTGTGCATAGCGTCCGCAGG CCC–3′ (the AS direction of human SKP-2 cDNA nucleotide 25 mer), scrambled control (SC), 5′-CCCGGACGC CTGCGATACGTGTCCT-3′ (SC for AS), sense (S), 5′-GGCGCAGGAGAGCCA-3′, and AS, 5′-TGGCTCTCCTGCGCC-3′ (the AS direction of human KIP-1cDNA nucleotide, 15 mer). All of the oligonucleotides were transfected into Raji cell directly according to the manufacturer’s instructions.[2]

Cell growth inhibition analysis (MTT assay)

Raji cells at 2 × 104 cells per well were cultured on 96-well plates (Falcon, AZ, USA) and incubated with DMEM 10% FCS. Then, cells were transfected with oligonucleotides at a final concentration of 100 μM. After 0, 24, and 48h, cells were added by the MTT solution [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (Sigma-Aldrich, Saint Louis, MO, USA)] for 4h. The cell absorbance was calculated using the BioRad microplate reader (BioRad, Hercules, California) at a wavelength of 550nm.

Migration chemotatic assay by Boyden chamber kit

Raji cells (5 × 105 cells/kit) were placed in the upper compartment (50 μL each well) and allowed to migrate through the membrane pores into the lower compartment containing chemotactic agents (DMEM 10% FCS + KIP-1 S and AS; DMEM 10% FCS + AS or S SKP-2). After the 24-h incubation, the PVDF membrane (BioRad) between the two compartments was removed, washed, and fixed with pure methanol (96.6%). The count of the number of cells migrating was determined by light microscopy at 40× magnification.

Activity of caspase-3 and caspase-9

The proteolysis activity of caspase-3 and caspase-9 was performed according to the manufacturer’s instructions. Briefly, 10 μL of Raji cell extracts transfected with SKP-2 AS and SKP-2 S, or KIP-1 S and KIP-1 AS were incubated with caspase-3 substrates (DVED-pNA) or caspase-9 (LEHD-pNA, BioVision colorimetric assay kit, California) in a buffer solution for 2h and incubated at 37°C. Absorbance was measured at a wavelength of 405nm using microplate reader (Bio-Rad). Replicated in this test was set in three times.

Western blot analysis

Raji-transfected cells for 48-h incubation were lyzed by Braddford solution (BioRad). Samples of protein (70 μg) were electrophoreted on an SDS-polyacrylamide gel and transferred to a polyvynilidene fluoride (PVDF) membrane (BioRad). At 5% nonfat milk powder in tris-buffered saline, the membranes were blocked at 37°C for 1h, and incubated with primary antibodies against the KIP-1 protein (clone 1B4, mouse monoclonal antibody; Novocastra Laboratories, New Castle, UK), SKP-2 protein (H-435, rabbit polyclonal antibody; Santa Cruz Biotech), MTA-1 protein (AV37737, rabbit polyclonal; Sigma-Aldrich), NF-kB (C-20, rabbit polyclonal; Santa Cruz Biotech, TX, USA), CDK2 (E304, rabbit monoclonal antibody, Abcam, Branford, CT, USA), and cyclin E protein (clone HE12, mouse monoclonal antibody, Santa Cruz Biotech) with a 1:500 dilution. The enhanced chemiluminescent (ECL) plus kit (Amersham Pharmacia Biotech, UK) was confirmed for detection of HRP-conjugated antibodies. Normalization and internal control were performed by anti-α-tubulin monoclonal antibody (Zymed Laboratories, San Francisco, California).

Statistical analysis

Data in this study were analyzed by Stat View 4.5 (Abacus Concepts, Berkeley, CA, USA) for one-way analysis of variacne (ANOVA) and followed by post hoc least significant difference (LSD) with level of significance at 95%.


  Results Top


Cell growth inhibition (MTT assay)

The relative cell number was evaluated by comparing the absorbance in each cell using MTT assay. No significant differences were observed in cell number between the KIP-1 AS and SKP-2 S for 24 and 48 h. However, cells transfected with KIP-1 S and SKP-2 AS were markedly suppressed in cell growth as compared with KIP-1 AS and SKP-2 S at 48h (P = 0.000). Interestingly, inhibition of cell growth at Raji-KIP-1 S was slightly stronger than Raji-SKP-2 AS [Figure 1].
Figure 1: Relative cell number examinated by comparing the absorbance in different groups in 0, 24, and 48h using MTT assay. Values shown are the mean of four determinations, and error bars indicate standard deviations. *P < 0.05 when compared with cell transfected with KIP-1 AS or SKP-2 S by two-way ANOVA

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Chemotactic migration activity

Boyden chamber kit for examining the ability of cell migration was evaluated for 24h incubation. [Figure 2] shows the chemotactic migration of Raji cells transfected by oligonucleotides sense (S) and antisense (AS) KIP-1 and SKP-2 for 24h (*P < 0.05). Appropriate with cell growth inhibition, Raji-KIP-1 S had the lower ability of cell invasion than SKP-2 AS.
Figure 2: (A) Chemotactic migration of Raji cells transfected by oligonucleotides sense (S) and antisense (AS) KIP-1 and SKP-2 for 24h (*P < 0.05 when compared with that of cell transfected with KIP-1 AS or SKP-2 S by one-way ANOVA). (B) Migratory chemotactic of Raji cell transfected with KIP-1 S, KIP-1 AS, SKP-2 S, and SKP-2 AS by Boyden chamber assay

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Western blotting analysis

The Western blot analysis was performed to detect the protein expression of KIP-1, SKP-2, MTA-1, CDK2–cyclin E complex, NF-kB, and α-tubulin in different Raji-treated group. As seen in [Figure 3], the upregulation of KIP-1 and SKP-2 protein was detected in Raji-KIP-1 S and Raji-SKP-2 AS cells compared with the expression of KIP-1 AS and SKP-2 S. Furthermore, decreased level of MTA-1, CDK2, cyclin E, and NF-kB protein was found in KIP-1 S and SKP-2 AS cells. Contraly, increased expression of MTA-1, CDK2, cyclin E, and NF-kB protein was detected in KIP-1 AS and SKP-2 S cells. In addition, the expression of internal control and α-tubulin was approximately the same in each group.
Figure 3: Protein expression of KIP-1, SKP-2, MTA-1, CDK2, cyclin E, NF-kB, and α-tubulin in Raji cells treated with KIP-1 S, KIP-1 AS, SKP-2 S, and SKP-2 AS by Western blotting analysis

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Induction of apoptosis by caspase-3 and caspase-9 colorimetric assay

The caspase-3 dan caspase-9 activity in Raji cells transfected with KIP-1 and SKP--2 S and AS were investigated. Raji-SKP-2 AS and KIP-1 S showed increased proteolytic activities of caspase-3 and caspase-9 as compared with that of SKP-2 S or KIP-1 AS [Figure 4]. Proteolytic activities of caspase-3 in Raji-SKP-2 AS were at 1.81 and in KIP-1 S at 2.3-fold increase compared with that of KIP-1 AS and SKP-2 S. Furthermore, proteolytic activities of caspase-9 in Raji-SKP-2 AS were 1.25 and in KIP-1 S at 1.41-fold increase (P = 0.001). Raji cell transfected with KIP-1 S and SKP-2 AS significantly increased the proteolitic activity of caspase-3 compared with that of neo or Raji-KIP-1 AS or SKP-2 S (P = 0.001). Increased proteolytic activity also occurs in caspase-9 to Raji-KIP-1 S (P < 0.05).
Figure 4: Induction of proteolitic activity of caspase-3 and caspase-9. Raji cells were transfected with KIP-1 S, KIP-1 AS, SKP-2 S, and SKP-2 AS (*P < 0.05 when compared with that of neo or KIP-1 AS or SKP-2 S by one-way ANOVA)

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  Discussion Top


Cell proliferation is influenced by the mechanism of programmed cell death (apoptosis). The balance between negative and positive regulator, as well as the balance of cell growth and cell death are the main conditions for normal cell growth. The occurrence of an imbalance between these regulators can cause cell malignancies. The characteristics of malignant cells include a more rapid increase in cell size, less differentiation (or lack of differentiation), tendency to invade surrounding tissues, and ability to metastasize to distant tissues. It was reported that KIP-1 acts as a negative regulator of the cell cycle, whereas SKP-2 has a role opposite to that of KIP-1.[9] In various types of human tumors, high levels of SKP-2 expression have associated with high aggressiveness and poor prognosis. Otherwise, accumulations of KIP-1 are related with good prognosis and favourable condition.[10],[11] In this study, the phosphorotioate oligonucleotide AS and S strategy was delivered to investigate the activity of SKP-2 and KIP-1 on cell growth and migration chemotactic suppresion and induction of apoptosis in an oral BL cell line through decreased level of MTA-1, CDK2–cyclin E complex, and NF-κB protein expressions.

Transfection of Raji cell with KIP-1 S and SKP-2 AS, as seen in [Figures 1] and [2], markedly increased the cell growth and migration chemotactic suppression effect as compared with KIP-1 AS and SKP-2S transfection. These data suggest that the oligonucleotide KIP-1 S and SKP-2 AS have potential to suppress cell growth and chemotactic migration, and not by the nonspecific effect like toxicity of oligonucleotide. Lane et al.[12] reported that these mechanisms can be discerned through the RNase H-dependent oligonucleotide AS. Interestingly, oligonucleotide-assisted RNase H-dependent reduction of targeted RNA expression can be quite efficient, reaching 80%–95% decrease of protein and mRNA expression.

Activation of caspase-3 and caspase-9 in KIP-1 S- and SKP-2 AS-treated cells were markedly increased. These data strongly suggest that apoptosis occured in those cultures [Figure 4]. Other result found that increased caspase-3 and caspase-9 in KIP-1 S- and SKP-2 AS-treated cells indicate apoptosis-ensued extrinsic and intrinsic pathways. Harada et al.[13] reported that induction of apoptosis can be caused by upregulation of KIP-1 and downregulation of SKP-2. In the other report, the cleavage of PARP and DNA fragmentation is performed by caspase-3, indicating that caspase-3 targets cellular for proteolytic cleavage resulting in cell death.[14] The activation of caspase-8, or an intrinsic apoptosis pathway, and the release of cytochrome-c from mitochondria can be activated by either an extrinsic apoptosis pathway, caspase-3. Activated caspase-8 can directly cleave and activate the caspase-3, or it can cleave one of the Bcl-2 family members, such as Bid, to induce the release of mitochondrial cytochrome c, which also leads to activation of caspase-3 via formation of apoptosome consisting of Apaf-1 and caspase-9.[14]

A relationship among KIP-1, SKP-2, and apoptosis in their experiments had already reported by several investigators. Decreased expression of KIP-1 has been detected in human cancer.[15] Loss of KIP-1 has been associated with disease progression and an unfavorable outcome in several types of malignancy.[16] Also, malignant human oral cancer cells transfected with KIP-1 gene lead to inhibition of proliferation, invasion, and metastasis.[17] Furthermore, S-phase kinase protein-2 induced by adenovirus-vector-mediated expression of SKP-2 in quiescent cells was followed by apoptosis.[9] Embryonic fibroblasts from SKP-2-deficient mice showed an increased tendency toward spontaneous apoptosis.[8] However, the crucial role of SKP-2 in apoptosis remains unclear.

Recent report upregulated of SKP-2 or functional loss of KIP-1 has been implicated in carcinogenesis and cancer progression.[2] Other investigator reported that degradation of KIP-1 can be promoted by phosphorylation of SKP-2 and Thr-187.[18] In this study, we observed that accumulation of KIP-1 S and SKP-2 AS can induce apoptosis characterized by elevating caspase-3 and caspase-9 activities.

Further data showed that decreased expression of MTA-1, CDK2–cyclin E complex, and NF-kB proteins was detected in Raji-KIP-1 S and Raji–SKP-2 AS. These suggested that KIP-1 S and SKP-2 AS had potential to suppress the proteins of MTA-1, CDK2–cyclin E complex, and NF-kB. The MTA-1 protein contributes to the process of cancer development and metastasis through many genes and protein targets. These interacting proteins play a role in transformation independent of anchorage growth, invasion, survival, DNA repair, angiogenesis, and hormone independence. MTA proteins control a spectrum of cancer-promoting processes by modulating the expression of target genes and/or the activity of MTA-interacting proteins.[19] It was reported that overexpression of MTA-1 protein indicated high proliferation, invasion, metastasis, and recurrence in gastric cancer,[20],[21] and also showed rapid formation of tumor angiogenesis and poor survival in lung cancer.[22] Furthermore, cyclin E/CDK2 regulates multiple cellular processes by phosphorylating numerous downstream proteins. Cyclin E/CDK2 plays a critical role in the G1 phase and in the G1-S phase transition. Cyclin E/CDK2 phosphorylates p27 and p21 during G1 and S phases, respectively. Smad3, a key mediator of TGF-β pathway that inhibits cell cycle progression, can be phosphorylated by cyclin E/CDK2. The phosphorylation of Smad3 by cyclin E/CDK2 inhibits its transcriptional activity and ultimately facilitates cell cycle progression.[23] Moreover, NF-κB is amediator of inflammatory responses, plays a significant roleincarcinogenesis,[24] and functions as a tumour promoter in inflammation associated cancer.[25] However, in this study we detected downregulation of MTA-1, cyclin E, CDK2, and NF-kB protein level through Western blotting analysis in cell transfected with KIP-1 S and SKP-2 AS.

On the basis of these data, the results may be applied in the clinic to determine the prognosis of patients with BL or other oral cancers. If it is known that the regulation of the MTA-1, cyclin E, CDK2, and NF-kB proteins has decreased, then the prognosis of this disease is good because the therapy given shows a good effect. Conversely, if the regulation of their proteins increased, the cell growth and aggressiveness will be higher, so that the prognosis will be worse. Furthermore, the results of study that have been obtained in vitro still require continuous research in vivo using animal models. In vivo examination includes tumorigenesis, metastatic, and immunohistochemical analysis. However, in this in vitro study, many obstacles were encountered such as electric power failure due to natural disasters, research materials that were difficult to obtain in Indonesia, so that it takes a long time to work on, research tools were limited and must queue to use them, as well as funds and time limited research. This limitation can be overcome by being disciplined in time, being creative in research, and by obeying the prevailing rules. Interestingly, this study suggests that KIP-1 S and SKP-2 AS have strong antitumor activity, even though KIP-1 S has higher anti-tumor activity than SKP-2 AS. Therefore, this research needs to be continued until these two genes can be used in the clinic.

In conclusion, oligonucleotide KIP-1 S and SKP-2 AS can induce cell growth and migration chemotactic suppression followed by apoptosis in an oral BL cell. Suppression of cell growth and induction of apoptosis through downregulation of MTA-1, CDK2–cyclin E complex an NF-κB proteins. Interestingly, KIP-1 S was detected to have stronger antitumor activity than SKP-2 AS. In addition, upregulation of KIP-1 S and SKP-2 AS may be a useful apoptosis-modulating strategy for the treatment of this type of cancer.

Acknowledgement

The researcher would like to thank Mrs. Rumbiwati ST., MSc., Laboratory of Parasitology, Faculty of Medicine, and the entire teaching staff of the oral medicine department, Universitas Gadjah Mada, who have helped and made this research a success.

Financial support and sponsorship

This study was supported by Hibah Kompetensi Kemen-Ristek DIKTI no. LPPM-UGM/1185/LIT/2017, Republic of Indonesia.

Conflicts of interest

There are no conflicts of interest.

Authors’ contributions

SS was involved in the study conception, data interpretation, manuscript writing, and checking final manuscript . DI was involved in data acquisition and analysis, data interpretation, and checking final manuscript. AM was involved in data collection, data interpretation, and checking final manuscript.

Ethical policy and institutional review board statement

All research processes have received approval from the ethics commission of the Faculty of Dentistry, Universitas Gadjah Mada with no. 001385/KKEP/FKG-UGM/EC/2018.

Declaration of patient consent

We do not use human subjects.

Data availability statement

All data in this study were available and stored properly by the first author. All data have never been published in any journal.

 
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