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ORIGINAL ARTICLE
Year : 2019  |  Volume : 15  |  Issue : 4  |  Page : 921-926

A study of natural IgG antibodies against ATP-binding cassette subfamily C member 3 in oral squamous cell carcinoma


1 Beijing Institution of Dental Research, Beijing Stomatological Hospital, Capital Medical University, Beijing, People's Republic of China
2 Department of Radiology, Jilin Cancer Hospital, Changchun, People's Republic of China
3 Department of Transfusion Research, Dongguan Blood Center, Dongguan, People's Republic of China
4 Institute of Laboratory Medicine, Guangdong Medical University, Dongguan, People's Republic of China
5 Beijing Institution of Dental Research, Beijing Stomatological Hospital, Capital Medical University, Beijing, China

Date of Web Publication14-Aug-2019

Correspondence Address:
Ying Hu
Beijing Stomatological Hospital, No. 4 Tiantan West, Dongcheng District, Beijing 100050
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_150_18

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 > Abstract 


Aims: ATP-binding cassette subfamily C member 3 (ABCC3) is involved in multidrug resistance and is overexpressed in some solid tumors. Recent work revealed an increase in circulating anti-ABCC3 antibodies in lung and esophageal cancers. This in vitro study was undertaken to investigate the effects of the natural IgG antibody against the ABCC3-derived peptide antigen on proliferation of oral squamous cell carcinoma (OSCC) cells and augment the development of efficient and effective treatments in patients with OSCC.
Subjects and Methods: An in-house enzyme-linked immunosorbent assay was applied to detect anti-ABCC3 IgG antibody in human plasma. Two OSCC cell lines, CAL27 and SCC15, were cultured with 20% plasma either positive or negative for anti-ABCC3 IgG. Cell proliferation was quantified by the CCK-8 method, and cell apoptosis and cell cycle distribution were analyzed by flow cytometry. The expression of the ABCC3 gene in the cell lines was analyzed by reverse transcriptase quantitative real-time polymerase chain reaction.
Results: The results showed that plasma anti-ABCC3 IgG significantly inhibited the proliferation of CAL27 cells but not SCC15 cells, although ABCC3 was expressed in both cell lines. The proportion of apoptotic cells was significantly higher in CAL27 cells treated with anti-ABCC3 IgG-positive plasma than in those treated with IgG-negative plasma. Cell cycle progression was arrested in CAL27 cells treated with anti-ABCC3 IgG-positive plasma.
Conclusions: Our data suggest that human plasma anti-ABCC3 IgG may be a promising agent in anti-OSCC therapy, although further studies are needed to arrive at a definitive conclusion.

Keywords: ATP-binding cassette subfamily C member 3, natural antibody, oral squamous cell carcinoma cells, tumor immunity


How to cite this article:
Liu X, Huang Z, He Z, Meng Q, Wang X, Hu Y. A study of natural IgG antibodies against ATP-binding cassette subfamily C member 3 in oral squamous cell carcinoma. J Can Res Ther 2019;15:921-6

How to cite this URL:
Liu X, Huang Z, He Z, Meng Q, Wang X, Hu Y. A study of natural IgG antibodies against ATP-binding cassette subfamily C member 3 in oral squamous cell carcinoma. J Can Res Ther [serial online] 2019 [cited 2019 Sep 18];15:921-6. Available from: http://www.cancerjournal.net/text.asp?2019/15/4/921/264279

Xiu Liu and Zhicheng Huang contributed equally to this work





 > Introduction Top


Oral squamous cell carcinoma (OSCC) is the most common head and neck cancer and the sixth most prevalent tumor with a high degree of malignancy.[1],[2] The incidence of OSCC has recently shown an upward trend globally, and the number of newly diagnosed patients are increasing each year, with younger individuals also being affected, especially men.[2] Recently, either early diagnosis or combined treatment involving radiotherapy and chemotherapy has been widely considered. However, the 5-year survival rate in patients with OSCC remains <50%.[3],[4] Nowadays, cisplatin and 5-fluorouracil are two of the most frequently utilized chemotherapeutic drugs for the treatment of OSCC.[5],[6] Although tumors are initially sensitive to chemotherapy, they can rapidly develop cross-resistance to several kinds of chemotherapeutic drugs, so-called multidrug resistance (MDR), which leads to the failure of tumor chemotherapy.[7],[8],[9]

At present, pharmacological and cellular contributions to MDR have been addressed to identify possible mechanisms. For example, the overexpression of ATP-binding cassette (ABC) transporters,[10],[11],[12] also called efflux pumps,[7],[13] has been found to be associated with MDR. The genes coding for ABC transporters are divided into seven subfamilies (A-G) according to their sequence homology and structural domain composition.[7] While the proteins related to drug efflux are mainly encoded by gene subfamilies including ABCA, ABCB, ABCC, and ABCG. ABCB1, ABCC1-3, and ABCG2 are reportedly involved in the development of MDR in multiple malignant tumors.[7],[9],[10],[11] These ABC transporters function as energy-driven pumps to maintain intracellular drug concentrations below toxic levels and play a crucial role in determining the bioavailability of different types of drugs. The inhibition of ABC transporters causes chemosensitization, suggesting that inhibitors of such transporters can improve the outcome of cancer treatments involving chemotherapy.[7] Research has shown that ABCC1 inhibitor reversion improved tumor free-survival in mice.[7] ABC subfamily C member 3 (ABCC3) is a member of the ABC family and is involved in the development of MDR.[8] ABCC3 has been found to be overexpressed in hepatocellular carcinoma, nonsmall cell lung carcinoma, and epidermal growth factor receptor 2-positive breast cancer.[14],[15] Similarly, in Abcc3-knockdown mice, cellular retention and accumulation of chemotherapeutic drugs has been observed along with reduced drug efflux.[7] However, the functional relevance of ABCC3 in drug resistance and its association with OSCC have not been well established.

Natural antibodies are mainly secreted by B1 lymphocytes in the absence of external antigen stimulation and are likely to serve as an important antitumorigenic component in the body.[16],[17] Healthy controls carry natural antibodies in their peripheral blood, which are able to destroy tumor cells formed in the body either by triggering complement-dependent cytotoxicity (CDC) or by induction of cell apoptosis.[16],[18],[19] It is possible that natural antibody-rich plasma from healthy donors could be used as a postoperative therapy to prevent the recurrence of human cancer.[20] Here, we sought to investigate the inhibitory effects of natural anti-ABCC3 IgG antibodies on OSCC-derived cell lines.


 > Subjects and Methods Top


Detection of anti-ATP-binding cassette subfamily C member 3 IgG in plasma

Human plasma samples were collected from healthy blood donors by the Blood Center of Dongguan, Guangdong Province, China. Pooled plasma from >20 randomly selected individuals was used as a reference sample for relative quantification of plasma anti-ABCC3 IgG levels. This work was approved by the local Ethics Committee based in Dongguan and conformed to the requirements of the Declaration of Helsinki.

Enzyme-linked immunosorbent assay (ELISA) was performed to detect plasma IgG antibody directed against the extracellular domain of the human ABCC3 protein (NCBI accession NP_003777.2).[13],[21] The ELISA antibody test kit was provided by Hailanshen Biotechnology Ltd, Qingdao, China, as described in our previous study.[18] Specific binding ratio (SBR) was used to represent plasma anti-ABCC3 IgG levels. Plasma with the highest SBR values from two healthy donors was used as anti-ABCC3 IgG-positive plasma (A and B); anti-ABCC3 IgG-negative plasma was taken from six healthy donors with the lowest SBR value and thoroughly mixed.

Cell proliferation assay

Two human OSCC cell lines, SCC15 and CAL27 (American Type Culture Collection, ATCC, Manassas, USA), were used in this study. Both cell lines were seeded in 96-well plates, 100 μl/well with a density of 5 × 104 cells/ml and 3 × 104 cells/ml in Dulbecco's Modified Eagle's Medium (DMEM, HyClone, Utah, USA) and RPMI 1640 Medium (HyClone) containing 10% fetal bovine serum (FBS). After 24 h incubation in a humidified atmosphere with 5% CO2 at 37°C, the medium was changed. Cal27 and SCC15 cells were respectively cultured with DMEM and RPMI 1640 medium containing 20% human plasma either positive or negative for anti-ABCC3 IgG antibodies for 48 h under the same conditions as indicated above. Cell counting kit-8 (CCK-8, Sigma-Aldrich, Pennsylvania, USA) was used to detect cell viability. Briefly, 10 μl CCK-8 solution was mixed with complete medium at a ratio of 1:10 and then added to each well. After incubation at 37°C for 2 h, the OD of each well was measured on a microplate reader at a wavelength of 450 nm. Complete medium was used as a blank. Cell viability measurements were used to present data and calculated as follows:

Cell viability = (ODpositive-ODblank)/(ODnegative-ODblank)

Analysis of apoptosis

OSCC cells were seeded in 6-well dishes, 2 ml/well, at a density of 4 × 105 cells/ml and 2.5 × 105 cells/ml DMEM and RPMI 1640 containing 20% human plasma either positive or negative for anti-ABCC3 IgG. Cultured cells were harvested at 24 and 48 h and stained with fluorescein isothiocyanate (FITC)-conjugated Annexin V and propidium iodide (PI) according to the manufacturer's instruction using the Annexin V-FITC/PI Kit (CWbiotech, Beijing, China). The cells were then analyzed using a Cytomics fold change (FC) 500 flow cytometry system. Apoptotic changes were detected by FITC-Annexin V staining, while PI was used to discriminate between apoptotic and necrotic cells among the Annexin V-positive cells.

Cell cycle progression study

OSCC cells were seeded in 6-well dishes, 2 ml/well, at a density of 4 × 105 cells/ml and 2.5 × 105 cells/ml DMEM and RPMI 1640 containing 10% FBS. After 24 h incubation in a humidified atmosphere with 5% CO2 at 37°C, the medium was changed and OSCC cells were then cultured with DMEM and RPMI 1640 containing 20% human plasma either positive or negative for anti-ABCC3 IgG. Cells were fixed overnight at 20°C in 75% ethanol. The washed, precipitated cells were then resuspended in PBS containing 0.1% RNaseA (Fermentas, Hanover, MD, USA) and 100 μl of 10 μg/ml PI (Sigma) for 30 min at room temperature. They were then subjected to flow cytometry using a FACScan platform (BD Biosciences).[22]

ATP-binding cassette subfamily C member 3 gene expression assay

OSCC cells were seeded in 6-well dishes, 2 ml/well at a density of 4 × 105 cells/ml and 2.5 × 105 cells/ml DMEM and RPMI 1640 containing 10% FBS. After 48 h incubation in a humidified atmosphere with 5% CO2 at 37°C, cells were collected for extraction of total RNA using TRIzol reagent (Invitrogen). Total RNA samples were treated using a DNA-free kit (Fermentas) to eliminate DNA contamination and then reverse transcribed into cDNA using GoScript RT System (Promega). A cDNA aliquot equivalent to 40 ng of total RNA was used for reverse transcriptase quantitative real-time polymerase chain reaction (RT-qPCR) analysis, and GoTaq ® PCR Master Mix (Promega) was used to quantify expression of the ABCC3 gene on an ABI 7500 real-time PCR system.[7] Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as a housekeeping gene for normalization. The sequences of primers used for RT-qPCR are shown in [Table 1]. Relative quantity of gene expression was calculated using the comparative Ct method; FC was used to present data and determined based on the formula: FC = 2−ΔΔCt.
Table 1: Primer sequences for analysis of gene expression by reverse transcriptase quantitative real-time polymerase chain reaction

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Data analysis

GraphPad Prism 5 and SPSS 17.0 software were used to analyze experimental data. All data were expressed as mean ± standard deviation. Student's t-test (two-tailed) and one-way analysis of variation were applied to analyze the results. P < 0.05 (*) and P < 0.01 (**) were considered to be statistically significant. All experiments were repeated at least three times.


 > Results Top


Inhibitory effects of anti-ATP-binding cassette subfamily C member 3 IgG plasma on proliferation of oral squamous cell carcinoma cells

In comparison with anti-ABCC3 IgG-negative plasma, anti-ABCC3 IgG-positive plasma A inhibited the proliferation of CAL27 cells prominently (P = 3.2 × 10-5), and positive plasma B has no inhibitory effects (P = 0.098) [Figure 1]a. Meanwhile, there were no inhibitory effects on the proliferation of SCC15 treated with either anti-ABCC3 IgG-positive plasma A or B (P = 0.420 and P = 0.325, respectively) [Figure 1]b.
Figure 1: Effects of anti-ABCC3 IgG-positive plasma on the proliferation of oral squamous cell carcinoma cell lines compared with IgG-negative plasma. CAL27 cells (a) and SCC15 cells (b) were treated with anti-ABCC3 IgG-positive plasma for 48 h. Plasma A and plasma B were obtained from two healthy donors, respectively. The data were expressed as mean ± standard deviation in cell viability; NS: Not significant

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Cell apoptosis induced by anti-ATP-binding cassette subfamily C member 3 IgG plasma

Based on the inhibitory effects of anti-ABCC3 IgG plasma on the proliferation of OSCC cells, we investigated their apoptosis induced by anti-ABCC3 IgG-positive plasma A in CAL27 cells. The proportion of apoptotic cells was significantly higher in CAL27 cells treated with anti-ABCC3 IgG-positive plasma than those treated with anti-ABCC3 IgG-negative plasma (P = 8.185 × 10−7 for 24 h treatment and P = 3.530 × 10−4 for 48 h treatment) [Figure 2]a and b].
Figure 2: Induction of apoptosis of oral squamous cell carcinoma cells by anti-ATP-binding cassette subfamily C member 3 IgG-positive plasma. (a) Apoptotic cells in CAL27 cells were treated with anti-ATP-binding cassette subfamily C member 3 IgG-positive plasma for 24 h and 48 h, respectively. (b) The data of apoptosis were expressed as mean ± standard deviation; NS: Not significant

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Cell cycle alteration induced by anti-ATP-binding cassette subfamily C member 3 IgG plasma

To explore the possible mechanism involved in inhibitory effect on cell proliferation, we investigated the cell cycle alteration of CAL27 cells, which was induced by anti-ABCC3 IgG-positive plasma A. The G2/M arrest in CAL27 cells was observed in CAL27 cells treated with anti-ABCC3 IgG-positive plasma for 48 h, exhibiting more distinct G2/M arrest than those treated with anti-ABCC3 IgG-negative plasma (P = 6.338 × 10-8) [Table 2].
Table 2: Alteration of cell cycle progression induced by anti-ATP-binding cassette subfamily C member 3 immunoglobulin G plasma

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Expression of the ATP-binding cassette subfamily C member 3 gene in SCC15 and CAL27 cells

Student's t-test revealed that expression of the ABCC3 gene was detectable in both CAL27 and SCC15 cells when individual sample Ct values were normalized to the GAPDH housekeeping gene [Figure 3].
Figure 3: The expression of ATP-binding cassette subfamily C member 3 mRNA in oral squamous cell carcinoma cells. The gene expression date were expressed as mean ± standard deviation in FC. NS: Not significant

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 > Discussion Top


Natural antibodies, also known as natural autoantibodies, refer to immunoglobulins naturally present in normal individuals, which exhibit reduction in patients with early stage cancer and are gradually increased with tumor progression.[8],[23],[24],[25] Therefore, natural antibodies can be used as biomarkers in terms of inchoate diagnosis and prognosis of malignant tumors. Among the three isotypes of natural antibodies (IgM, IgA, and IgG), IgG is the most common type in adults and plays important roles in maintaining homeostasis of the immune system such as elimination of bacteria, viruses, and other invasive pathogens, clearance of cellular debris and nonfunctional proteins, and destruction of tumor cells arising in the body.[16],[20],[26] Recently, the antitumor role of natural antibodies has drawn much attention. Based on in vitro studies, natural antibodies could inhibit the proliferation of tumor cells and induce apoptosis. For example, natural anti-VEGFR1 IgG antibodies displayed inhibition of malignant proliferation in liver cancer cells,[18] although the effects of natural antibodies on OSCC cells remain unclear.

In recent years, the incidence of OSCC has been reported to rise each year, and chemotherapy has become an important adjuvant treatment of OSCC, but overall expectations in terms of outcome are still not satisfactory. The greatest obstacle in tumor chemotherapy is the development of MDR to anticancer drugs.[7] In fact, drug resistance in clinical treatment is related to the heterogeneity of drug target organs, the conversion ability of the active metabolites, and the effective concentration of the drugs.[27],[28],[29] The ABC transporter system may be involved in mediating the efflux of anticancer drugs from OSCC cells.[7] ABCC3 is a MDR-associated protein and has been found to be highly expressed in several tumor types, such as breast cancer, lung cancer, cervical carcinoma as well as OSCC. Animal studies identified that the sensitivity and accumulation of chemotherapeutic drugs could be increased through knockdown of Abcc3.[7]

In this study, we found that plasma anti-ABCC3 IgG could significantly inhibit the proliferation of CAL27 cells, but not SCC15 cells, although both cell lines express the ABCC3 gene. We hypothesized that cell surface antigens may have different structures in different types of cancer cells, resulting in different responses to anti-ABCC3 IgG antibodies. In addition, CAL27 cells are derived from a metastatic tongue tumor, while SCC15 cells are derived from preinvasive carcinoma. Based on the study of apoptosis and cell cycle progression in CAL27 cells, anti-ABCC3 IgG antibodies are likely to target the extracellular domain of receptors and induce apoptosis as well as G2/M-phase arrest that involves in DNA repair in these malignant cells. To the best our knowledge, this is the first report regarding inhibitory effects of plasma anti-ABCC3 IgG on the proliferation of OSCC cells. The present results provide evidence for the potential of therapeutic intervention with natural anti-ABCC3 IgG-positive plasma or extracted immunoglobulins.

In the present study, two individual plasma samples enriched in natural anti-ABCC3 IgG antibodies (A and B) were used to treat OSCC cells, but only plasma A exhibited the inhibitory effects on CAL27 cells. Possibly, natural antibodies require the presence of other anticancer components, such as the complement system that may exert effects at different levels between individuals, to act collectively in targeting tumor cells. It has been reported that natural antibodies can exert antitumor activities through antibody-dependent cellular cytotoxicity (ADCC), CDC, and through other pathways.[20] ADCC is mediated by the interaction between the Fc region of an antibody and the FcγRIIIa receptor present on the surface of immune cells, to activate natural killer cells that release cytotoxic substances such as perforin and granzyme, which kill target cells.[17],[20] CDC is launched when C1q, the initiating component of the classical complement pathway, is fixed to the Fc portion of target-bound antibodies. As the complement cascade progresses, the formation of the membrane attack complex was initiated and ultimately destroyed cancer cells by alteration of cellular membrane permeability.[17] Further investigation will be carried out to reveal the precise mechanisms by which natural anti-ABCC3 antibodies destroy OSCC cells.


 > Conclusions Top


Plasma anti-ABCC3 IgG was able to inhibit the proliferation of OSCC cells mainly through induction of apoptosis and inhibition of cell cycle progression, although there are some limitations in this study. Therefore, the inhibitory effects of anti-ABCC3 IgG-positive plasma on OSCC invasion/metastasis and the mechanisms involved should be investigated thoroughly in the future to confirm this initial finding.

Acknowledgments

We thank all the patients and controls for their participation in this study.

Financial support and sponsorship

This work was supported by Beijing Natural Science Foundation (Grant #7162075), National Natural Science Foundation of China (Grant #81570958) and Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry (grant # 2015-1098).

Conflicts of interest

There are no conflicts of interest.



 
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