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Expression of small glutamine-rich TPR-containing protein A (SGTA) in Non-Hodgkin's Lymphomas promotes tumor proliferation and reverses cell adhesion-mediated drug resistance (CAM-DR)
Leukemia Research, 8, 38, pages 955 - 963
- High expression of SGTA was associated with clinical prognostic factors.
- Knockdown of SGTA expression inhibited proliferation of NHL cells.
- Adhesion to FN or HS-5 cells led to SGTA down-regulation, vice versa.
- Knockdown of SGTA expression induced adhesion-mediated drug resistance.
The expression and biologic function of SGTA in Non-Hodgkin's Lymphomas (NHL) was investigated in this study. Clinically, by immunohistochemistry analysis we detected SGTA expression in both reactive lymphoid tissues and NHL tissues. In addition, we also correlated high expression of SGTA with poor prognosis. Functionally, SGTA expression was positively related with cell proliferation and negative related with cell adhesion. Finally, SGTA knockdown induced adhesion-mediated drug resistance. Our finding supports a role of SGTA in NHL cell proliferation, adhesion and drug resistance, and it may pave the way for a novel therapeutic approach for CAM-DR in NHL.
Keywords: Non-Hodgkin's Lymphomas (NHL), SGTA, Proliferation, Cell adhesion, Drug resistance.
Non-Hodgkin's Lymphomas (NHL) is a heterogeneous group of solid tumors that derives from lymphocytes and involves many kinds of lymphoma except Hodgkin's lymphoma  . The classification of NHL is diverse, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), extranodal lymphoma of mucosa-associated lymphoid tissue (MALT), and Nasal natural killer (NK)/T-cell lymphoma (NK/T), etc. , , and . Significant improvements have been made in the treatment of NHL where event-free survival rate has increased from 30% in the 1970s to 60–95% nowadays. The outcome for people with relapsed or refractory disease, however, remains poor  and . About an additional 10–20% of NHL patients can be rescued with high-dose chemotherapy following stem cell transplantation, implicating drug resistance as a significant reason of treatment failure in lymphoma  .
Stromal cells are essential for bone marrow microenvironment that regulate tumor cell survival. Bone marrow stroma has been regarded as a ‘sanctuary site’ for lymphoma cells during traditional chemotherapy  and . Mounting evidence suggests that interaction between the bone marrow microenvironment and lymphoma cells may play an essential role in tumor development  . Previous studies have indicated that adhesion to bone marrow stromal cells or fibronectin (FN)-coated surface can protect malignant lymphoma cells from apoptosis induced by chemotherapy drugs [cell adhesion-mediated drug resistance (CAM-DR)] , , , and . However, how bone marrow stroma regulates CAM-DR in lymphoma, and the underlying molecular mechanisms involved, are unclear to date. In this article, we used NHL as a disease model to characterize the mechanism by which bone marrow stroma regulates chemotherapeutic drug resistance.
Small glutamine-rich tetratricopeptide repeat (TPR)-containing protein A (SGTA, also known as SGT, hSGT or Vpu-binding protein), was originally discovered as a binding partner of the non-structural protein of autonomous parvovirus H-1, , and . The TPR motifs are involved in a variety of processes, such as cell cycle, protein folding, transcription, protein transport, hormone receptor signaling and several other pathways , , and . It has been reported that knockdown of SGTA results in the suppression of androgen and phosphatidylinositol 3 kinase (PI3K)/Akt signaling and inhibition of prostate cancer cell proliferation  . Also, previous studies have reported that SGTA down-regulate receptor tyrosine kinases (RTK) signaling and might participate in a regulatory loop acting to enhance sensitivity of cancer cells to chaperone inhibitors  . Deficiency of SGTA might lead to partial cell cycle arrest in G2/M and inability to complete cell division due to mitotic arrest  . In NHL, it has been reported that cell adhesion to bone marrow stroma induces a reversible cell-cycle arrest. Therefore, it is of interest to investigate whether SGTA can also affect cell proliferation and cell cycle arrest of NHL.
In our previous study, it has been showed that SGTA is highly expressed in several solid neoplasms such as pulmonary carcinoma, esophageal squamous carcinoma and human hepatocellular carcinoma , , and . In this study, we aimed to investigate SGTA expression in NHL and to explore the relationship between SGTA expression and cell proliferation or CAM-DR. We also investigated its association with clinical and pathologic factors, as well as prognosis after chemotherapy. Our study first reported that SGTA expression promoted tumor proliferation and reversed CAM-DR in NHL, and it may provide a novel perspective for a better understanding of the mechanism of drug resistance in NHL.
2. Materials and methods
2.1. Patients and tissue samples
This study was carried out on a total of 96 B-cell lymphomas and 19 reactive lymphadenopathy samples, which were histopathologically and clinically diagnosed at Affiliated Cancer Hospital of Nantong University, during the period of January 1, 1993, to April 1, 2 005. All of these tissue samples were new diagnosed and classified according to the WHO criteria, which included: 37 diffuse large B-cell lymphomas (DLBCL), 16 follicular lymphomas (FL), 28 mucosa-associated lymphoid tissue B cell lymphomas (MALT), 15 Nasal natural killer (NK)/T-cell lymphoma (NK/T), and 19 reactive lymphoid tissues (RL). A written consent form was obtained from all patients.
Western Blot was performed according to methods described previously  and . The antibodies used for immunohistochemistry and Western blotting were obtained from Santa Cruz Biotechnology, USA. The primary antibodies in this study included: SGTA (1:1000), cyclin A (1:500), P2Kip1 (1:1000), PCNA (1:1000), and GAPDH (1:1000).
2.3. Immunohistochemical staining and evaluation
The procedures were carried out similarly to previously described methods  and . Three independent observers (YJH, YCW and LLJ) evaluated the immunostaining results. Cells with brown-colored staining were considered as positive. Staining intensity was graded according to the following criteria: 0 (no); 1 (weak); 2 (moderate) and 3 (strong).
The percentage of staining tumor cell was scored as follows: 0 (no positive tumor cells); 1 (1%-25% positive tumor cells); 2 (25–49% positive tumor cells) and 3 (50–100% positive tumor cells). The staining index (SI) was used to calculate the staining intensity score and the percentage of positive tumor cells score. Using this method, we assessed SGTA expression by the SI with scores of 0, 1, 2, 3, 4, 6 or 9. For statistical analysis: an SI score of ≥4 was used to define tumors with high SGTA expression, and an SI score of ≤3 was used to indicate low SGTA expression.
2.4. Cell cultures and transient transfection
The human NHL cell line Daudi and the human bone marrow stromal cells (BMSC) line HS-5, were both obtained from Jiangsu Institute of Hematology, China. The NHL cells were cultured in suspension in RPMI 1640 (Sigma–Aldrich, Rehovot) while HS-5 were cultured in F12 (Sigma–Aldrich, Rehovot) with 10% fetal bovine serum at 37 °C and 5%CO2.
The SGTA-siRNA and control-siRNA were obstained from Biomices Biotechnologies Co. Ltd. The siRNA targeting SGTA sequences were 1#: 5′-CGUGCAUUUCUACGGAAAA-3′; 2#: 5′-AAGCACGUGGAGGCCGUGG-3′, and 3#: 5′-CUUCGAACCUAAUGAACAA-3′. Cells were seeded in susupension in 1640 medium with 10% FBS without antibiotics before transfection. The siRNA transfection was performed using lipofectamine 2000 in accordance with the manufacturer's protocol. Cells were cultured at 37 °C in 1640 with no serum or antibiotics for 6 h at 105/ml. Transfected cells were harvested 48 h after transfection.
2.5. Cell cycle analysis and viability assay
After cells were harvested, they were fixed in 70% ethanol at −20 °C and then incubated with 1 mg/ml RNase A for 30 min. Afterwards, cells were collected by centrifugation at 2000 rpm for 5 min and stained with propidium iodide (50 μg/ml PI; Becton–Dickinson, San Jose, CA, USA) in phosphate-buffered saline (PBS), 0.5% Tween-20. After that, cells were analyzed using a Becton–Dickinson BD fluorescence activating cell sorter (FACScan) flow cytometer.
Cell viability was measured using the Cell Counting Kit-8 (CCK-8) assay (Dojindo Molecular Technologies, Gaithersburg, MD, USA) according to the manufacturer's instructions. Frist, all the cells were inoculated into a 96 well plate at the density of 105 cells/well. Then, cells were treated with Doxorubicin or Mitoxantrone for 48 or 72 h. CCK-8 reagents were added to each well at due time, incubated for an additional 1 h at 37 °C, and the absorbance at 450 nm was read in an automated plate reader. Each experiment was repeated three times at least.
2.6. Cell co-culture and adhesion assay
Firstly, the dishes were mantled overnight at 37 °C with HS-5 cells or 40 μg/mL human FN (Sigma–Aldrich, Rehovot) in a final volume of 1 mL PBS. Secondly, Daudi cells (105 cells/mL) were adhered to pre-established monolayers of HS-5 or FN for 2–4 h. Lastly, adherent cells were carefully removed for next experiments, with the HS-5 monolayer kept intact.
The ability of cell adhesion was assessed by staining lymphocytes with calcein (Santa Cruz Biotechnology) for 30 min according to the manufacturer's protocol and then incubating them in 96-well plates with a FN-coated surface or pre-established monolayers of HS-5 in RPMI 1640 medium. After 2 h of co-culture, the non-adherent cells were washed off twice with 1 ml of PBS and the number of adherent cells was measured with an automated plate reader.
2.7. Statistical analysis
The calculations were analyzed using the Statistical Package for the Social Sciences SPSS 13.0 software. The association between SGTA expression and clinicopathological features was analyzed using the χ2 test. As the data were not normally distributed, SGTA and Ki-67 expressions were studied using the Spearman rank correlation test. Multivariate analysis was performed using Cox's proportional hazards model. Statistical significance was determined using the Student's t-test. All data shown represent the results of three independent experiments at least and P–values <0.05 were considered significant.
3.1. SGTA was expressed in reactive lymphoid tissues and human B-cell Non-Hodgkin's Lymphoma
In our previous study, SGTA was found to be highly expressed in several solid neoplasms , , and . But whether this is the case for hematologic malignancies remains still unclear. Hence, immunohistochemical assay was performed to investigate the expression of SGTA in vivo in clinical NHL specimens including FL, DLBCL, MALT and NK/T except for RL tissues. In non-tumor RL tissues, SGTA was found to be expressed predominantly in proliferating germinal centers ( Fig. 1 a and b). Moreover, in lymphoma issues other than MALT, overexpression of SGTA was observed. SGTA immunoreactivity was seen primarily localized in the follicular mantle zones of FL ( Fig. 1 c and d), while in DLBCL and NK/T tissues SGTA was diffusely strong expressed ( Fig. 1 e–h). However, compared with FL and DLBCL tissues, the expression of SGTA in MALT tissues was much weaker ( Fig. 1 i and j). Finally, we used PBS-based control as an alternative approach to evaluate the specificity of IHC signaling ( Fig. 1 k and l).
3.2. SGTA expression was associated with high-risk clinical parameters in NHL
The level of SGTA and Ki-67 expression was divided into high group and low group according to the cuf-off value stated in aforementioned methods. Pearson χ2 test was performed to analyze the association of SGTA expression with clinicopathologic variables including Ki-67 expression ( Table 1 ). The expression of SGTA was found to be significantly positive correlated with poor prognostic factor Ki-67 (P < 0.001), which is a proliferation index. In addition, SGTA was found to be high expressed in DLBCL with positive rate of 64.86% (24/37), while low expressed in MALT with positive rate of 25% (7/28). However, no significant correlation was detected between SGTA expression and other International Prognostic Index (IPI) risk factors, including age, gender, extranodal sites, serum lactate dehydrogenase, and treatment  and . To further confirm the correlation of SGTA and Ki-67 expression by twos, Spearman's correlation test was performed by positive rate ( Table 2 ). Significant positive correlation was found in DLBCL, MALT and NK/T. And Spearman correlation coefficient (γ) equals to 0.457 (P = 0.004), 0.486 (P = 0.009) and 0.009 (P = 0.009) respectively. Additionally, multivariate analysis using the Cox proportional hazards model demonstrated that SGTA expression (P < 0.001), Ki-67 expression (P < 0.001), and age (P < 0.001) were independent prognostic factors of overall survival ( Table 3 ).
|Parameters||Total||SGTA expression||P value|
|Lactate dehydrogenase a||0.532|
|Ki-67 expression||<0.001 *|
a Information not available in some cases.
* P < 0.05 was considered significant.
Statistical analyses were performed by the Pearson χ2 test.
* P < 0.05 was considered significant.
|Relative ratio||95% confidence interval||P value|
|Lactate dehydrogenase *||1.536||0.833–2.833||0.170|
|Ki-67 expression||4.389||2.239–8.048||<0.001 *|
|SGTA expression||4.062||2.212–7.461||<0.001 *|
* P < 0.05 was considered significant.
Statistical analyses were performed by Cox test.
3.3. SGTA expression was up-regulated in proliferating NHL cells
Previous studies have demonstrated that the SGTA might play an important role in the cell cycle progression of various carcinomas , , and . Here, to investigate the expression of SGTA during NHL progression, Daudi cells were cultured in serum-free conditioned medium for 48 h and then recovered serum refeeding. FACS assay demonstrated that cells were arrested in the G1 phase after serum deprivation. On serum re-addition, cells were released from the G1 phase and re-entered the S phase ( Fig. 2 a). Next Western blot assay was performed to analyze the expression of SGTA, cyclin A and p27Kip1 in proliferating NHL cells ( Fig. 2 b and c). As expected, the expression of SGTA was gradually increased as early as 4 h after serum refeeding and it reached the peak level 24 h later, which was in accordance with the expression of cell cycle marker cyclin A. However, the expression of cyclin-dependent kinases (CDK) inhibitor p2Kip1, a major regulator of G1–S transition in the cell cycle progression, was conversely decreased during NHL cell proliferation. These data indicated that SGTA and p2Kip1 were conversely related to each other, and SGTA expression might promote proliferation of NHL cells.
3.4. Knockdown of SGTA inhibited the proliferation of NHL cells
To further investigate the potential effect of SGTA on NHL cell proliferation, Daudi cells were transiently transfected with SGTA-siRNA or control siRNA for 48 h, and the efficiency of transfection was confirmed by Western blot analysis ( Fig. 3 a and b). It showed that SGTA-siRNA#2 had the highest efficiency and was chosen for the next assay. Daudi and OCI-LY8 cells were then transfected with SGTA-siRNA#2 and the expression of SGTA, PCNA, cyclin A and p2Kip1 was measured by western blot assay ( Fig. 3 c). It showed that knockdown of SGTA resulted in significant decrease of PCNA expression, which is a cell proliferation marker. Moreover, down-regulation of SGTA was correlated with decreased expression of cyclin A, which is a key cell cycle regulator. In consistent with the previous serum starvation and release experiments, SGTA down-regulation led to inversely up-regulation of p2 Kip1. Next, CCK-8 assay was performed to measure cell viability of SGTA knocked-down cells ( Fig. 3 d). It showed that knockdown of SGTA resulted in a significant inhibition of cell growth rate. To explore the mechanism of the decreased cell growth affected by SGTA-siRNA, cell cycle distributions of cells transfected with SGTA-siRNA or control siRNA were determined by FACS. The percentage of cells in the S phase of SGTA knocked down cells was obviously decreased as compared with that of control siRNA cells ( Fig. 3 e), suggesting that SGTA may be able to promote the G0/G1-S transition and thus the cell growth. In conclusion, these data suggested that the expression of SGTA might associate with the expression of cell cycle regulator and promote the G1/S transition, which might be responsible for the NHL cells proliferation.
3.5. Adhesion to FN or bone marrow stroma down regulated SGTA expression, which in turn induced cell adhesion
It has been reported that adhesion of hematologic malignancies cells to FN results in a reversible cell cycle arrest, which in turn promotes CAM-DR , , and . Therefore, cell adhesion assay was performed to elucidate the correlation between cell adhesion and the expression of SGTA. The expression of SGTA was evaluated following 2 h of Daudi or OCI-LY8 cell adhesion to FN or HS-5 cells by western blot assay. It showed that SGTA expression was significantly decreased in cells adhered to FN or HS-5 cells compared with those in suspension ( Fig. 4 a and b). Next the role of SGTA in NHL cell adhesion was investigated by SGTA-siRNA assay. Cell adhesion assay revealed that cell adhesion rate was significantly increased after knockdown of SGTA ( Fig. 4 c). Taken together these data suggested that SGTA expression might negatively correlated with cell adhesion.
3.6. SGTA silencing induced adhesion-mediated drug resistance
CAM-DR is thought to be one of the major mechanisms by which tumor cells escape the cytotoxic effects of therapeutic agents , , and . In this study, we have shown that SGTA expression inhibited adhesion of lymphoma cells. However, the specific contribution of SGTA in drug resistance has yet to be addressed. Therefore, SGTA-siRNA assay was performed to knock down SGTA expression in Daudi and OCI-LY8 cells cultured in 3 different conditions including adhesion to FN, or HS-5 cells or in suspension. In our preliminary experiment, the proper Doxorubicin concentration for treatment of the two cell lines was set for 1 μM, at which cells were sensitive to drug induced apoptosis ( Fig. 5 a and d). Next to evaluate the effect of SGTA down-regulation on Doxorubicin resistance, CCK-8 assay was performed following addition of 1 μM Doxorubicin for 48 h ( Fig. 5 b and e) or 72 h ( Fig. 5 c and f). In another experiment, when Mitoxantrone was substituted for Doxorubicin with double concentration, we came to the similar results (date not shown). It showed that adhesion to FN or HS-5 cells significantly protected Daudi cells or OCI-LY8 cells from cytotoxicity of Doxorubicin compared with cells in suspension, and this effect was further enhanced with down-regulation of SGTA. In a word, these data supported a role of SGTA down-regulation in conferring drug resistance through cell-adhesion mechanisms.
NHL comprises a group of clinically and biologically diverse diseases, which range from indolent to aggressive clinical courses  . Although the rates of morbidity and mortality have decreased in recent years with conventional chemotherapy, the prognosis of NHL still remains unsatisfactory. What's more, many indolent tumors show a higher percentage of recurrence and metastasis. However, recent studies have shown that tumor microenvironment, which affords NHL cells a network of proliferative and survival factors, must be considered when evaluating drug response  and . Therefore, a deeper understanding of the molecular events associated with tumor microenvironment in NHL is of great necessity. High expression of SGTA accelerates the growth of several solid carcinomas , , and , indicating that it has a critical role in regulation of tumor cell proliferation. However, whether SGTA involves in NHL development remains largely unknown.
In this study, we first detected SGTA expression in both reactive lymphoid tissues and several lymphomas, including FL, DLBCL and NK/T. Generally speaking, SGTA expression pattern was different according to different lymphoma subtypes. SGTA signals were predominantly distributed in the proliferating germinal centers in RL and the follicular mantle zones in FL, while in DLBCL and NK/T tissues SGTA immunoreactivity was diffusely strong. However the expression of SGTA in MALT was much weaker, which could be attributed to its indolent tumor nature. Moreover, we also have correlated SGTA expression in NHL with poor survival by Kaplan–Meier survival analysis. SGTA expression was associated with high-risk clinical parameters and it was identified as an independent prognostic factor for NHL by multivariate analysis. SGTA may be an important factor in identifying a poor prognostic group of NHL.
Previous studies have demonstrated that adhesion to bone marrow stroma contributes greatly to the development of drug resistance to chemotherapy in multiple myeloma, Non-Hodgkin's Lymphomas and acute, chronic leukemia , , and . The emergence of acquired drug resistance continues to impede progress in the treatment of many hematologic neoplasms. This issue had not been extensively addressed, although the adhesion status of NHL cells may be of outstanding significance for their response to therapeutic drugs. Previously, our laboratory has shown that adhesion of multiple myeloma cells to FN can confer a form of drug resistance , , , and . In this study the relationship between SGTA expression and adhesion of NHL cells was investigated. Down-regulation of SGTA induced cell adhesion, thus involved in the survival of NHL cells against chemotherapy and protected NHL cells from doxorubicin-induced apoptosis. SGTA knockdown increased adhesion which gave rise to CAM-DR. Hence, SGTA appeared to have specific effects on CAM-DR which was similar to anti-apoptotic proteins. These data indicates that SGTA up-regulation may sensitize lymphoma cells to chemotherapy and therefore be target for drug resistance. However, the mechanism underlying SGTA mediated drug sensitivity is not fully characterized and needs to be further investigated. Nevertheless it should be noted that down-regulation of SGTA induced p27kip1 expression ( Fig. 3 c). Overexpression of p27kip1 has been reported to protect cells from apoptosis induced by chemotherapeutic drugs. Cell adhesion can mediate p27 kip1 elevation and it is associated with cell-cycle arrest , , and . Knockdown of SGTA could lead to the CAM-DR phenotype, which might be related to p27 kip1 overexpression. Our study, for the first time, demonstrated that the negative correlation between SGTA and p2Kip1 expression might be the reason for cell cycle arrest and CAM-DR in NHL cells. Further investigation needs to be performed to illustrate the mechanism of regulation between SGTA and p27kip1.
In conclusion, our study showed that SGTA may play a role in tumor cell proliferation and CAM-DR in NHL. SGTA down regulation might decrease NHL cell proliferation, but lead to induction of adhesion, which in turn resulting in drug resistance. The balance between the two aspects of SGTA should be taken into account in terms of NHL treatment.
Conflict of interest statement
We declare that we have no conflict of interest.
Supported by grants from the National Natural Science Foundation of China (No. 81172879, No. 81201858, No. 81372537); Natural Scientific Foundation of Jiangsu Province Grant (No. BK2012231); A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).
Authors contributions: YCW, YJH, LLJ and SH conceived the experiment. YJH and JT designed and performed the experiments. XTH screened antibodies and optimized the technique. As pathologists, XBM and YXW evaluated antibody performance and determine the optimal concentrations. LLJ provided pathological consultation on image quality and experimental design. XHX performed IHC scoring in this study and helped to select suitable cases. All authors contributed to the data analysis and interpretation. JYZ and FY performed the statistical analysis. YCW and YJH searched the relevant literature and prepared the manuscript. All authors were involved in editing the paper and have approved the submitted version.
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a Department of Pathology, Affiliated Cancer Hospital of Nantong University, Nantong 226361, Jiangsu, China
b Department of Pathology, Medical College, Nantong University, Nantong 226001, Jiangsu, China
c Department of Pediatrics, Medical College, Nantong University, Nantong 226001, Jiangsu, China
1 These authors contributed equally to this work.
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