Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 


 
 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 15  |  Issue : 4  |  Page : 927-932

Interleukin 10 promotes growth and invasion of glioma cells by up-regulating KPNA 2 in vitro


1 Department of Medical, Queen Mary School, Nanchang University, Nanchang, Jiangxi, China
2 Department of Neurosurgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China
3 Department of Neurosurgery, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang, Jiangxi, China
4 Department of Neurosurgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong; Department of Neurosurgery, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang, Jiangxi, China

Date of Web Publication14-Aug-2019

Correspondence Address:
Wei Sun
No. 92 Aiguo Road, Nanchang, 330006 Jiangxi
China
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_284_19

Rights and Permissions
 > Abstract 


Objective: Glioma is one of the leading causes of death worldwide with high incidence, recurrence, and mortality. Interleukin-10 (IL-10) is a cytokine with dual function in many types of tumors. Although IL-10 is overexpressed and promotes tumor progression in human primary brain tumor, the mechanisms are largely unknown.
Materials and Methods: Glioma cells were treated with different dosages of IL-10. The cell growth was detected by CCK-8, and the invasion was measured by Transwell. The relative expression of messenger RNAs was detected by quantitative real-time polymerase chain reaction.
Results: We found that IL-10 treatment significantly enhanced glioma cell growth and invasion. Moreover, KPNA2 was significantly upregulated after treatment with IL-10. By performing knockdown experiments, we found that the glioma cell growth and invasion were significantly declined.
Conclusions: The results indicated that knockdown of KPNA2 significantly inhibited the growth and invasion of glioma cells. Moreover, IL-10 promotes glioma progression via upregulation of KPNA2. This study will be of important significance and provides a potential target for treatment of patients with glioma.

Keywords: Cell growth, cell invasion, glioma, interleukin-10, KPNA2


How to cite this article:
Zhang Z, Huang X, Li J, Fan H, Yang F, Zhang R, Yang Y, Feng S, He D, Sun W, Xin T. Interleukin 10 promotes growth and invasion of glioma cells by up-regulating KPNA 2 in vitro. J Can Res Ther 2019;15:927-32

How to cite this URL:
Zhang Z, Huang X, Li J, Fan H, Yang F, Zhang R, Yang Y, Feng S, He D, Sun W, Xin T. Interleukin 10 promotes growth and invasion of glioma cells by up-regulating KPNA 2 in vitro. J Can Res Ther [serial online] 2019 [cited 2019 Sep 18];15:927-32. Available from: http://www.cancerjournal.net/text.asp?2019/15/4/927/264284




 > Introduction Top


Glioma is the most common tumor arising from the central nervous system with an incidence of 22/100,000 population,[1] accounting for 75% of malignant primary brain tumors in adults.[2] It initiates from glial or precursor cells, and the 5-year survival rates are around 10%.[3] Currently, the therapeutic strategies for glioma are surgical resection, combined with radiotherapy (RT), chemotherapy, and/or targeted therapy according to the molecular features of the tumor for patients with newly diagnosed with glioma.[4] However, glioma remains incurable and its poor prognosis contributes to high rates of recurrence. Thus, it is essential to develop new strategies to inhibit glioma progression.

Interleukin-10 (IL-10) was first considered as a T helper 2 cytokine, which modulates the growth and differentiation of innate immune cells, endothelial cells, and keratinocytes and suppresses the activation and functions of T-cells.[5] Numerous kinds of cells can produce IL-10, such as Tregs, B-cells, macrophages, mast cells, dendritic cells, and epithelial cells in mice and human.[6],[7] IL-10 was regarded as a suppressive factor that impaired the proliferation, cytokine production, and migration of effector T-cells;[8] elevated level of IL-10 inhibited cytolytic activity in transplanted tumors.[9],[10] In the context of tumor, IL-10 is a double-edged sword. IL-10 administration suppressed tumor growth and led to tumor rejection in a variety of tumors, such as melanoma, sarcomas, and colorectal cancer.[11],[12],[13],[14] Conversely, IL-10 can also promote the development of lung cancer, esophageal squamous cell carcinoma, melanoma, and cervical carcinoma.[15],[16],[17],[18] In human brain tumor, IL-10 is overexpressed in human glioma, and its overexpression increases glioma cell proliferation and motility and promotes tumorigenesis.[19],[20],[21],[22] However, the mechanisms of IL-10 on glioma development are not clearly understood.

KPNA2 is a member of karyopherin α family which belongs to a family of nuclear transport proteins.[23] KPNA2 is composed of an N-terminal hydrophilic importin β -bingding domain, a central hydrophobic region, and a short acidic C-terminus and functions through regulating the subcellular translocation of cancer-associated cargo proteins.[24],[25] It was reported that KPNA2 was overexpressed in a variety of types of cancer and promoted cell growth and survival, such as breast cancer, cervical cancer, colorectal cancer, and esophageal squamous cell carcinoma.[26],[27],[28],[29],[30] In human brain tumor, KPAN2 is overexpressed in meningiomas and infiltrative astrocytomas and correlates significantly with the histological grade and proliferative activity.[31],[32] In human glioblastoma, Lu et al. reported that MIR517C inhibited the epithelial-to-mesenchymal (-like) transition phenotype through KPNA2-dependent disruption of TP53 nuclear translocation, indicating that KPNA2 is correlated with glioblastoma development.[33] Therefore, whether IL-10-mediated inhibition of glioma cell growth and motility is dependent on KPNA2 remains unclear.

In this study, we first evaluated the effect of IL-10 on glioma cell growth and invasion. Then, the expression of KPNA2 was quantified by quantitative polymerase chain reaction (q-PCR) and knocked down using small interfering RNA (siRNA) to demonstrate the role of KPNA2 in glioma cell growth and invasion. This study will be of important significance and provides a potential target for treatment of patients with glioma.


 > Materials and Methods Top


Cell line and cell culture

Glioma cell line U87 was purchased from the American Type Culture Collection (ATCC, VA, USA) and cultured in RPMI-1640 (GIBCO, NY, USA) supplemented with 10% fetal bovine serum (FBS, HyClone, UT, USA), 100 U/ml penicillin G, and 100 μg/ml streptomycin (Sigma-Aldrich, Shanghai, China) at 37°C in a 5% CO2 incubator. In all experiments, U87 cells were trypsinized at 80% confluency for further experiments.

Cell proliferation assay

The CCK-8 assay was used to determine cell proliferation ability. In brief, cells were seeded at a density of 1 × 103 cells/well in 96-well plates and incubated overnight at 37°C. IL-10 was then added into the culture medium. At the indicated time points (1, 2, 3, and 4 days), 10 μl of CCK-8 solution was added into the culture medium, and the cells were incubated for an additional 1.5 h at 37°C. Then, the absorbance of each well was measured at 450 nm using a microplate reader (Elx800, BioTek, VT, USA). All experiments were performed in quintuplicate.

Cell invasion assay

Cell invasion was performed with a Transwell Chamber (3422, Corning, NY, USA) according to the manufacturer's instruction. In brief, 100 μl diluted matrigel was put into the upper chamber of the 24-well invasion chamber and incubated at 37°C in a 5% CO2 atmosphere for 4–6 h to hydrate the matrigel. Then, 500 μl serum-free medium was added into the lower chambers for 30 min. Cells were resuspended in 100 μl serum-free media at a density of 106 cells/ml, and cell suspension was added into the upper chamber and 500μl completed medium was added into the lower chambers. After incubation overnight, cells on the upper surface of the filter membrane were scraped with cotton swabs, and those cells on the lower surface of the chamber were fixed with polyoxymethylene for 30 min and stained with 0.1% crystal violet solution for 20 min. Five visual fields were randomly selected and photographed under a light microscope at ×100 (Micropublisher 3.3RTV, Olympus, Tokyo, Japan), and the invaded cells were counted.

RNA extraction and quantitative real-time polymerase chain reaction

Total RNA from U87 cells was extracted and purified using RNA extraction kit according to the manufacturer's protocol. Reserve transcription was performed to generate complementary DNA according to the manufacturer's protocol. The messenger RNA (mRNA) level of KPNA2 was measured by q-PCR using SYBR Premix Ex Tap. The primers were used as follows:

  • β-actin forward, 5'-CCCGAGCCGTGTTTCCT-3'
  • β-actin reserve, 5'-GTCCCAGTTGGTGACGATGC-3'
  • KPNA2 forward, 5'-TGATATGTCATCTTTAGCATGTGGC-3'
  • KPNA2 reserve, 5'-GCCCACACAGCTTCCTTTTG-3'.


β-actin was used as internal control. The relative mRNA expression of these genes was calculated using the 2− ΔΔ Ct method.[34]

siRNA transfection

The siRNAs were purchased from RiboBio Company (Guangzhou, China), and the sequence of siRNA for KPNA2 is as follows:

  • siKPNA2-1: ATTTACAGTGCCCTGGTTG
  • siKPNA2-2: ATGAACGAATTGGCATGGT
  • siKPNA2-3: GCATGTGGCTACTTACGTA.


U87 cells were seeded in 6-well plates and cultured overnight. Next day, cells were transfected with the three siRNAs for KPNA2 at optimal concentration. Forty-eight hours later, cells were used for further experiments.

Statistical analysis

The Student's t-test was used to quantify the significant differences. GraphPad Prism 5 software (Graphpad, software, Inc, LaJolla, CA, USA) was used for statistical analysis. Data are presented as the mean ± standard deviation, and P < 0.05 was considered statistically significant.


 > Results Top


Interleukin-10 promotes the proliferation of glioma cells

Cancer progression is a complex process involving cell growth, migration, invasion, colony formation, and metastasis. To explore whether IL-10 affected glioma progression, we first detected the role of IL-10 in glioma cell growth. We cocultured glioma cell line U87 with different dosages of IL-10. After 24 h, CCK-8 assay was performed. We found that IL-10 promoted the cell growth of U87 in a dose-dependent manner [Figure 1]a. As shown in [Figure 1]a, IL-10 at the concentration of 50 ng/ml enhanced the proliferation of U87 cells much significantly than others [Figure 1]a (P = 0.02443235). Therefore, we used IL-10 at 50 ng/ml for further experiments. We also found that IL-10 significantly promoted the cell growth of U87 cells at day 4 compared with negative control (NC) cells [Figure 1]b (P = 0.024350635). Thus, these data demonstrated that IL-10 promotes the proliferation of glioma cells.
Figure 1: Interleukin-10 enhances glioma cell proliferation. (a) U87 cells were cultured and treated with different concentrations (5 ng/ml, 10 ng/ml, 20 ng/ml, 25 ng/ml, 50 ng/ml, and 75 ng/ml) of interleukin-10 for 24 h, and then, CCK-8 assay was performed. The results were presented as mean ± standard deviation. *P < 0.05, **P < 0.01. (b) U87 cells were treated with or without interleukin-10 (50 ng/ml) for 24 h. Cells without treatment of interleukin-10 were used as controls (negative control). CCK-8 assay was performed every day at each time points (day 1, day 2, day 3, and day 4). The experiment was performed in quintuplicate. Data were shown as mean ± standard deviation. *P < 0.05

Click here to view


Interleukin-10 enhances the invasion of glioma cells

Next, we assessed the role of IL-10 in glioma cell invasion by cell invasion assay. As compared with NC cells, IL-10 treatment remarkably increases the number of invasion cells [Figure 2]a and [Figure 2]b (P = 0.049071933). These results demonstrated that IL-10 treatment enhanced the invasion of human glioma cells.
Figure 2: Interleukin-10 promotes glioma cell invasion. (a and b) U87 cells treated with or without (negative control) interleukin-10 were seeded in Matrigel-coated Transwell chamber overnight. Cell invasion assay was performed (a) and invasion cells were counted from at least five random fields at ×100 (b). Data are shown as mean ± standard deviation of three independent experiments. *P < 0.05

Click here to view


Interleukin-10 increases the expression of KPNA2 in glioma cells

We further explored the mechanisms by which IL-10 promoted the glioma cell proliferation and invasion. Many studies have shown that KPNA2 played a role in cell growth and invasion of many cancer cells, including human brain tumor.[26],[27],[29],[31],[32] Therefore, we examined the expression of KPNA2 in IL-10-treated U87 cells. We found that IL-10 significantly increased KPNA2 mRNA levels in U87 cells compared with untreated control cells [Figure 3] (P = 0.02405).
Figure 3: Interleukin-10 increases the expression of KPNA2 in glioma cells. U87 cells were treated with or without (negative control) interleukin-10 for 48 h. The mRNA levels of KPNA2 were assessed by quantitative real-time polymerase chain reaction. Results shown are the mean ± standard deviation of three independent experiments. *P < 0.05

Click here to view


Knockdown of KPNA2 inhibits the proliferation of glioma cells

To investigate the role of KPNA2 in glioma cell growth, we used siRNA to specifically silence KPNA2 in U87 cells. We first examined the knockdown efficiency of KPNA2. As shown in [Figure 4]a, the expression of KPNA2 was significantly inhibited in U87 cells [Figure 4]a (P = 0.00852). We found that knockdown of KPNA2 significantly inhibited the cell growth of U87 cells at day 3 and day 4 compared with NC cells [Figure 4]b (P = 0.015472 and P = 0.0285163). Taken together, these data demonstrated that KPNA2 affected the glioma cell growth.
Figure 4: KPNA2 knockdown suppressed glioma cell growth. (a and b) U87 cells were transfected with negative control (siNC) or siKPNA2. (a) The mRNA levels of KPNA2 were assessed using quantitative real-time polymerase chain reaction. Data are shown as mean ± standard deviation of three independent experiments. (b) CCK-8 assay assessed cell proliferation every day for 4 days. The experiment was performed in quintuplicate. Data were shown as mean ± standard deviation. *P < 0.05

Click here to view


Knockdown of KPNA2 suppressed the invasion of glioma cells

We also assessed the effect of KPNA2 on cell invasion of U87 cells. The results showed that knockdown of KPNA2 significantly decreased the cell invasion of U87 cells [Figure 5] (P = 0.033081433). Thus, we confirmed that KPNA2 contributes to the invasion of glioma cells. Taken together, we found that IL-10 promoted glioma cell progression via upregulation of KPNA2.
Figure 5: KPNA2 knockdown inhibited the glioma cell invasion. (a and b) U87 cells transfected with negative control (siNC) or siKPNA2 were seeded in Matrigel-coated Transwell chamber overnight. Then, cell invasion assay was performed (a). Invasion cells were counted from at least five random fields at × 100 (b). Data were presented as mean ± standard deviation of three independent experiments. *P < 0.05

Click here to view



 > Discussion Top


In this study, we report that IL-10 promotes cell growth and invasion in glioma cells. We found that IL-10 increased the expression of KPNA2, and knockdown of KPNA2 significantly inhibited the glioma cell growth and invasion, indicating that IL-10 promotes glioma cell growth and invasion via upregulation of KPNA2.

The survival rate in high-grade glioma patients receiving a combined regimen of RT and temozolomide after tumor resection was increased. However, cognitive deficits and depression after the treatments challenge the treatments.[35] Immunotherapy for cancer is a new and promising treatment method besides operation, RT, and chemotherapy. Moreover, it has been applied to treat malignancies, such as lung cancer, melanoma, renal carcinoma, and hematological malignancy.[36] IL-10 is a cytokine which plays a dual function in many types of cancers.[11],[12],[13],[14],[15],[16],[17],[18] For example, IL-10 promotes resistance to apoptosis and metastatic potential in lung cancer cell lines.[15] Overexpression of IL-10 leads to frequent event of immune evasion in esophageal squamous cell carcinoma.[17] IL-10 facilitates the progression of cervical cancer.[18] However, IL-10 is also reported to inhibit tumor development, growth, and metastasis in melanoma, colon cancer, and fibrosarcoma.[12],[14] Increased production of IL-10 was reported in glioma.[37],[38] In glioma, IL-10 stimulates the tumor-associated macrophages to express B7-H1, thus suppressing the immune system.[39] On the other hand, under the influence of glioma, microglia release several classes of molecules, including IL-10, that promote glioma growth, progression, and inflammatory activation.[40] To clarify the function of IL-10 in human glioma progression, we detected the glioma cell growth and invasion after treatment with IL-10. Our results and previous reports all revealed that IL-10 treatment promoted the glioma cell growth and invasion.

Heterogeneity is a hallmark of cancer.[41],[42] Thus, the mechanisms of tumor cell growth, invasion, migration, and metastasis in various types of tumor may be different, and there are many factors to promote tumor progression in the same type of tumor. For example, long noncoding RNAs, circular RNAs, cytokines, and migrating myeloid cells are all associated with glioma progression.[19],[22],[43],[44],[45],[46],[47] KPNA2 is a member of karyopherin α family. It promotes tumor progression in many kinds of tumors, including glioma, breast cancer, cervical cancer, colorectal cancer, and esophageal squamous cell carcinoma.[26],[27],[28],[29],[31],[32],[33] KPNA2 is required for IL-1β-induced MMP-mediated metastasis in oral cavity squamous cell carcinoma.[48] KPNA2 also enhanced the TNFα-induced expression of IL-6, MMP-1, and MMP-13 and increased the P65 phosphorylation in human synovial sarcoma cells.[49] Thus, whether KPNA2 mediates IL-10-induced glioma cell growth and invasion remains unclear. In this study, we found that KPNA2 was significantly upregulated in glioma cells after treatment with IL-10. Using shRNA, knockdown of KPNA2 significantly inhibited glioma cell growth and invasion, suggesting that IL-10 maybe promote glioma cell growth dependent on KPNA2. However, further experiments will be necessary to identify the interaction of IL-10 with KPNA2.

In view of a recent study showing that KPNA2 plays a crucial role in the metabolic reprogramming of glioma cells by mediating the nuclear transportation of c-Myc and E2F1,[30] we hypothesize that IL-10 may have an important role in regulating the metabolism of glioma cells, but further experiments are needed to prove it.


 > Conclusions Top


We confirmed that IL-10 promoted glioma cell growth and invasion, and we proposed for the first time that IL-10 promoted glioma cell growth and invasion via upregulation of KPNA2. The present study provided a potential target for treatment of patients with glioma.

Financial support and sponsorship

This work was financially supported by the Science and Technology Project of Jinan city (Grant No. 201602162), Shandong Provincial Natural Science Foundation (Grant No.ZR2014HM010), and Shandong Province Science and Technology Development Program (Grant No. 2015GSF118164).

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Ostrom QT, Gittleman H, Liao P, Vecchione-Koval T, Wolinsky Y, Kruchko C, et al. CBTRUS statistical report: Primary brain and other central nervous system tumors diagnosed in the United States in 2010-2014. Neuro Oncol 2017;19:v1-88.  Back to cited text no. 1
    
2.
Lapointe S, Perry A, Butowski NA. Primary brain tumours in adults. Lancet 2018;392:432-46.  Back to cited text no. 2
    
3.
Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009;10:459-66.  Back to cited text no. 3
    
4.
Jiang T, Mao Y, Ma W, Mao Q, You Y, Yang X, et al. CGCG clinical practice guidelines for the management of adult diffuse gliomas. Cancer Lett 2016;375:263-73.  Back to cited text no. 4
    
5.
Moore KW, O'Garra A, de Waal Malefyt R, Vieira P, Mosmann TR. Interleukin-10. Annu Rev Immunol 1993;11:165-90.  Back to cited text no. 5
    
6.
Dennis KL, Blatner NR, Gounari F, Khazaie K. Current status of interleukin-10 and regulatory T-cells in cancer. Curr Opin Oncol 2013;25:637-45.  Back to cited text no. 6
    
7.
Jung HC, Eckmann L, Yang SK, Panja A, Fierer J, Morzycka-Wroblewska E, et al. A distinct array of proinflammatory cytokines is expressed in human colon epithelial cells in response to bacterial invasion. J Clin Invest 1995;95:55-65.  Back to cited text no. 7
    
8.
Moore KW, de Waal Malefyt R, Coffman RL, O'Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 2001;19:683-765.  Back to cited text no. 8
    
9.
De Santo C, Arscott R, Booth S, Karydis I, Jones M, Asher R, et al. Invariant NKT cells modulate the suppressive activity of IL-10-secreting neutrophils differentiated with serum amyloid A. Nat Immunol 2010;11:1039-46.  Back to cited text no. 9
    
10.
Steinbrink K, Jonuleit H, Müller G, Schuler G, Knop J, Enk AH. Interleukin-10-treated human dendritic cells induce a melanoma-antigen-specific anergy in CD8(+) T cells resulting in a failure to lyse tumor cells. Blood 1999;93:1634-42.  Back to cited text no. 10
    
11.
Suzuki T, Tahara H, Narula S, Moore KW, Robbins PD, Lotze MT. Viral interleukin 10 (IL-10), the human herpes virus 4 cellular IL-10 homologue, induces local anergy to allogeneic and syngeneic tumors. J Exp Med 1995;182:477-86.  Back to cited text no. 11
    
12.
Zheng LM, Ojcius DM, Garaud F, Roth C, Maxwell E, Li Z, et al. Interleukin-10 inhibits tumor metastasis through an NK cell-dependent mechanism. J Exp Med 1996;184:579-84.  Back to cited text no. 12
    
13.
Berman RM, Suzuki T, Tahara H, Robbins PD, Narula SK, Lotze MT. Systemic administration of cellular IL-10 induces an effective, specific, and long-lived immune response against established tumors in mice. J Immunol 1996;157:231-8.  Back to cited text no. 13
    
14.
Tanikawa T, Wilke CM, Kryczek I, Chen GY, Kao J, Núñez G, et al. Interleukin-10 ablation promotes tumor development, growth, and metastasis. Cancer Res 2012;72:420-9.  Back to cited text no. 14
    
15.
Zeng L, O'Connor C, Zhang J, Kaplan AM, Cohen DA. IL-10 promotes resistance to apoptosis and metastatic potential in lung tumor cell lines. Cytokine 2010;49:294-302.  Back to cited text no. 15
    
16.
Vahl JM, Friedrich J, Mittler S, Trump S, Heim L, Kachler K, et al. Interleukin-10-regulated tumour tolerance in non-small cell lung cancer. Br J Cancer 2017;117:1644-55.  Back to cited text no. 16
    
17.
Gholamin M, Moaven O, Memar B, Farshchian M, Naseh H, Malekzadeh R, et al. Overexpression and interactions of interleukin-10, transforming growth factor beta, and vascular endothelial growth factor in esophageal squamous cell carcinoma. World J Surg 2009;33:1439-45.  Back to cited text no. 17
    
18.
Berti FC, Pereira AP, Cebinelli GC, Trugilo KP, Brajão de Oliveira K. The role of interleukin 10 in human papilloma virus infection and progression to cervical carcinoma. Cytokine Growth Factor Rev 2017;34:1-3.  Back to cited text no. 18
    
19.
Huettner C, Czub S, Kerkau S, Roggendorf W, Tonn JC. Interleukin 10 is expressed in human gliomas in vivo and increases glioma cell proliferation and motility in vitro. Anticancer Res 1997;17:3217-24.  Back to cited text no. 19
    
20.
Qiu B, Zhang D, Wang C, Tao J, Tie X, Qiao Y, et al. IL-10 and TGF-β2 are overexpressed in tumor spheres cultured from human gliomas. Mol Biol Rep 2011;38:3585-91.  Back to cited text no. 20
    
21.
Qi L, Yu H, Zhang Y, Zhao D, Lv P, Zhong Y, et al. IL-10 secreted by M2 macrophage promoted tumorigenesis through interaction with JAK2 in glioma. Oncotarget 2016;7:71673-85.  Back to cited text no. 21
    
22.
Zhen Z, Guo X, Liao R, Yang K, Ye L, You Z. Involvement of IL-10 and TGF-β in HLA-E-mediated neuroblastoma migration and invasion. Oncotarget 2016;7:44340-9.  Back to cited text no. 22
    
23.
Goldfarb DS, Corbett AH, Mason DA, Harreman MT, Adam SA. Importin alpha: A multipurpose nuclear-transport receptor. Trends Cell Biol 2004;14:505-14.  Back to cited text no. 23
    
24.
Christiansen A, Dyrskjøt L. The functional role of the novel biomarker karyopherin α 2 (KPNA2) in cancer. Cancer Lett 2013;331:18-23.  Back to cited text no. 24
    
25.
Wang CI, Chien KY, Wang CL, Liu HP, Cheng CC, Chang YS, et al. Quantitative proteomics reveals regulation of karyopherin subunit alpha-2 (KPNA2) and its potential novel cargo proteins in nonsmall cell lung cancer. Mol Cell Proteomics 2012;11:1105-22.  Back to cited text no. 25
    
26.
Dahl E, Kristiansen G, Gottlob K, Klaman I, Ebner E, Hinzmann B, et al. Molecular profiling of laser-microdissected matched tumor and normal breast tissue identifies karyopherin alpha2 as a potential novel prognostic marker in breast cancer. Clin Cancer Res 2006;12:3950-60.  Back to cited text no. 26
    
27.
van der Watt PJ, Maske CP, Hendricks DT, Parker MI, Denny L, Govender D, et al. The karyopherin proteins, Crm1 and karyopherin beta1, are overexpressed in cervical cancer and are critical for cancer cell survival and proliferation. Int J Cancer 2009;124:1829-40.  Back to cited text no. 27
    
28.
Sakai M, Sohda M, Miyazaki T, Suzuki S, Sano A, Tanaka N, et al. Significance of karyopherin-{alpha} 2 (KPNA2) expression in esophageal squamous cell carcinoma. Anticancer Res 2010;30:851-6.  Back to cited text no. 28
    
29.
Yu L, Wang G, Zhang Q, Gao L, Huang R, Chen Y, et al. Karyopherin alpha 2 expression is a novel diagnostic and prognostic factor for colorectal cancer. Oncol Lett 2017;13:1194-200.  Back to cited text no. 29
    
30.
Li J, Liu Q, Liu Z, Xia Q, Zhang Z, Zhang R, et al. KPNA2 promotes metabolic reprogramming in glioblastomas by regulation of c-myc. J Exp Clin Cancer Res 2018;37:194.  Back to cited text no. 30
    
31.
Gousias K, Niehusmann P, Gielen GH, Simon M. Karyopherin a2 and chromosome region maintenance protein 1 expression in meningiomas: Novel biomarkers for recurrence and malignant progression. J Neurooncol 2014;118:289-96.  Back to cited text no. 31
    
32.
Gousias K, Becker AJ, Simon M, Niehusmann P. Nuclear karyopherin a2: A novel biomarker for infiltrative astrocytomas. J Neurooncol 2012;109:545-53.  Back to cited text no. 32
    
33.
Lu Y, Xiao L, Liu Y, Wang H, Li H, Zhou Q, et al. MIR517C inhibits autophagy and the epithelial-to-mesenchymal (-like) transition phenotype in human glioblastoma through KPNA2-dependent disruption of TP53 nuclear translocation. Autophagy 2015;11:2213-32.  Back to cited text no. 33
    
34.
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;25:402-8.  Back to cited text no. 34
    
35.
Wang Q, Qi F, Song X, Di J, Zhang L, Zhou Y, et al. A prospective longitudinal evaluation of cognition and depression in postoperative patients with high-grade glioma following radiotherapy and chemotherapy. J Cancer Res Ther 2018;14:S1048-51.  Back to cited text no. 35
    
36.
Rosenberg SA. Progress in human tumour immunology and immunotherapy. Nature 2001;411:380-4.  Back to cited text no. 36
    
37.
Hishii M, Nitta T, Ishida H, Ebato M, Kurosu A, Yagita H, et al. Human glioma-derived interleukin-10 inhibits antitumor immune responses in vitro. Neurosurgery 1995;37:1160-6.  Back to cited text no. 37
    
38.
Huettner C, Paulus W, Roggendorf W. Messenger RNA expression of the immunosuppressive cytokine IL-10 in human gliomas. Am J Pathol 1995;146:317-22.  Back to cited text no. 38
    
39.
Bloch O, Crane CA, Kaur R, Safaee M, Rutkowski MJ, Parsa AT. Gliomas promote immunosuppression through induction of B7-H1 expression in tumor-associated macrophages. Clin Cancer Res 2013;19:3165-75.  Back to cited text no. 39
    
40.
Li W, Graeber MB. The molecular profile of microglia under the influence of glioma. Neuro Oncol 2012;14:958-78.  Back to cited text no. 40
    
41.
Allison KH, Sledge GW. Heterogeneity and cancer. Oncology (Williston Park) 2014;28:772-8.  Back to cited text no. 41
    
42.
Burrell RA, McGranahan N, Bartek J, Swanton C. The causes and consequences of genetic heterogeneity in cancer evolution. Nature 2013;501:338-45.  Back to cited text no. 42
    
43.
Ramos AD, Attenello FJ, Lim DA. Uncovering the roles of long noncoding RNAs in neural development and glioma progression. Neurosci Lett 2016;625:70-9.  Back to cited text no. 43
    
44.
Yang Y, Gao X, Zhang M, Yan S, Sun C, Xiao F, et al. Novel role of FBXW7 circular RNA in repressing glioma tumorigenesis. J Natl Cancer Inst 2018;110:djx166.  Back to cited text no. 44
    
45.
Lim M, Xia Y, Bettegowda C, Weller M. Current state of immunotherapy for glioblastoma. Nat Rev Clin Oncol 2018;15:422-42.  Back to cited text no. 45
    
46.
Ma L, Wang H, Li Z, Geng X, Li M. Chemokine (C-C motif) ligand 18 is highly expressed in glioma tissues and promotes invasion of glioblastoma cells. J Cancer Res Ther 2019;15:358-64.  Back to cited text no. 46
    
47.
Wang F, Chen Q. The analysis of deregulated expression of the timeless genes in gliomas. J Cancer Res Ther 2018;14:S708-12.  Back to cited text no. 47
    
48.
Wang CI, Yu CJ, Huang Y, Yi JS, Cheng HW, Kao HK, et al. Association of overexpressed karyopherin alpha 2 with poor survival and its contribution to interleukin-1β-induced matrix metalloproteinase expression in oral cancer. Head Neck 2018;40:1719-33.  Back to cited text no. 48
    
49.
Liu Z, Zhang D, Sun C, Tao R, Xu X, Xu L, et al. KPNA2 contributes to the inflammatory processes in synovial tissue of patients with rheumatoid arthritis and SW982 cells. Inflammation 2015;38:2224-34.  Back to cited text no. 49
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  >Abstract>Introduction>Materials and Me...>Results>Discussion>Conclusions>Article Figures
  In this article
>References

 Article Access Statistics
    Viewed184    
    Printed0    
    Emailed0    
    PDF Downloaded6    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]