Top

Published in:

Open Access 01-12-2021 | Soft Tissue Sarcoma | Research

Expression of IL4Rα and IL13Rα1 are associated with poor prognosis of soft-tissue sarcoma of the extremities, superficial trunk, and retroperitoneum

Authors: Kyoung Min Kim, Usama Khamis Hussein, See-Hyoung Park, Young Jae Moon, Zhongkai Zhang, Asmaa Gamal Ahmed, Ae-Ri Ahn, Ho Sung Park, Jung Ryul Kim, Kyu Yun Jang

Published in: Diagnostic Pathology | Issue 1/2021

Abstract

Background

IL4Rα and IL13Rα1 are constituents of the type II IL4 receptor. Recently, IL4Rα and IL13Rα1 were reported to have roles in cancer progression and suggested as potential prognostic markers. However, studies on IL4Rα and IL13Rα1 in soft-tissue sarcomas have been limited.

Methods

This study investigated the immunohistochemical expression of IL4Rα and IL13Rα1 in 89 soft-tissue sarcomas of the extremities, superficial trunk, and retroperitoneum. Immunohistochemical staining for IL4Rα and IL13Rα1 were scored according to a combination of staining intensity and staining area in tissue microarray samples. Positivity for the immunohistochemical expression of IL4Rα and IL13Rα1 were determined using receiver operating curve analysis. Statistical analysis was performed using regression analysis and a chi-square test.

Results

In human soft-tissue sarcomas, immunohistochemical expression of IL4Rα was significantly associated with IL13Rα1 expression. Nuclear and cytoplasmic expression of IL4Rα and IL13Rα1 were significantly associated with shorter survival of soft-tissue sarcoma patients in univariate analysis. Multivariate analysis indicated that nuclear expression of IL4Rα and IL13Rα1 were independent indicators of shorter overall survival (IL4Rα; p = 0.002, IL13Rα1; p = 0.016) and relapse-free survival (IL4Rα; p = 0.022, IL13Rα1; p < 0.001) of soft-tissue sarcoma patients. Moreover, the co-expression pattern of nuclear IL4Rα and IL13Rα1 was an independent indicator of shorter survival of soft-tissue sarcoma patients (overall survival; overall p < 0.001, relapse-free survival; overall p < 0.001).

Conclusions

This study suggests IL4Rα and IL13Rα1 are associated with the progression of soft-tissue sarcoma, and the expression of IL4Rα and IL13Rα1 might be novel prognostic indicators of soft-tissue sarcoma patients.

Hallett MA, Venmar KT, Fingleton B. Cytokine stimulation of epithelial cancer cells: the similar and divergent functions of IL-4 and IL-13. Cancer Res. 2012;72:6338–43.PubMedPubMedCentralCrossRef

Bankaitis KV, Fingleton B. Targeting IL4/IL4R for the treatment of epithelial cancer metastasis. Clin Exp Metastasis. 2015;32:847–56.PubMedPubMedCentralCrossRef

Suzuki A, Leland P, Joshi BH, Puri RK. Targeting of IL-4 and IL-13 receptors for cancer therapy. Cytokine. 2015;75:79–88.PubMedCrossRef

LaPorte SL, Juo ZS, Vaclavikova J, Colf LA, Qi X, Heller NM, et al. Molecular and structural basis of cytokine receptor pleiotropy in the interleukin-4/13 system. Cell. 2008;132:259–72.PubMedPubMedCentralCrossRef

Thul PJ, Akesson L, Wiking M, Mahdessian D, Geladaki A, Ait Blal H, et al. A subcellular map of the human proteome. Science. 2017;356:6340.CrossRef

Ito T, Suzuki S, Kanaji S, Shiraishi H, Ohta S, Arima K, et al. Distinct structural requirements for interleukin-4 (IL-4) and IL-13 binding to the shared IL-13 receptor facilitate cellular tuning of cytokine responsiveness. J Biol Chem. 2009;284:24289–96.PubMedPubMedCentralCrossRef

Chen L, Liu Y, Hou Y, Kato Y, Sano H, Kanno T. Expression and structure of interleukin 4 receptor (IL-4R) complex in human invasive pituitary adenomas. Neurosci Lett. 2007;417:30–5.PubMedCrossRef

Puri S, Joshi BH, Sarkar C, Mahapatra AK, Hussain E, Sinha S. Expression and structure of interleukin 4 receptors in primary meningeal tumors. Cancer. 2005;103:2132–42.PubMedCrossRef

Han J, Puri RK. Analysis of the cancer genome atlas (TCGA) database identifies an inverse relationship between interleukin-13 receptor alpha1 and alpha2 gene expression and poor prognosis and drug resistance in subjects with glioblastoma multiforme. J Neuro-Oncol. 2018;136:463–74.CrossRef

10.

Burt BM, Bader A, Winter D, Rodig SJ, Bueno R, Sugarbaker DJ. Expression of interleukin-4 receptor alpha in human pleural mesothelioma is associated with poor survival and promotion of tumor inflammation. Clin Cancer Res. 2012;18:1568–77.PubMedCrossRef

11.

Park MH, Kwon HJ, Kim JR, Lee B, Lee SJ, Bae YK. Elevated Interleukin-13 receptor alpha 1 expression in tumor cells is associated with poor prognosis in patients with invasive breast cancer. Ann Surg Oncol. 2017;24:3780–7.PubMedCrossRef

12.

Kang MA, Lee J, Ha SH, Lee CM, Kim KM, Jang KY, et al. Interleukin4Ralpha (IL4Ralpha) and IL13Ralpha1 are associated with the Progress of renal cell carcinoma through Janus kinase 2 (JAK2)/Forkhead box O3 (FOXO3) pathways. Cancers (Basel). 2019;11:1394.CrossRef

13.

Kwon M, Kim JW, Roh JL, Park Y, Cho KJ, Choi SH, et al. Recurrence and cancer-specific survival according to the expression of IL-4Ralpha and IL-13Ralpha1 in patients with oral cavity cancer. Eur J Cancer. 2015;51:177–85.PubMedCrossRef

14.

Ul-Haq Z, Naz S, Mesaik MA. Interleukin-4 receptor signaling and its binding mechanism: a therapeutic insight from inhibitors tool box. Cytokine Growth Factor Rev. 2016;32:3–15.PubMedCrossRef

15.

Board WCoTE. Soft tissue and bone tumours. 5th ed. International Agency for Research on Cancer: Lyon; 2020.

16.

Hosoyama T, Aslam MI, Abraham J, Prajapati SI, Nishijo K, Michalek JE, et al. IL-4R drives dedifferentiation, mitogenesis, and metastasis in rhabdomyosarcoma. Clin Cancer Res. 2011;17:2757–66.PubMedPubMedCentralCrossRef

17.

Yan J, Wang Q, Zou K, Wang L, Schwartz EB, Fuchs JR, et al. Inhibition of the JAK2/STAT3 signaling pathway exerts a therapeutic effect on osteosarcoma. Mol Med Rep. 2015;12:498–502.PubMedCrossRef

18.

Amin MB. American joint committee on cancer., American Cancer Society.: AJCC cancer staging manual. 8th ed. American Joint Committee on Cancer, Springer: Chicago; 2017.

19.

Allred D, Harvey JM, Berardo M, Clark GM. Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod Pathol. 1998;11:155–68.PubMed

20.

Ahn SW, Ahn AR, Ha SH, Hussein UK, Do Yang J, Kim KM, et al. Expression of FAM83H and ZNF16 are associated with shorter survival of patients with gallbladder carcinoma. Diagn Pathol. 2020;15:63.PubMedPubMedCentralCrossRef

21.

Kim KM, Hussein UK, Park SH, Kang MA, Moon YJ, Zhang Z, et al. FAM83H is involved in stabilization of beta-catenin and progression of osteosarcomas. J Exp Clin Cancer Res. 2019;38:267.PubMedPubMedCentralCrossRef

22.

Hussein UK, Ha SH, Ahmed AG, Kim KM, Park SH, Kim CY, et al. FAM83H and SCRIB stabilize beta-catenin and stimulate progression of gastric carcinoma. Aging (Albany NY). 2020;12:11812–34.CrossRef

23.

DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics. 1988;44:837–45.CrossRef

24.

Li Z, Zou X, Xie L, Dong H, Chen Y, Liu Q, et al. Prognostic importance and therapeutic implications of PAK1, a drugable protein kinase, in gastroesophageal junction adenocarcinoma. PLoS One. 2013;8:e80665.PubMedPubMedCentralCrossRef

25.

Zlobec I, Steele R, Terracciano L, Jass JR, Lugli A. Selecting immunohistochemical cut-off scores for novel biomarkers of progression and survival in colorectal cancer. J Clin Pathol. 2007;60:1112–6.PubMedCrossRef

26.

Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017;45:W98–W102.PubMedPubMedCentralCrossRef

27.

Venmar KT, Kimmel DW, Cliffel DE, Fingleton B. IL4 receptor alpha mediates enhanced glucose and glutamine metabolism to support breast cancer growth. Biochim Biophys Acta. 1853;2015:1219–28.

28.

Traub B, Sun L, Ma Y, Xu P, Lemke J, Paschke S, et al. Endogenously expressed IL-4Ralpha promotes the malignant phenotype of human pancreatic cancer in vitro and in vivo. Int J Mol Sci. 2017;18:716.PubMedCentralCrossRef

29.

Cao H, Zhang J, Liu H, Wan L, Zhang H, Huang Q, et al. IL-13/STAT6 signaling plays a critical role in the epithelial-mesenchymal transition of colorectal cancer cells. Oncotarget. 2016;7:61183–98.PubMedPubMedCentralCrossRef

30.

Lee HL, Park MH, Song JK, Jung YY, Kim Y, Kim KB, et al. Tumor growth suppressive effect of IL-4 through p21-mediated activation of STAT6 in IL-4Ralpha overexpressed melanoma models. Oncotarget. 2016;7:23425–38.PubMedPubMedCentralCrossRef

31.

Ingram N, Northwood EL, Perry SL, Marston G, Snowden H, Taylor JC, et al. Reduced type II interleukin-4 receptor signalling drives initiation, but not progression, of colorectal carcinogenesis: evidence from transgenic mouse models and human case-control epidemiological observations. Carcinogenesis. 2013;34:2341–9.PubMedPubMedCentralCrossRef

32.

Uhlen M, Fagerberg L, Hallstrom BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Proteomics. Tissue-based map of the human proteome. Science. 2015;347:1260419.PubMedCrossRef

33.

Todaro M, Lombardo Y, Francipane MG, Alea MP, Cammareri P, Iovino F, et al. Apoptosis resistance in epithelial tumors is mediated by tumor-cell-derived interleukin-4. Cell Death Differ. 2008;15:762–72.CrossRef

34.

Shaik AP, Shaik AS, Majwal AA, Faraj AA. Blocking Interleukin-4 receptor alpha using polyethylene glycol functionalized Superparamagnetic iron oxide Nanocarriers to inhibit breast cancer cell proliferation. Cancer Res Treat. 2017;49:322–9.PubMedCrossRef

35.

Venmar KT, Carter KJ, Hwang DG, Dozier EA, Fingleton B. IL4 receptor ILR4alpha regulates metastatic colonization by mammary tumors through multiple signaling pathways. Cancer Res. 2014;74:4329–40.PubMedPubMedCentralCrossRef

36.

Yang CY, Liu HW, Tsai YC, Tseng JY, Liang SC, Chen CY, et al. Interleukin-4 receptor-targeted liposomal doxorubicin as a model for enhancing cellular uptake and antitumor efficacy in murine colorectal cancer. Cancer Biol Ther. 2015;16:1641–50.PubMedPubMedCentralCrossRef

37.

Volonte A, Di Tomaso T, Spinelli M, Todaro M, Sanvito F, Albarello L, et al. Cancer-initiating cells from colorectal cancer patients escape from T cell-mediated immunosurveillance in vitro through membrane-bound IL-4. J Immunol. 2014;192:523–32.PubMedCrossRef

38.

Todaro M, Alea MP, Di Stefano AB, Cammareri P, Vermeulen L, Iovino F, et al. Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4. Cell Stem Cell. 2007;1:389–402.PubMedCrossRef

Title: Expression of IL4Rα and IL13Rα1 are associated with poor prognosis of soft-tissue sarcoma of the extremities, superficial trunk, and retroperitoneum
Authors: Kyoung Min Kim
Usama Khamis Hussein
See-Hyoung Park
Young Jae Moon
Zhongkai Zhang
Asmaa Gamal Ahmed
Ae-Ri Ahn
Ho Sung Park
Jung Ryul Kim
Kyu Yun Jang
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Soft Tissue Sarcoma
Sarcoma
Published in: Diagnostic Pathology / Issue 1/2021
Electronic ISSN: 1746-1596
DOI: https://doi.org/10.1186/s13000-020-01066-z

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Expression of IL4Rα and IL13Rα1 are associated with poor prognosis of soft-tissue sarcoma of the extremities, superficial trunk, and retroperitoneum

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2021

Lipoprotein glomerulopathy associated with the Osaka/Kurashiki APOE variant: two cases identified in Latin America

Case report: Rare myeloid sarcoma development following renal transplantation with KRAS and DNMT3A gene mutations

miR-3113-5p, miR-223-3p, miR-133a-3p, and miR-499a-5p are sensitive biomarkers to diagnose sudden cardiac death

Chronic cholestasis detection by a novel tool: automated analysis of cytokeratin 7-stained liver specimens

Long noncoding RNA TUG1 regulates the progression of colorectal cancer through miR-542-3p/TRIB2 axis and Wnt/β-catenin pathway

Urothelial carcinoma of the graft kidney with molecular analyses: a rare case report