IL-6 Promotes Cell Proliferation and Antiapoptosis Through Activation Of The JAK/STAT3 Pathway In Patients With NK/T - Cell Lymphoma and Correlates With Poor Treatmemt Outcome
Authors: Cai Qichun , Huang Hui-qiang , Bai Bing , Lin Suxia , Gao Yan , Xia Yi , Wang XiaoXiao , Lu Jiabin 
Published: October 2019

Abstract

Backgroud
It has been demonstrated that Natural/killer T-cell lymphoma (NK/TCL) derives from chronic EBV infection of nasopharynx. In recent years, IL-6 has been proved to be associated with a variety of inflammation-related malignancies in terms of carcinogenesis, tumor proliferation and metastasis. However, there hasn’t been any report about IL-6 on the pathogenesis and development of NK/TCL.

Patients and Methods
From January 2005 to December 2012, the paraffin sections of 91 patients with NK/TCL in Sun Yat-sen University Cancer Center were collected. The activation/expression of NF-ΚB(P50, P52, P65), IL-6,P-STAT3(Tyr705),BCL-2 in tumor microenviroment were investigated by immunohistochemistry. The NK/TCL cell lines were treated by IL-6(80ng/ml) and neutralizing IL-6 antibody, then the viability and apoptosis of lymphoma cell lines (NK-YS, SNK-6 and SNT-8) were assessed by CCK-8 and flow cytometry; and the expression of p-STAT3, BCL-2, BCL-XL, MCL-1, Survivin、p-ERK and p-AKT were examined by Western blot .

Results
Overall, ninety-one patients with NK/TCL were analyzed. There were 68 male patients. The median age was 43 years (range 10-68 years). There were 52, 14 and 25 patients diagnosed as stage I, II and IV disease, respectively. Sixty-one patients had B symptoms. The P52 activation was observed in the microenviroment of most patients, while P65 and P50 activation were observed in minority of patients. In patients with P52 activation, P52 activation was observed both in macrophages and lymphoma cells, and vice versa. IL-6 was primarily secreted by macrophages and tumor cells, and 69.2% (63/91) patients were positive (IL-6 secreting cells ≥ 10 / HP). The STAT3 activation was observed in 67.0% (61/91) of patients, most of which were combined with expression of BCL-2. The expression of P52、IL-6、P-STAT3、bcl-2 in the microenvironment of NK/TCL were in uniform (all positive or all negative). Patients with positive expression of IL-6 were associated with fever, advanced stage, high serum level of C-reactive protein (CRP), chemotherapy resistance and poor survival (P < 0.05). Comparing with blank control group and the neutralizing IL-6 antibody group, the cell viability and antiapoptosis ratio of NK-YS、 SNK-6、SNT-8 cells were higher in the IL-6 group (P<0.05). Constitutive activation of p-STAT3, BCL-2, BCL-XL, MCL-1, and survivin were observed in the NK/TCL cell lines. IL-6 could up-regulate the expression of these proteins. The expression of p-ERK and p-AKT were irrelevant with IL-6 or IL-6 antibody treatment.

Conclusions
The NK-κB(P52)/IL-6/STAT3 pathway is activated in tumor microenvironment, and is associated with fever, advanced stage, high serum level of CRP in patients with NK/TCL. IL-6 could activate the JAK/STAT3 pathway in NK/T lymphoma cell lines, and promote lymphoma proliferation and anti-apoptosis. The activation of NK-κB(P52)/IL-6/STAT3 pathway may lead to chemotherapy resistance and poor survival in patients with NK/TCL.

Disclosures:
No relevant conflicts of interest to declare.