Alterations of oncogenes expression in NK cells in patients with cancer.

Gulnur K Zakiryanova,Narymzhan N Nakisbekov,Michael R Shurin,Nataliya T Urazalieva,Aday Amirbekov,Emile T Baimuchametov,Elena Kustova

doi:10.1002/iid3.179

Abstract

IntroductionC‐kit/SCF signaling plays a key role in regulating NK cell homeostasis, maturation, proliferation, and cytotoxicity. C‐kit‐deficiency in NK cells results in significant reduction of their number, suggesting an imperative role for c‐kit signaling in NK cell biology. We have recently showed that human NK cells express not only c‐kit‐receptor, but also both membrane‐bound and soluble forms of c‐kit ligand—Stem cell factor. The goal of this study was to characterize the c‐kit/SCF autocrine loop in peripheral blood NK cells obtained from patients with cancer.MethodsUsing Smart Flare and qRT‐PCR, we have characterized expression of c‐kit and two forms of SCF in patients’ NK cells and correlated these results with the expression of c‐myc and STAT3.ResultsOur results demonstrated that the expression of proto‐oncogenes c‐myc and c‐kit was significantly decreased in NK cells from all cancer patients. Expression of membrane‐bound SCF in NK cells correlated with the presence of remote metastases.ConclusionsWe suggest that the abnormal signaling and expression of c‐kit/SCF, c‐myc, and STAT3 in NK cells is responsible for the defect in their cytolytic activity in cancer and these defects at the gene expression level may be the cause rather than the result of tumor progression.

Highlights

C-kit/SCF signaling plays a key role in regulating NK cell homeostasis, maturation, proliferation, and cytotoxicity
Our results revealed a strongly declined expression of oncogenes c-myc and c-kit, while Signal transducers and activators of transcription (STAT)-3 expression in contrary was increased in NK cells from lung cancer patients but was down-regulated in NK cells from gastric, sigmoid, and colon cancer patients
Detection of c-kit expression in CD117(c-kit)-positive and -negative fractions of NK cells from cancer patients and healthy donors was carried by two methods: qRT-PCR and Smart Flare

Summary

Introduction

C-kit/SCF signaling plays a key role in regulating NK cell homeostasis, maturation, proliferation, and cytotoxicity. Methods: Using Smart Flare and qRT-PCR, we have characterized expression of c-kit and two forms of SCF in patients’ NK cells and correlated these results with the expression of c-myc and STAT3. Conclusions: We suggest that the abnormal signaling and expression of c-kit/SCF, c-myc, and STAT3 in NK cells is responsible for the defect in their cytolytic activity in cancer and these defects at the gene expression level may be the cause rather than the result of tumor progression. Profound impairment of NK cell activity has been demonstrated in cancer patients, including decreased cytotoxicity, defective expression of activating receptors, or intracellular signaling molecules, overexpression of inhibitory receptors, abnormal proliferation, decreased tumor infiltration, and defective cytokine production [1, 2]. The stem cell factor/c-Kit signaling pathway is pivotal for the survival, differentiation, and maturation of NK cells [5]

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