Notch signaling defects in NK cells in patients with cancer
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ORIGINAL ARTICLE
Notch signaling defects in NK cells in patients with cancer Gulnur K. Zakiryanova1 · Elena Kustova2 · Nataliya T. Urazalieva2 · Emile T. Baimukhametov3 · Valeriy A. Makarov4 · Gulmariya M. Turaly5 · Galina V. Shurin6 · Zarema M. Biyasheva1 · Narymzhan N. Nakisbekov5 · Michael R. Shurin6 Received: 4 July 2020 / Accepted: 15 October 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Altered expressions of proto-oncogenes have been reported during normal lymphocytes mitogenesis and in T and B lymphocytes in patients with autoimmune diseases. We have recently demonstrated a significantly decreased expression of c-kit and c-Myc in NK cells isolated from patients with cancer, which might be related to the functional deficiency of NK cells in the tumor environment. Here, focusing on the regulatory mechanisms of this new clinical phenomenon, we determined expression of c-Myc, Notch1, Notch2, p-53, Cdk6, Rb and phosphorylated Rb in NK cells isolated from the healthy donors and cancer patients. The results of our study revealed a significant down-regulation of expression of Notch receptors and upregulation of Cdk6 expression in NK cells in cancer, while no significant changes in the expression of p53 and Rb proteins were seen. These data revealed novel signaling pathways altered in NK cells in the tumor environment and support further investigation of the origin of deregulated expression of proto-oncogenes in NK cells patients with different types of cancer. Keywords NK cells · T cells · c-myc · Notch1 · Notch2
Introduction Cancer is a complex disease primarily driven by divergent signaling pathways of oncogenes and associated with the development of the tumor microenvironment. Oncogenes contribute to cancer development and diversity not only by inducing proliferation but also by developmental reprogramming of the epigenome [1]. Therefore, the tumor * Gulnur K. Zakiryanova [email protected] * Michael R. Shurin [email protected] 1
Al-Farabi Kazakh National University, Almaty, Kazakhstan
2
Laboratory of Immunology, Scientific Center of Pediatric and Children Surgery, Almaty, Kazakhstan
3
Department of Oncology, Kazakh Medical University of Continuing Education, Almaty, Kazakhstan
4
Department of Oncosurgery, Almaty Oncology Center, Almaty, Kazakhstan
5
Joint Use Center, Atchabarov Scientific Research Institute of Fundamental and Applied Medicine, Asfendiyarov Kazakh National Medical University, Almaty, Kazakhstan
6
Departments of Pathology and Immunology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
microenvironment is characterized by variable and dynamic patterns of cellular diversity, which leads to intratumoral heterogeneity, genetic and epigenetic diversification, growth dynamics and sensitivity to specific treatments. Members of the Myc family of proto-oncogenes are the most commonly deregulated genes in human neoplasms. Myc proteins drive an increase in cellular proliferation and facilitate multiple aspects of tumor initiation an
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