Hereditary Genetics: Current Research

Metastasis-associated protein 2 (MTA2) as a regulator of NF-kB in lung cancer

4^th International Congress on Epigenetics & Chromatin

September 03-05, 2018 | London, UK

Nefertiti El-Nikhely

Institute of Graduate Studies and Research-Alexandria University, Egypt

Posters & Accepted Abstracts: Hereditary Genet Curr Res

Abstract:

Statement of the Problem: Lung cancer is a multifactorial disease with poor prognosis and survival. Inflammation is an important aspect in tumorigenesis that is gaining increasing attention in many studies. A key player of variant processes in tumour growth is the transcription factor nuclear factor kappa B (NF-kB) which shows aberrant expression in several cancers and plays a role in drug resistance. As NF-kB is a pleiotropic agent, it is tightly regulated on several levels. Methodology: A transgenic animal model was used, where IKK2, the key kinase activating NF-kB, was altered (downregulated IKK2, IKK2DN or activated IKK2; IKK2CA) in CRaf BxB-induced tumor in alveolar epithelial type-II cells (Sftpc/CRaf/IKK2DN and Sftpc/CRaf/IKK2CA). Xenograft model was used with LLC1 cells for subcutaneous tumours whose immune cell repertoire was analysed by flow cytometry. Findings: We could observe impaired tumour growth when IKK2 was downregulated. Using several lung cancer cell lines, we revealed that NF-kB is regulated by metastasis-associated protein 2 (MTA2). NF-kB activity was decreased when MTA2 was overexpressed in A549 cells. Moreover, knockdown of MTA2 by shMTA2 in LLC1 cells lead to increased subcutaneous tumours in a xenograft model. The tumours with lower MTA2 levels included macrophages showing rather type 1 markers which are pro-tumorigenic and thus contributing to the increased tumour sizes. Conclusion: This study sheds more light into the epigenetic regulation of NF-kB signalling pathway. The interaction between NF-kB and MTA2 can be subject of novel therapy modalities. Figure 1: Mechanism of feedback regulation of NF-kB by MTA2/NuRD complex. Recent Publications: 1. Soni Savai Pullamsetti, Baktybek Kojonazarov, Samantha Storn, Henning Gall, Ylia Salazar, Janine Wolf, Andreas Weigert, Nefertiti El-Nikhely, Ardeschir Ghofrani, Gabriele A Krombach, Ludger Fink, Stefan Gattenl�hner, Ulf R Rapp, Ralph Theo Schermuly, Friedrich Grimminger, Werner Seeger and Rajkumar Savai (2017) Lung cancer??? associated pulmonary hypertension: role of micro-environmental inflammation based on tumor cell-immune cell crosstalk. Sci Transl Med. 9(416). 2. Kiehl S, Herkt S C, Richter A M, Fuhrmann L, El-Nikhely N, Seeger W, Savai R and Dammann R H (2014) ABCB4 is frequently epigenetically silenced in human cancers and inhibits tumor growth. Sci Rep. 4:6899. 3. Kopp F, Hermawan A, Oak P S, Ulaganathan V K, Herrmann A, El-Nikhely N, Thakur C, Xiao Z, Knyazev P, Ataseven B, Savai R, Wagner E and Roidl A (2014) Sequential salinomycin treatment results in resistance formation through clonal selection of epithelial-like tumor cells. Transl Oncol. 7(6):702-11. 4. Zanucco E, El-Nikhely N, G�tz R, Weidmann K, Pfeiffer V, Savai R, Seeger W, Ullrich A and Rapp U R (2014) Elimination of B-RAF in oncogenic C-RAF-expressing alveolar epithelial type II cells reduces MAPK signal intensity and lung tumor growth. J Biol Chem. 289(39):26804- 16. 5. Larzabal L, El-Nikhely N, Redrado M, Seeger W, Savai R, Calvo A (2013) Differential effects of drugs targeting cancer stem cell (CSC) and non-CSC populations on lung primary tumors and metastasis. PLoS One 8(11):e79798.

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