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Masarykova Univerzita Přírodovědecká Fakulta Ústav MASARYKOVA UNIVERZITA PŘÍRODOVĚDECKÁ FAKULTA ÚSTAV EXPERIMENTÁLNÍ BIOLOGIE VÝZNAM KOVŮ V PATOGENEZI A PROGRESI NÁDOROVÝCH ONEMOCNĚNÍ Bakalářská práce Alžběta Ressnerová Vedoucí práce: MUDr. Jaromír Gumulec Brno 2015 Bibliografický záznam Autor: Alžběta Ressnerová Přírodovědecká fakulta, Masarykova Univerzita Ústav Experimentální biologie Význam kovů v patogenezi a progresi nádorových Název práce: onemocnění Studijní program: Experimentální biologie Studijní obor: Speciální biologie Vedoucí práce: MUDr. Jaromír Gumulec Akademický rok: 2014/2015 Počet stran: 52 Klíčová slova: Kovy; Měď; Zinek; Rakovina; Rakovina hlavy a krku Bibliographic Entry Author Alžběta Ressnerová Faculty of Science, Masaryk University Department of Experimental biology The role of metals in the pathogenesis and progression of Title of Thesis: cancer Degree programme: Experimental biology Field of Study: Special biology Supervisor: MUDr. Jaromír Gumulec Academic Year: 2014/2015 Number of Pages: 52 Keywords: Metals; Copper; Zinc; Cancer; Head and neck cancer Abstrakt Kovy jsou známé tím, že hrají nezbytnou roli v lidské fyziologii. Zvláště měď a zinek jsou stopové prvky úzce závislé jeden na druhém, zapojené do buněčné proliferace, růstu, genové exprese, apoptózy a dalších procesů. Jejich homeostáza je klíčová, úzce kontrolovaná důmyslným systémem transportérů a transportních proteinů, které dodávají ionty mědi a zinku na jejich cílová místa. Abnormální homeostázu zinku a mědi lze pozorovat u množství malignit a také u rakoviny hlavy a krku. Nerovnováha v této homeostáze se může projevit jako zvýšení nebo úbytek v hladinách měďných a zinečnatých iontů v séru nebo tkáni pacientů. U rakoviny hlavy a krku tyto změny hladin vyčnívají z řad ostatních malignit. Vzhledem k tomuto mohou být zinečnaté a měďné ionty dobrým předmětem budoucího výzkumu rozvoje a progrese tohoto typu rakoviny. Abstract Metals are known for playing essential roles in human physiology. Copper and zinc are trace elements tightly dependent on one another involved in cell proliferation, growth, gene expression, apoptosis and other processes. Their homeostasis is crucial and thoroughly controlled by resourceful system of transporters and transport proteins which deliver copper and zinc ions to its target sites. Abnormal zinc and copper homeostasis can be seen in number of malignancies also in head and neck cancer. Imbalance in this copper or zinc homeostasis can be observable as elevation or decrease in serum or tissue levels in patients with cancer. In head and neck cancer, these altered levels stand out of other malignancies which make it object of interest, therefore zinc and copper ions might be good target for further research of head and neck cancer development and progression. Poděkování Na tomto místě bych chtěla poděkovat především MUDr. Jaromíru Gumulcovi za trpělivé vedení při vypracovávání této bakalářské práce, cenné rady a velkou podporu. Prohlášení Prohlašuji, že jsem svoji bakalářskou práci vypracovala samostatně s využitím informačních zdrojů, které jsou v práci citovány. Brno 8. května 2015 …………………………….. Alžběta Ressnerová Obsah 1 Introduction ................................................................................................................................... 8 2 Physiological role of zinc and copper ........................................................................................ 10 2.1 Dietary requirements, Daily intake and toxic levels .............................................................. 11 2.1.1 Zinc ................................................................................................................................ 11 2.1.2 Copper ........................................................................................................................... 12 2.2 Intestinal absorption .............................................................................................................. 13 2.2.1 Zinc ............................................................................................................................... 13 2.2.2 Copper ........................................................................................................................... 14 2.3 Serum transport ..................................................................................................................... 16 2.3.1 Zinc ............................................................................................................................... 16 2.3.2 Copper ........................................................................................................................... 17 2.4 Cellular transport and intracellular buffering ........................................................................ 19 2.4.1 Zinc ............................................................................................................................... 19 2.4.2 Copper ........................................................................................................................... 21 3 Role of zinc and copper in pathology ......................................................................................... 26 3.1 Dysregulation of metal level ................................................................................................. 26 3.1.1 Serum zinc dysregulation .............................................................................................. 26 3.1.2 Serum copper dysregulation .......................................................................................... 27 3.1.3 Tumour tissue zinc levels .............................................................................................. 27 3.1.4 Tumour tissue copper levels .......................................................................................... 27 3.2 Proposed molecular mechanism of metal dysregulation ....................................................... 28 3.2.1 Zinc ............................................................................................................................... 28 3.2.2 Copper ........................................................................................................................... 35 4 Conclusion .................................................................................................................................... 39 5 Literature ..................................................................................................................................... 40 1 Introduction Cancer is major public health problem and after heart diseases the second leading cause of death. The most common cancer include lung, breast, prostate and head and neck. Every year, 650, 000 patients are newly diagnosed with head and neck cancer and 350, 000 of these patients die every year due to this disease. That makes head and neck cancer the sixth most common type of cancer worldwide (Parkin et al., 2005). 45, 780 – that is expected number of new cases and 8, 650 – deaths of patients with cancer of oral cavity and pharynx in USA 2015 (Siegel et al., 2015). There is still big significance of head and neck cancer because the five year survival outcomes of patients are poor – approx. 40–50 %. The vast majority of head and neck cancers are squamous cell carcinomas. Anatomically, cancer of head and neck may arise from epithelium of any part of the upper aerodigestive tract including oral cavity, nasal cavity, nasopharynx, oropharynx, hypopharynx, larynx and paranasal sinuses. Role in pathogenesis of head and neck cancer has alcohol consumption, tobacco smoke (Blot et al., 1988), and also infection with Human papillomavirus (HPV) (D'Souza et al., 2007). Early detection is the key for successful therapy of any malignancy and it is also applicable for the tumours of head and neck. However, alternative ways of diagnostics, and so novel anticancer agents, are needed. Nevertheless, diagnosis of this type of cancer has several limitations. There are numerous tumour markers for the most common types of cancers – prostate (prostate-specific antigen PSA), breast (CA15-3, CA27.29, BRCA, HER2, oestrogen receptor ER, CEA and others), lung (EGFR, cytokeratin fragments 21–1, ALK and others). However, no such easy-to-detect substance has been described for head and neck cancer. Therefore we need to go deeper to molecular mechanisms of cancer and focus on mechanisms that can be targeted by specific therapeutics and that is a big challenge for science. 8 In the recent decades, numerous researches have pointed out to the fact that various metals – notably zinc and copper – are important regulator of physiological and pathological processes. Accordingly, with regard to the fact, that metals are involved in the crucial processes such as apoptosis, gene expression or cell differentiation, it is not surprising that alteration the metal-level-regulators may lead to the development of various diseases, including cancers. Recently, it was found that the levels of zinc ions and zinc-binding protein Metallothionein are significantly altered in prostate, breast, gynaecological, lung and other cancers (Gumulec et al., 2014b, Gumulec et al., 2014a). Surprising results were in head and neck cancer whose levels were different compared to other epithelial malignancies, which calls for further elucidation. There is a large amount of studies dealing with role of metals in breast and prostate cancer. However, there is not any thesis dealing complexly with topic of metals in pathogenesis of head and neck cancer and
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