Expression of tesmin (MTL5) in non‑small cell lung cancer: A preliminary study

Grzegrzolka,Jedrzej; Gomulkiewicz,Agnieszka; Olbromski,Mateusz; Glatzel‑Plucinska,Natalia; Piotrowska,Aleksandra; Ratajczak‑Wielgomas,Katarzyna; Rzechonek,Adam; Podhorska‑Okolow,Marzena; Krawczuk,Zbigniew; Dziegiel,Piotr

doi:10.3892/or.2019.7145

Expression of tesmin (MTL5) in non‑small cell lung cancer: A preliminary study

Authors:
- Jedrzej Grzegrzolka
- Agnieszka Gomulkiewicz
- Mateusz Olbromski
- Natalia Glatzel‑Plucinska
- Aleksandra Piotrowska
- Katarzyna Ratajczak‑Wielgomas
- Adam Rzechonek
- Marzena Podhorska‑Okolow
- Zbigniew Krawczuk
- Piotr Dziegiel
View Affiliations

Affiliations: Department of Histology and Embryology, Wroclaw Medical University, 50‑368 Wroclaw, Poland, Department of Thoracic Surgery, Wroclaw Medical University, 50‑368 Wroclaw, Poland, Department of General Surgery, Poviat Hospital Complex in Olesnica, 56‑400 Olesnica, Poland
Published online on: May 2, 2019 https://doi.org/10.3892/or.2019.7145
Pages: 253-262

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Lung cancer is the most commonly diagnosed cancer and the most frequent cause of death worldwide. Tesmin (testis‑specific metallothionein‑like protein; MTL‑5) is a 60‑kDa protein which has cysteine‑rich motifs (CXC domain), characteristic of metallothioneins (MTs). Tesmin expression has been observed in germ cells during spermatogenesis, oogenesis and also in various cell nuclei after exposure to heavy metal ions. Yet, the role of tesmin in carcinogenesis is unknown. The aim of the present study was to evaluate the localization and intensity of tesmin expression in non‑small cell lung cancer (NSCLC) and its association with the clinicopathological data of patients. A total of 121 cases of NSCLC and 20 cases of non‑cancerous tissue samples from the surgical margin (control) were used for immunohistochemistry (IHC). In addition, 20 cases of frozen NSCLC tissues and 20 cases of control were used for the in vivo study. Normal lung fibroblasts (IMR‑90) and lung cancer cell lines NCI‑H1703 (lung squamous cell carcinoma), NCI‑H522 and A549 (both adenocarcinomas of the lung) were used for western blot analysis (WB) and RT‑PCR studies. Positive cytoplasmic tesmin expression was observed in 88.42% of the examined cases of NSCLC. Statistical analysis showed increased IHC tesmin expression in cancer cells compared to that noted in the controls. In addition, MTL5 mRNA and WB tesmin protein expression were also higher in cancer cases compared to the controls. A positive correlation between tesmin and Ki‑67 IHC expression was demonstrated (r=0.32; P<0.001). Higher WB tesmin expression was also associated with shorter overall survival (P<0.05, Mantel‑Cox test). The in vitro study revealed higher tesmin protein (WB) and MTL5 (qPCR) in lung cancer cell lines compared to the lung fibroblast control cell line. Higher tesmin expression in cancer cells compared to control cells may suggest a role of tesmin in NSCLC carcinogenesis. A positive correlation between tesmin and Ki‑67 could indicate a possible role of tesmin in the proliferation of NSCLC.

View Figures

View References

1	Stewart BW and Wild CP: Word Cancer Report 2014. World Health Organization; Lyon: 2014
2	Didkowska J, Wojciechowska U and Olasek P: Zachorowania i zgony na nowotwory złośliwe w Polsce. Krajowy Rejestr Nowotworów, Centrum Onkologii-Instytut im. Marii Skłodowskiej-Curie. http://onkologia.org.pl/k/epidemiologiaJuly 06–2018
3	Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: Cancer incidence and mortality worldwide sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 136:E359–E386. 2015. View Article : Google Scholar : PubMed/NCBI
4	Krzakowski M, Jassem J, Dziadziuszko R, Kowalski DM, Olszewski W, Orłowski T, Rzyman W and Smorczewska M: Zalecenia postępowania diagnostyczno-terapeutycznego w nowotworach złośliwych-2013 r. Nowotwory płuca i opłucnej oraz śródpiersia, Via Medica. 1:69–101, Gdańsk. 2013.
5	Theocharis SE, Margeli AP and Koutselinis A: Metallothionein: A multifunctional protein from toxicity to cancer. Int J Biol Markers. 18:162–169. 2003. View Article : Google Scholar : PubMed/NCBI
6	Vašák M: Advances in metallothionein structure and functions. J Trace Elem Med Biol. 19:13–17. 2005. View Article : Google Scholar : PubMed/NCBI
7	Wierzowiecka B, Gomulkiewicz A, Cwynar-Zajac L, Olbromski M, Grzegrzolka J, Kobierzycki C, Podhorska-Okolow M and Dziegiel P: Expression of metallothionein and vascular endothelial growth factor isoforms in breast cancer cells. In Vivo. 30:271–278. 2016.PubMed/NCBI
8	Theocharis SE, Margeli AP, Klijanienko JT and Kouraklis GP: Metallothionein expression in human neoplasia. Histopathology. 45:103–118. 2004. View Article : Google Scholar : PubMed/NCBI
9	Romero-Isart N and Vašák M: Advances in the structure and chemistry of metallothioneins. J In Org Biochem. 88:388–396. 2002.
10	Bay BH, Jin R, Huang J and Tan PH: Metallothionein as a prognostic biomarker in breast cancer. Exp Biol Med (Maywood). 231:1516–1521. 2006. View Article : Google Scholar : PubMed/NCBI
11	Shimoda R, Achanzar WE, Qu W, Nagamine T, Takagi H, Mori M and Waalkes MP: Metallothionein is a potential negative regulator of apoptosis. Toxicol Sci. 73:294–300. 2003. View Article : Google Scholar : PubMed/NCBI
12	Cherian MG, Jayasurya A and Bay BH: Metallothioneins in human tumors and potential roles in carcinogenesis. Mutat Res. 533:201–209. 2003. View Article : Google Scholar : PubMed/NCBI
13	Dziegiel P, Pula B, Kobierzycki C, Stasiolek M and Podhorska-Okolow M: Metallothioneins in normal and cancer cells. Adv Anat Embryol Cell Biol. 218:1–117. 2016. View Article : Google Scholar : PubMed/NCBI
14	Werynska B, Pula B, Kobierzycki C, Dziegiel P and Podhorska-Okolow M: Metallothioneins in the lung cancer. Folia Histochem Cytobiol. 53:1–10. 2015. View Article : Google Scholar : PubMed/NCBI
15	Ostrakhovitch EA, Olsson PE, Jiang S and Cherian MG: Interaction of metallothionein with tumor suppressor p53 protein. FEBS Letters. 580:1235–1238. 2006. View Article : Google Scholar : PubMed/NCBI
16	Ostrakhovitch EA, Olsson PE, von Hofsten J and Cherian MG: P53 mediated regulation of metallothionein transcription in breast cancer cells. J Cell Biochem. 102:1571–1583. 2007. View Article : Google Scholar : PubMed/NCBI
17	Coyle P, Philcox JC, Carey LC and Rofe AM: Metallothionein: The multipurpose protein. Cell Mol Life Sci. 59:627–647. 2002. View Article : Google Scholar : PubMed/NCBI
18	Sutou S, Miwa K, Matsuura T, Kawasaki Y, Ohinata Y and Mitsui Y: Native tesmin is a 60-kilodalton protein that undergoes dynamic changes in its localization during spermatogenesis in mice. Biol Reprod. 68:1861–1869. 2003. View Article : Google Scholar : PubMed/NCBI
19	HUGO Gene Nomenclature Comitte. http://www.genenames.orgJune 1–2018
20	Sugihara T, Wadhwa R, Kaul SC and Mitsui Y: A novel testis-specific metallothionein-like protein, tesmin, is an early marker of male germ cell differentiation. Genomics. 57:130–136. 1999. View Article : Google Scholar : PubMed/NCBI
21	Olesen C, Møller M and Byskov AG: Tesmin transcription is regulated differently during male and female meiosis. Mol Reprod Dev. 67:116–126. 2004. View Article : Google Scholar : PubMed/NCBI
22	Matsuura T, Kawasaki Y, Miwa K, Sutou S, Ohinata Y, Yoshida F and Mitsui Y: Germ cell-specific nucleocytoplasmic shuttling protein, tesmin, responsive to heavy metal stress in mouse testes. J Inorg Biochem. 88:183–191. 2002. View Article : Google Scholar : PubMed/NCBI
23	Maremanda KP, Khan S and Jene G: Zinc protects cyclophosphamide-induced testicular damage in rat: Involvement of metallothionein, tesmin and Nrf2. Biochem Biophys Res Commun. 445:591–596. 2014. View Article : Google Scholar : PubMed/NCBI
24	Rogerson FM, Yao YZ, Young MJ and Fuller PJ: Identification and characterization of a ligand-selective mineralocorticoid receptor coactivator. FASEB J. 28:4200–4210. 2014. View Article : Google Scholar : PubMed/NCBI
25	Fic M, Pula B, Rogala K and Dziegiel P: Role of metallothionein expression in gastrointestinal cancers. Postępy Biol Komórki. 40:5–20. 2013.
26	Oh JH, Yang JO, Hahn Y, Kim MR, Byun SS, Jeon YJ, Kim JM, Song KS, Noh SM, Kim S, et al: Transcriptome analysis of human gastric cancer. Mamm Genome. 16:942–954. 2005. View Article : Google Scholar : PubMed/NCBI
27	Penney KL, Sinnott JA, Tyekucheva S, Gerke T, Shui IM, Kraft P, Sesso HD, Freedman ML, Loda M, Mucci LA and Stampfer MJ: Association of prostate cancer risk variants with gene expression in normal and tumor tissue. Cancer Epidemiol Biomarkers Prev. 24:255–260. 2015. View Article : Google Scholar : PubMed/NCBI
28	Remmele W and Stegner HE: Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Pathologe (German). 8:138–140. 1987.
29	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2^−ΔΔCt method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
30	Laemmli UK: Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 227:680–685. 1970. View Article : Google Scholar : PubMed/NCBI
31	Győrffy B, Surowiak P, Budczies J and Lánczky A: Online survival analysis software to assess the prognostic value of biomarkers using transcriptomic data in non-small-cell lung cancer. PLoS One. 8:e822412013. View Article : Google Scholar : PubMed/NCBI