<em>Bex1</em> significantly contributes to the proliferation and invasiveness of malignant tumor cells

Doi,Takefumi; Ogawa,Hiroyuki; Tanaka,Yugo; Hayashi,Yoshitake; Maniwa,Yoshimasa

doi:10.3892/ol.2020.12226

Bex1 significantly contributes to the proliferation and invasiveness of malignant tumor cells

Authors:
- Takefumi Doi
- Hiroyuki Ogawa
- Yugo Tanaka
- Yoshitake Hayashi
- Yoshimasa Maniwa
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Affiliations: Division of Thoracic Surgery, Kobe University Graduate School of Medicine, Kobe, Hyogo 650‑0017, Japan, Department of Thoracic Surgery, Hyogo Cancer Center, Akashi, Hyogo 673‑8558, Japan, Division of Molecular Medicine and Medical Genetics, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Hyogo 650‑0017, Japan
Published online on: October 14, 2020 https://doi.org/10.3892/ol.2020.12226
Article Number: 362
Copyright: © Doi et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Invasion has a significant role in cancer progression, including expansion to surrounding tissue and metastasis. Previously, we assessed the invasive ability of cancer cells using an easy‑to‑prepare double‑layered collagen gel hemisphere (DL‑CGH) method by which cancer cell invasion can be easily visualized. The present study examined multiple lung adenocarcinoma and malignant pleural mesothelioma (MPM) cell lines using the DL‑CGH method and identified inherently invasive cell lines. Next, by comparing gene expression between invasive and non‑invasive cells by cDNA microarray, the potential candidate gene brain‑expressed x‑linked protein 1 (Bex1) was identified to be involved in cancer invasion, as it was highly expressed in the invasive cell lines. Downregulation of Bex1 suppressed the invasion and proliferation of the invasive tumor cell lines. The findings of the present study suggested that Bex1 may promote metastasis in vivo and could be a potential oncogene and molecular therapeutic target in lung adenocarcinoma and MPM.

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1	Herbst RS, Heymach JV and Lippman SM: Lung cancer. N Engl J Med. 359:1367–1380. 2008. View Article : Google Scholar : PubMed/NCBI
2	Cheng TY, Cramb SM, Baade PD, Youlden DR, Nwogu C and Reid ME: The international epidemiology of lung cancer: Latest trends, disparities, and tumor characteristics. J Thorac Oncol. 11:1653–1671. 2016. View Article : Google Scholar : PubMed/NCBI
3	Robinson BW, Musk AW and Lake RA: Malignant mesothelioma. Lancet. 366:397–408. 2005. View Article : Google Scholar : PubMed/NCBI
4	Pistolesi M and Rusthoven J: Malignant pleural mesothelioma: Update, current management, and newer therapeutic strategies. Chest. 126:1318–1329. 2004. View Article : Google Scholar : PubMed/NCBI
5	Antman KH: Natural history and epidemiology of malignant mesothelioma. Chest. 103:373S–376S. 1993. View Article : Google Scholar : PubMed/NCBI
6	Zhong J, Gencay MM, Bubendorf L, Burgess JK, Parson H, Robinson BW, Tamm M, Black JL and Roth M: ERK1/2 and p38 MAP kinase control MMP-2, MT1-MMP, and TIMP action and affect cell migration: A comparison between mesothelioma and mesothelial cells. J Cell Physiol. 207:540–552. 2006. View Article : Google Scholar : PubMed/NCBI
7	Chambers AF, Groom AC and MacDonald IC: Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer. 2:563–572. 2002. View Article : Google Scholar : PubMed/NCBI
8	Sahai E: Illuminating the metastatic process. Nat Rev Cancer. 7:737–749. 2007. View Article : Google Scholar : PubMed/NCBI
9	Takata M, Maniwa Y, Doi T, Tanaka Y, Okada K, Nishio W, Ohbayashi C, Yoshimura M, Hayashi Y and Okita Y: Double-layered collagen gel hemisphere for cell invasion assay: Successful visualization and quantification of cell invasion activity. Cell Commun Adhes. 14:157–167. 2007. View Article : Google Scholar : PubMed/NCBI
10	Doi T, Maniwa Y, Tanaka Y, Tane S, Hashimoto S, Ohno Y, Nishio W, Nishimura Y, Ohbayashi C, Okita Y, et al: MT1-MMP plays an important role in an invasive activity of malignant pleural mesothelioma cell. Exp Mol Pathol. 90:91–96. 2011. View Article : Google Scholar : PubMed/NCBI
11	Bolstad BM, Irizarry RA, Astrand M and Speed TP: A comparison of normalization methods for high density oligonucleotide array data based on variance and bias. Bioinformatics. 19:185–193. 2003. View Article : Google Scholar : PubMed/NCBI
12	Gentleman RC, Carey VJ, Bates DM, Bolstad B, Dettling M, Dudoit S, Ellis B, Gautier L, Ge Y, Gentry J, et al: Bioconductor: Open software development for computational biology and bioinformatics. Genome Biol. 5:R802004. View Article : Google Scholar : PubMed/NCBI
13	Quackenbush J: Microarray data normalization and transformation. Nat Genet. 32:496–501. 2002. View Article : Google Scholar : PubMed/NCBI
14	Izumi H, Takahashi M, Uramoto H, Nakayama Y, Oyama T, Wang KY, Sasaguri Y, Nishizawa S and Kohno K: Monocarboxylate transporters 1 and 4 are involved in the invasion activity of human lung cancer cells. Cancer Sci. 102:1007–1013. 2011. View Article : Google Scholar : PubMed/NCBI
15	Albini A, Iwamoto Y, Kleinman HK, Martin GR, Aaronson SA, Kozlowski JM and McEwan RN: A rapid in vitro assay for quantitating the invasive potential of tumor cells. Cancer Res. 47:3239–3245. 1987.PubMed/NCBI
16	Nyström ML, Thomas GJ, Stone M, Mackenzie IC, Hart IR and Marshall JF: Development of a quantitative method to analyse tumour cell invasion in organotypic culture. J Pathol. 205:468–475. 2005. View Article : Google Scholar : PubMed/NCBI
17	Duong HS, Le AD, Zhang Q and Messadi DV: A novel 3-dimensional culture system as an in vitro model for studying oral cancer cell invasion. Int J Exp Pathol. 86:365–374. 2005. View Article : Google Scholar : PubMed/NCBI
18	Kazi JU, Kabir NN and Rönnstrand L: Brain-Expressed X-linked (BEX) proteins in human cancers. Biochim Biophys Acta. 1856:226–233. 2015.PubMed/NCBI
19	Khazaei MR, Halfter H, Karimzadeh F, Koo JH, Margolis FL and Young P: Bex1 is involved in the regeneration of axons after injury. J Neurochem. 115:910–920. 2010. View Article : Google Scholar : PubMed/NCBI
20	Vilar M, Murillo-Carretero M, Mira H, Magnusson K, Besset V and Ibáñez CF: Bex1, a novel interactor of the p75 neurotrophin receptor, links neurotrophin signaling to the cell cycle. EMBO J. 25:1219–1230. 2006. View Article : Google Scholar : PubMed/NCBI
21	Naderi A, Teschendorff AE, Beigel J, Cariati M, Ellis IO, Brenton JD and Caldas C: BEX2 is overexpressed in a subset of primary breast cancers and mediates nerve growth factor/nuclear factor-kappaB inhibition of apoptosis in breast cancer cell lines. Cancer Res. 67:6725–6736. 2007. View Article : Google Scholar : PubMed/NCBI
22	Naderi A, Liu J and Bennett IC: BEX2 regulates mitochondrial apoptosis and G1 cell cycle in breast cancer. Int J Cancer. 126:1596–1610. 2010.PubMed/NCBI
23	de Ronde JJ, Lips EH, Mulder L, Vincent AD, Wesseling J, Nieuwland M, Kerkhoven R, Vrancken Peeters MJ, Sonke GS, Rodenhuis S, et al: SERPINA6, BEX1, AGTR1, SLC26A3, and LAPTM4B are markers of resistance to neoadjuvant chemotherapy in HER2-negative breast cancer. Breast Cancer Res Treat. 137:213–223. 2013. View Article : Google Scholar : PubMed/NCBI
24	Hofsli E, Wheeler TE, Langaas M, Laegreid A and Thommesen L: Identification of novel neuroendocrine-specific tumour genes. Br J Cancer. 99:1330–1339. 2008. View Article : Google Scholar : PubMed/NCBI
25	Foltz G, Ryu GY, Yoon JG, Nelson T, Fahey J, Frakes A, Lee H, Field L, Zander K, Sibenaller Z, et al: Genome-wide analysis of epigenetic silencing identifies BEX1 and BEX2 as candidate tumor suppressor genes in malignant glioma. Cancer Res. 66:6665–6674. 2006. View Article : Google Scholar : PubMed/NCBI
26	Karakoula K, Jacques TS, Phipps KP, Harkness W, Thompson D, Harding BN, Darling JL and Warr TJ: Epigenetic genome-wide analysis identifies BEX1 as a candidate tumour suppressor gene in paediatric intracranial ependymoma. Cancer Lett. 346:34–44. 2014. View Article : Google Scholar : PubMed/NCBI
27	Lindblad O, Li T, Su X, Sun J, Kabir NN, Levander F, Zhao H, Lu G, Rönnstrand L and Kazi JU: BEX1 acts as a tumor suppressor in acute myeloid leukemia. Oncotarget. 6:21395–21405. 2015. View Article : Google Scholar : PubMed/NCBI
28	Ding K, Su Y, Pang L, Lu Q, Wang Z, Zhang S, Zheng S, Mao J and Zhu Y: Inhibition of apoptosis by downregulation of hBex1, a novel mechanism, contributes to the chemoresistance of Bcr/Abl⁺ leukemic cells. Carcinogenesis. 30:35–42. 2009. View Article : Google Scholar : PubMed/NCBI
29	Xiao Q, Hu Y, Liu Y, Wang Z, Geng H, Hu L, Xu D, Wang K, Zheng L, Zheng S, et al: BEX1 promotes imatinib-induced apoptosis by binding to and antagonizing BCL-2. PLoS One. 9:e917822014. View Article : Google Scholar : PubMed/NCBI
30	Che ZM, Jung TH, Choi JH, Yoon DJ, Jeong HJ, Lee EJ and Kim J: Collagen-based co-culture for invasive study on cancer cells-fibroblasts interaction. Biochem Biophys Res Commun. 346:268–275. 2006. View Article : Google Scholar : PubMed/NCBI
31	Gaggioli C, Hooper S, Hidalgo-Carcedo C, Grosse R, Marshall JF, Harrington K and Sahai E: Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells. Nat Cell Biol. 9:1392–1400. 2007. View Article : Google Scholar : PubMed/NCBI
32	Tane S, Maniwa Y, Hokka D, Tauchi S, Nishio W, Okita Y and Yoshimura M: The role of Necl-5 in the invasive activity of lung adenocarcinoma. Exp Mol Pathol. 94:330–335. 2013. View Article : Google Scholar : PubMed/NCBI
33	Friedl P and Wolf K: Tumour-cell invasion and migration: Diversity and escape mechanisms. Nat Rev Cancer. 3:362–374. 2003. View Article : Google Scholar : PubMed/NCBI
34	Wolf K, Mazo I, Leung H, Engelke K, von Andrian UH, Deryugina EI, Strongin AY, Bröcker EB and Friedl P: Compensation mechanism in tumor cell migration: Mesenchymal-amoeboid transition after blocking of pericellular proteolysis. J Cell Biol. 160:267–277. 2003. View Article : Google Scholar : PubMed/NCBI
35	Friedl P and Alexander S: Cancer invasion and the microenvironment: Plasticity and reciprocity. Cell. 147:992–1009. 2011. View Article : Google Scholar : PubMed/NCBI