Skip to main content
Top
Published in: BMC Cancer 1/2015

Open Access 01-12-2015 | Research article

ACTN4 and the pathways associated with cell motility and adhesion contribute to the process of lung cancer metastasis to the brain

Authors: Yufei Gao, Guanghu Li, Liankun Sun, Yichun He, Xiaoyan Li, Zhi Sun, Jihan Wang, Yang Jiang, Jingwei Shi

Published in: BMC Cancer | Issue 1/2015

Login to get access

Abstract

Background

The aim of this study was to identify critical gene pathways that are associated with lung cancer metastasis to the brain.

Methods

The RNA-Seq approach was used to establish the expression profiles of a primary lung cancer, adjacent benign tissue, and metastatic brain tumor from a single patient. The expression profiles of these three types of tissues were compared to define differentially expressed genes, followed by serial-cluster analysis, gene ontology analysis, pathway analysis, and knowledge-driven network analysis. Reverse transcription–polymerase chain reaction (RT-PCR) was used to validate the expression of essential candidate genes in tissues from ten additional patients.

Results

Differential gene expression among these three types of tissues was classified into multiple clusters according to the patterns of their alterations. Further bioinformatic analysis of these expression profile data showed that the network of the signal transduction pathways related to actin cytoskeleton reorganization, cell migration, and adhesion was associated with lung cancer metastasis to the brain. The expression of ACTN4 (actinin, alpha 4), a cytoskeleton protein gene essential for cytoskeleton organization and cell motility, was significantly elevated in the metastatic brain tumor but not in the primary lung cancer tissue.

Conclusions

The signaling pathways involved in the regulation of cytoskeleton reorganization, cell motility, and focal adhesion play a role in the process of lung cancer metastasis to the brain. The contribution of ACTN4 to the process of lung cancer metastasis to the brain could be mainly through regulation of actin cytoskeleton reorganization, cell motility, and focal adhesion.
Appendix
Available only for authorised users
Literature
1.
go back to reference Patchell RA, Tibbs PA, Walsh JW, Dempsey RJ, Maruyama Y, Kryscio RJ, et al. A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med. 1990;322:494–500.CrossRefPubMed Patchell RA, Tibbs PA, Walsh JW, Dempsey RJ, Maruyama Y, Kryscio RJ, et al. A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med. 1990;322:494–500.CrossRefPubMed
2.
go back to reference Schouten LJ, Rutten J, Huveneers HAM, Twijnstra A. Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, and lung and melanoma. Cancer. 2002;94:2698–705.CrossRefPubMed Schouten LJ, Rutten J, Huveneers HAM, Twijnstra A. Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, and lung and melanoma. Cancer. 2002;94:2698–705.CrossRefPubMed
3.
go back to reference Kikuchi T, Daigo Y, Ishikawa N, Katagiri T, Tsunoda T, Yoshida S, et al. Expression profiles of metastatic brain tumor from lung adenocarcinomas on cDNA microarray. Int J Oncol. 2006;28:799–805.PubMed Kikuchi T, Daigo Y, Ishikawa N, Katagiri T, Tsunoda T, Yoshida S, et al. Expression profiles of metastatic brain tumor from lung adenocarcinomas on cDNA microarray. Int J Oncol. 2006;28:799–805.PubMed
4.
go back to reference Honda K, Yamada T, Endo R, Ino Y, Gotoh M, Tsuda H, et al. Actinin-4, a novel actin-bundling protein associated with cell motility and cancer invasion. J Cell Biol. 1998;140:1383–93.CrossRefPubMedPubMedCentral Honda K, Yamada T, Endo R, Ino Y, Gotoh M, Tsuda H, et al. Actinin-4, a novel actin-bundling protein associated with cell motility and cancer invasion. J Cell Biol. 1998;140:1383–93.CrossRefPubMedPubMedCentral
5.
go back to reference Khurana S, Chakraborty S, Cheng X, Su Y-T, Kao H-Y. The actin-binding protein, actinin alpha 4 (ACTN4), is a nuclear receptor coactivator that promotes proliferation of MCF-7 breast cancer cells. J Biol Chem. 2011;286:1850–9.CrossRefPubMed Khurana S, Chakraborty S, Cheng X, Su Y-T, Kao H-Y. The actin-binding protein, actinin alpha 4 (ACTN4), is a nuclear receptor coactivator that promotes proliferation of MCF-7 breast cancer cells. J Biol Chem. 2011;286:1850–9.CrossRefPubMed
6.
go back to reference Honda K, Yamada T, Hayashida Y, Idogawa M, Sato S, Hasegawa F, et al. Actinin-4 increases cell motility and promotes lymph node metastasis of colorectal cancer. Gastroenterology. 2005;128:51–62.CrossRefPubMed Honda K, Yamada T, Hayashida Y, Idogawa M, Sato S, Hasegawa F, et al. Actinin-4 increases cell motility and promotes lymph node metastasis of colorectal cancer. Gastroenterology. 2005;128:51–62.CrossRefPubMed
7.
go back to reference Kikuchi S, Honda K, Tsuda H, Hiraoka N, Imoto I, Kosuge T, et al. Expression and gene amplification of actinin-4 in invasive ductal carcinoma of the pancreas. Clin Cancer Res. 2008;14:5348–56.CrossRefPubMed Kikuchi S, Honda K, Tsuda H, Hiraoka N, Imoto I, Kosuge T, et al. Expression and gene amplification of actinin-4 in invasive ductal carcinoma of the pancreas. Clin Cancer Res. 2008;14:5348–56.CrossRefPubMed
8.
go back to reference Yamagata N, Shyr Y, Yanagisawa K, Edgerton M, Dang TP, Gonzalez A, et al. A training–testing approach to the molecular classification of resected non-small cell lung cancer. Clin Cancer Res. 2003;9:4695–704.PubMed Yamagata N, Shyr Y, Yanagisawa K, Edgerton M, Dang TP, Gonzalez A, et al. A training–testing approach to the molecular classification of resected non-small cell lung cancer. Clin Cancer Res. 2003;9:4695–704.PubMed
9.
go back to reference Honda K, Yamada T, Seike M, Hayashida Y, Idogawa M, Ino Y, et al. Alternative splice variant of actinin-4 in small cell lung cancer. Oncogene. 2004;23:5257–62.CrossRefPubMed Honda K, Yamada T, Seike M, Hayashida Y, Idogawa M, Ino Y, et al. Alternative splice variant of actinin-4 in small cell lung cancer. Oncogene. 2004;23:5257–62.CrossRefPubMed
10.
go back to reference Miyanaga A, Honda K, Tsuta K, Masuda M, Yamaguchi U, Fujii G, et al. Diagnostic and prognostic significance of the alternatively spliced ACTN4 variant in high-grade neuroendocrine pulmonary tumours. Ann Oncol. 2013;24:84–90.CrossRefPubMed Miyanaga A, Honda K, Tsuta K, Masuda M, Yamaguchi U, Fujii G, et al. Diagnostic and prognostic significance of the alternatively spliced ACTN4 variant in high-grade neuroendocrine pulmonary tumours. Ann Oncol. 2013;24:84–90.CrossRefPubMed
11.
go back to reference Quick Q, Skalli O. Alpha-actinin 1 and alpha-actinin 4: contrasting roles in the survival, motility, and RhoA signaling of astrocytoma cells. Exp Cell Res. 2010;316:1137–47.CrossRefPubMed Quick Q, Skalli O. Alpha-actinin 1 and alpha-actinin 4: contrasting roles in the survival, motility, and RhoA signaling of astrocytoma cells. Exp Cell Res. 2010;316:1137–47.CrossRefPubMed
12.
go back to reference Koizumi T, Nakatsuji H, Fukawa T, Avirmed S, Fukumori T, Takahashi M, et al. The role of actinin-4 in bladder cancer invasion. Urology. 2010;75:357–64.CrossRefPubMed Koizumi T, Nakatsuji H, Fukawa T, Avirmed S, Fukumori T, Takahashi M, et al. The role of actinin-4 in bladder cancer invasion. Urology. 2010;75:357–64.CrossRefPubMed
13.
go back to reference Yoshii H, Ito K, Asano T, Horiguchi A, Hayakawa M, Asano T. Increased expression of α-actinin-4 is associated with unfavorable pathological features and invasiveness of bladder cancer. Oncol Rep. 2013;30:1073–80.PubMed Yoshii H, Ito K, Asano T, Horiguchi A, Hayakawa M, Asano T. Increased expression of α-actinin-4 is associated with unfavorable pathological features and invasiveness of bladder cancer. Oncol Rep. 2013;30:1073–80.PubMed
14.
go back to reference Yamamoto S, Tsuda H, Honda K, Kita T, Takano M, Tamai S, et al. Actinin-4 expression in ovarian cancer: a novel prognostic indicator independent of clinical stage and histological type. Mod Pathol. 2007;20:1278–85.CrossRefPubMed Yamamoto S, Tsuda H, Honda K, Kita T, Takano M, Tamai S, et al. Actinin-4 expression in ovarian cancer: a novel prognostic indicator independent of clinical stage and histological type. Mod Pathol. 2007;20:1278–85.CrossRefPubMed
15.
go back to reference Yamamoto S, Tsuda H, Honda K, Onozato K, Takano M, Tamai S, et al. Actinin-4 gene amplification in ovarian cancer: a candidate oncogene associated with poor patient prognosis and tumor chemoresistance. Mod Pathol. 2009;22:499–507.CrossRefPubMed Yamamoto S, Tsuda H, Honda K, Onozato K, Takano M, Tamai S, et al. Actinin-4 gene amplification in ovarian cancer: a candidate oncogene associated with poor patient prognosis and tumor chemoresistance. Mod Pathol. 2009;22:499–507.CrossRefPubMed
16.
go back to reference Barbolina MV, Adley BP, Kelly DL, Fought AJ, Scholtens DM, Scholtens DM, et al. Motility-related actinin alpha-4 is associated with advanced and metastatic ovarian carcinoma. Lab Invest. 2008;88:602–14.CrossRefPubMedPubMedCentral Barbolina MV, Adley BP, Kelly DL, Fought AJ, Scholtens DM, Scholtens DM, et al. Motility-related actinin alpha-4 is associated with advanced and metastatic ovarian carcinoma. Lab Invest. 2008;88:602–14.CrossRefPubMedPubMedCentral
17.
go back to reference Watabe Y, Mori T, Yoshimoto S, Nomura T, Shibahara T, Yamada T, et al. Copy number increase of ACTN4 is a prognostic indicator in salivary gland carcinoma. Cancer Med. 2014;3:613–22.CrossRefPubMedPubMedCentral Watabe Y, Mori T, Yoshimoto S, Nomura T, Shibahara T, Yamada T, et al. Copy number increase of ACTN4 is a prognostic indicator in salivary gland carcinoma. Cancer Med. 2014;3:613–22.CrossRefPubMedPubMedCentral
18.
go back to reference Hara T, Honda K, Shitashige M, Ono M, Matsuyama H, Naito K, et al. Mass spectrometry analysis of the native protein complex containing actinin-4 in prostate cancer cells. Mol Cell Proteomics. 2007;6:479–91.CrossRefPubMed Hara T, Honda K, Shitashige M, Ono M, Matsuyama H, Naito K, et al. Mass spectrometry analysis of the native protein complex containing actinin-4 in prostate cancer cells. Mol Cell Proteomics. 2007;6:479–91.CrossRefPubMed
19.
go back to reference Nikolopoulos SN, Spengler BA, Kisselbach K, Evans AE, Biedler JL, Ross RA. The human non-muscle alpha-actinin protein encoded by the ACTN4 gene suppresses tumorigenicity of human neuroblastoma cells. Oncogene. 2000;19:380–6.CrossRefPubMed Nikolopoulos SN, Spengler BA, Kisselbach K, Evans AE, Biedler JL, Ross RA. The human non-muscle alpha-actinin protein encoded by the ACTN4 gene suppresses tumorigenicity of human neuroblastoma cells. Oncogene. 2000;19:380–6.CrossRefPubMed
21.
go back to reference Draghici S, Khatri P, Tarca AL, Amin K, Done A, Voichita C, et al. A systems biology approach for pathway level analysis. Genome Res. 2007;17:1537–45.CrossRefPubMedPubMedCentral Draghici S, Khatri P, Tarca AL, Amin K, Done A, Voichita C, et al. A systems biology approach for pathway level analysis. Genome Res. 2007;17:1537–45.CrossRefPubMedPubMedCentral
24.
go back to reference Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Amin N, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13:2498–504.CrossRefPubMedPubMedCentral Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Amin N, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13:2498–504.CrossRefPubMedPubMedCentral
25.
go back to reference Mortazavi A, Williams BA, McCue K, Schaeffer L, Wold B. Mapping and quantifying mammalian transcriptomes by rna-seq. Nat Methods. 2008;5(7):621–8.CrossRefPubMed Mortazavi A, Williams BA, McCue K, Schaeffer L, Wold B. Mapping and quantifying mammalian transcriptomes by rna-seq. Nat Methods. 2008;5(7):621–8.CrossRefPubMed
26.
go back to reference Magdolen U, Schroeck F, Creutzburg S, Schmitt M, Magdolen V. Non-muscle alpha-actinin-4 interacts with plasminogen activator inhibitor type-1 (PAI-1). Biol Chem. 2004;385:801–8.CrossRefPubMed Magdolen U, Schroeck F, Creutzburg S, Schmitt M, Magdolen V. Non-muscle alpha-actinin-4 interacts with plasminogen activator inhibitor type-1 (PAI-1). Biol Chem. 2004;385:801–8.CrossRefPubMed
27.
go back to reference Shao H, Travers T, Camacho CJ, Wells A. The carboxyl tail of alpha-actinin-4 regulates its susceptibility to m-calpain and thus functions in cell migration and spreading. Int J Biochem Cell Biol. 2013;45:1051–63.CrossRefPubMedPubMedCentral Shao H, Travers T, Camacho CJ, Wells A. The carboxyl tail of alpha-actinin-4 regulates its susceptibility to m-calpain and thus functions in cell migration and spreading. Int J Biochem Cell Biol. 2013;45:1051–63.CrossRefPubMedPubMedCentral
29.
go back to reference Foley KS, Young PW. An analysis of splicing, actin-binding properties, heterodimerization and molecular interactions of the non-muscle α-actinins. Biochem J. 2013;452:477–88.CrossRefPubMed Foley KS, Young PW. An analysis of splicing, actin-binding properties, heterodimerization and molecular interactions of the non-muscle α-actinins. Biochem J. 2013;452:477–88.CrossRefPubMed
30.
go back to reference Fife CM, McCarroll JA, Kavallaris M. Movers and shakers: cell cytoskeleton in cancer metastasis. Br J Pharmacol. 2014. [Epub ahead of print]. Fife CM, McCarroll JA, Kavallaris M. Movers and shakers: cell cytoskeleton in cancer metastasis. Br J Pharmacol. 2014. [Epub ahead of print].
31.
go back to reference Li B, Zhao W-D, Tan Z-M, Fang W-G, Zhu L, Chen YH. Involvement of Rho/ROCK signalling in small cell lung cancer migration through human brain microvascular endothelial cells. FEBS Lett. 2006;580:4252–60.CrossRefPubMed Li B, Zhao W-D, Tan Z-M, Fang W-G, Zhu L, Chen YH. Involvement of Rho/ROCK signalling in small cell lung cancer migration through human brain microvascular endothelial cells. FEBS Lett. 2006;580:4252–60.CrossRefPubMed
Metadata
Title
ACTN4 and the pathways associated with cell motility and adhesion contribute to the process of lung cancer metastasis to the brain
Authors
Yufei Gao
Guanghu Li
Liankun Sun
Yichun He
Xiaoyan Li
Zhi Sun
Jihan Wang
Yang Jiang
Jingwei Shi
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2015
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-015-1295-9

Other articles of this Issue 1/2015

BMC Cancer 1/2015 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine